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Health-related quality of life analysis in stage III melanoma patients treated with adjuvant dendritic cell therapy.
Nov 2018 | Bloemendal, M; Rietveld, M J A; van Willigen, W W; Gerritsen, W R; Figdor, C G; Bonenkamp, J J; Westdorp, H; Boudewijns, S; Koornstra, R H T; Adang, E M M; Schreibelt, G; Ottevanger, P B; de Vries, I J M; Bol, K F
Health-related quality of life (HRQoL) is an important issue in the rapidly evolving field of adjuvant treatment for stage III melanoma. Dendritic cell vaccination is one of the adjuvant forms of therapy currently investigated. PMID 30465182

The Dilemma of Cure and Damage in Oligodendroglioma: Ways to Tip the Balance Away from the Damage.
Nov 2018 | Torensma, Ruurd
Current treatments for oligodendrogliomas are powerful but have a negative impact on the rest of the body. The bone marrow is damaged by the chemotherapeutics, but other parts of the body are also affected. In this paper, the current treatment method and its collateral damage is described. Therefore, therapies are needed that are more effective against the tumor while having less negative effects on the patient's quality of life. Some potential therapies include optimal removal of the tumor by fluorescent-guided surgery (FGS), intraoperative desorption electrospray ionization-mass spectrometry (DESI-MS), better monitoring of the effects of therapy by pseudo-coloring shades of gray of MRI pictures, and using recent data from RNA sequencing of single cells and immunotherapy. These are all open new ways of treating this tumor. The RNA sequencing of single tumor cells unravels specific tumor antigens present in the differentiation status of the cancer cell. Stem cell antigens were expressed in dividing cells, while hypoxia inducible factor-α (HIF-1α) is expressed in all tumor cells. Cancer stem cell antigens can be loaded on dendritic cells to induce cytotoxic T-cells directed to cancer stem cells. These recent discoveries suggest a better quality of life with the same overall survival. PMID 30424475

Empowering dendritic cell cancer vaccination: the role of combinatorial strategies.
Oct 2018 | Galati, Domenico; Zanotta, Serena
Dendritic cells (DCs) are bone marrow-derived immune cells that play a crucial role in inducing the adaptive immunity and supporting the innate immune response independently from T cells. In the last decade, DCs have become a hopeful instrument for cancer vaccines that aims at re-educating the immune system, leading to a potent anti-cancer immune response able to overcome the immunosuppressive tumor microenvironment (TME). Although several studies have indicated that DC-based vaccines are feasible and safe, the clinical advantages of DC vaccination as monotherapy for most of the neoplasms remain a distant target. Recently, many reports and clinical trials have widely used innovative combinatorial therapeutic strategies to normalize the immune function in the TME and synergistically enhance DC function. This review will describe the most relevant and updated evidence of the anti-cancer combinatorial approaches to boost the clinical potency of DC-based vaccines. PMID 30360963

Dendritic Cell Cancer Therapy: Vaccinating the Right Patient at the Right Time.
Oct 2018 | van Willigen, Wouter W; Bloemendal, Martine; Gerritsen, Winald R; Schreibelt, Gerty; de Vries, I Jolanda M; Bol, Kalijn F
Immune checkpoint inhibitors propelled the field of oncology with clinical responses in many different tumor types. Superior overall survival over chemotherapy has been reported in various metastatic cancers. Furthermore, prolonged disease-free and overall survival have been reported in the adjuvant treatment of stage III melanoma. Unfortunately, a substantial portion of patients do not obtain a durable response. Therefore, additional strategies for the treatment of cancer are still warranted. One of the numerous options is dendritic cell vaccination, which employs the central role of dendritic cells in activating the innate and adaptive immune system. Over the years, dendritic cell vaccination was shown to be able to induce an immunologic response, to increase the number of tumor infiltrating lymphocytes and to provide overall survival benefit for at least a selection of patients in phase II studies. However, with the success of immune checkpoint inhibition in several malignancies and considering the plethora of other treatment modalities being developed, it is of utmost importance to delineate the position of dendritic cell therapy in the treatment landscape of cancer. In this review, we address some key questions regarding the integration of dendritic cell vaccination in future cancer treatment paradigms. PMID 30327656

High-grade glioma associated immunosuppression does not prevent immune responses induced by therapeutic vaccines in combination with T depletion.
Oct 2018 | Löhr, Mario; Freitag, Benjamin; Technau, Antje; Krauss, Jürgen; Monoranu, Camelia-Maria; Rachor, Johannes; Lutz, Manfred B; Hagemann, Carsten; Kessler, Almuth F; Linsenmann, Thomas; Wölfl, Matthias; Ernestus, Ralf-Ingo; Engelhardt, Sabrina; Gelbrich, Götz; Schlegel, Paul G; Eyrich, Matthias
High-grade gliomas (HGG) exert systemic immunosuppression, which is of particular importance as immunotherapeutic strategies such as therapeutic vaccines are increasingly used to treat HGGs. In a first cohort of 61 HGG patients we evaluated a panel of 30 hematological and 34 plasma biomarkers. Then, we investigated in a second cohort of 11 relapsed HGG patients receiving immunomodulation with metronomic cyclophosphamide upfront to a DC-based vaccine whether immune abnormalities persisted and whether they hampered induction of IFNγ T-cell responses. HGG patients from the first cohort showed increased numbers of leukocytes, neutrophils and MDSCs and in parallel reduced numbers of CD4/CD8 T-cells, plasmacytoid and conventional DC2s. MDSCs and T-cell alterations were more profound in WHO IV° glioma patients. Moreover, levels of MDSCs and epidermal growth factor were negatively associated with survival. Serum levels of IL-2, IL-4, IL-5 and IL-10 were altered in HGG patients, however, without any impact on clinical outcome. In the immunotherapy cohort, 6-month overall survival was 100%. Metronomic cyclophosphamide led to > 40% reduction of regulatory T cells (T). In parallel to T-depletion, MDSCs and DC subsets became indistinguishable from healthy controls, whereas T-lymphopenia persisted. Despite low T-cells, IFNγ-responses could be induced in 9/10 analyzed cases. Importantly, frequency of CD8VLA-4 T-cells with CNS-homing properties, but not of CD4 VLA-4 T-cells, increased during vaccination. Our study identifies several features of systemic immunosuppression in HGGs. Metronomic cyclophosphamide in combination with an active immunization alleviates the latter and the combined treatment allows induction of a high rate of anti-glioma immune responses. PMID 30054667

Phase I/II clinical trial of a Wilms' tumor 1-targeted dendritic cell vaccination-based immunotherapy in patients with advanced cancer.
Oct 2018 | Zhang, Wen; Lu, Xu; Cui, Peilin; Piao, Chunmei; Xiao, Man; Liu, Xuesong; Wang, Yue; Wu, Xuan; Liu, Jingwei; Yang, Lin
Dendritic cell (DC)-based immunotherapies have been created for a broad expanse of cancers, and DC vaccines prepared with Wilms' tumor protein 1 (WT1) peptides have shown great therapeutic efficacy in these diseases. In this paper, we report the results of a phase I/II study of a DC-based vaccination for advanced breast, ovarian, and gastric cancers, and we offer evidence that patients can be effectively vaccinated with autologous DCs pulsed with WT1 peptide. There were ten patients who took part in this clinical study; they were treated biweekly with a WT1 peptide-pulsed DC vaccination, with toxicity and clinical and immunological responses as the principal endpoints. All of the adverse events to DC vaccinations were tolerable under an adjuvant setting. The clinical response was stable disease in seven patients. Karnofsky Performance Scale scores were enhanced, and computed tomography scans revealed tumor shrinkage in three of seven patients. Human leukocyte antigen (HLA)/WT1-tetramer and cytoplasmic IFN-γ assays were used to examine the induction of a WT-1-specific immune response. The immunological responses to DC vaccination were significantly correlated with fewer myeloid-derived suppressor cells (P = 0.045) in the pretreated peripheral blood. These outcomes offered initial clinical evidence that the WT1 peptide-pulsed DC vaccination is a potential treatment for advanced cancer. PMID 30306202

A randomized phase II clinical trial of dendritic cell vaccination following complete resection of colon cancer liver metastasis.
Oct 2018 | Rodriguez, Javier; Castañón, Eduardo; Perez-Gracia, Jose Luis; Rodriguez, Inmaculada; Viudez, Antonio; Alfaro, Carlos; Oñate, Carmen; Perez, Guiomar; Rotellar, Fernando; Inogés, Susana; López-Diaz de Cerio, Ascensión; Resano, Leyre; Ponz-Sarvise, Mariano; Rodriguez-Ruiz, Maria E; Chopitea, Ana; Vera, Ruth; Melero, Ignacio
Surgically resectable synchronic and metachronic liver metastases of colon cancer have high risk of relapse in spite of standard-of-care neoadjuvant and adjuvant chemotherapy regimens. Dendritic cell vaccines loaded with autologous tumor lysates were tested for their potential to avoid or delay disease relapses (NCT01348256). Patients with surgically amenable liver metastasis of colon adenocarcinoma (n = 19) were included and underwent neoadjuvant chemotherapy, surgery and adjuvant chemotherapy. Fifteen patients with disease-free resection margins were randomized 1:1 to receive two courses of four daily doses of dendritic cell intradermal vaccinations versus observation. The trial had been originally designed to include 56 patients but was curtailed due to budgetary restrictions. Follow-up of the patients indicates a clear tendency to fewer and later relapses in the vaccine arm (median disease free survival -DFS-) 25.26 months, 95% CI 8.74-n.r) versus observation arm (median DFS 9.53 months, 95% CI 5.32-18.88). PMID 30268156

Recombinant Newcastle disease virus expressing human IFN-λ1 (rL-hIFN-λ1)-induced apoptosis of A549 cells is connected to endoplasmic reticulum stress pathways.
Sep 2018 | Yan, Yulan; Liu, Sha; Li, Mi; Zhao, Yinghai; Shao, Xiaomei; Hang, Min; Bu, Xuefeng
IFN-λs are a kind of cytokine with anti-tumor, immunomodulatory, and anti-proliferative activity. Recent studies have shown that the recombinant Newcastle disease virus expresses human IFN-λ1 (rL-hIFN-λ1), which plays a role in gastric cancer cell apoptosis. Endoplasmic reticulum stress (ERS) induces autophagy and apoptosis in tumor cells. In this study, we explored the relationship between ERS and rL-hIFN-λ1-induced apoptosis of lung adenocarcinoma A549 cells and its underlying mechanism. PMID 30246439

Autologous Dendritic Cell Therapy in Mesothelioma Patients Enhances Frequencies of Peripheral CD4 T Cells Expressing HLA-DR, PD-1, or ICOS.
Sep 2018 | de Goeje, Pauline L; Klaver, Yarne; Kaijen-Lambers, Margaretha E H; Langerak, Anton W; Vroman, Heleen; Kunert, André; Lamers, Cor H J; Aerts, Joachim G J V; Debets, Reno; Hendriks, Rudi W
Malignant pleural mesothelioma (MPM) is a malignancy with a very poor prognosis for which new treatment options are urgently needed. We have previously shown that dendritic cell (DC) immunotherapy provides a clinically feasible treatment option. In the current study, we set out to assess the immunological changes induced by DC immunotherapy in peripheral blood of MPM patients. Peripheral blood was collected from nine patients enrolled in a phase I dose escalation study, before and after treatment with DCs that were pulsed with an allogeneic tumor lysate preparation consisting of a mixture of five cultured mesothelioma cell lines. We used immune profiling by multiplex flow cytometry to characterize different populations of immune cells. In particular, we determined frequencies of T cell subsets that showed single and combinatorial expression of multiple markers that signify T cell activation, maturation and inhibition. Therapy-induced T cell reactivity was assessed in peptide/MHC multimer stainings using mesothelin as a prototypic target antigen with confirmed expression in the clinical tumor lysate preparation. T cell receptor (TCR) diversity was evaluated by gene PCR assays. We observed an increase in the numbers of B cells, CD4 and CD8 T cells, but not NK cells at 6 weeks post-treatment. The increases in B and T lymphocytes were not accompanied by major changes in T cell reactivity toward mesothelin nor in diversity. Notably, we did observe enhanced proportions of CD4 T cells expressing HLA-DR, PD-1 (at 2 weeks after onset of treatment) and ICOS (6 weeks) and a CD8 T cell population expressing LAG3 (2 weeks). DC immunotherapy using allogeneic tumor lysate resulted in enhanced frequencies of B cells and T cells in blood. We did not detect a skewed antigen-reactivity of peripheral CD8 T cells. Interestingly, frequencies of CD4 T cells expressing activation markers and PD-1 were increased. These findings indicate a systemic activation of the adaptive immune response and may guide future immune monitoring studies of DC therapies. PMID 30245692

Long-term survival of pancreatic cancer patients treated with multimodal therapy combined with WT1-targeted dendritic cell vaccines.
Sep 2018 | Hanada, Shuichi; Tsuruta, Tomoko; Haraguchi, Kouichi; Okamoto, Masato; Sugiyama, Haruo; Koido, Shigeo
Pancreatic ductal adenocarcinoma (PDA) remains one of the most aggressive tumors with a dismally poor prognosis. Although surgical resection remains the only potentially curative treatment, most PDAs are not surgically resectable at diagnosis. Therefore, multimodal therapy is urgently needed to improve the long-term survival of PDA patients. PMID 30230959

Phase II study of ERC1671 plus bevacizumab versus bevacizumab plus placebo in recurrent glioblastoma: interim results and correlations with CD4 T-lymphocyte counts.
Aug 2018 | Bota, Daniela A; Chung, Jinah; Dandekar, Manisha; Carrillo, Jose A; Kong, Xiao-Tang; Fu, Beverly D; Hsu, Frank Pk; Schönthal, Axel H; Hofman, Florence M; Chen, Thomas C; Zidovetzki, Raphael; Pretto, Chrystel; Strik, Ankie; Schijns, Virgil Ejc; Stathopoulos, Apostolos
ERC1671 is an allogeneic/autologous therapeutic glioblastoma (GBM) vaccine - composed of whole, inactivated tumor cells mixed with tumor cell lysates derived from the patient and three GBM donors. PMID 30157683

Molecular subgroups and B7-H4 expression levels predict responses to dendritic cell vaccines in glioblastoma: an exploratory randomized phase II clinical trial.
Aug 2018 | Yao, Yu; Luo, Feifei; Tang, Chao; Chen, Dikang; Qin, Zhiyong; Hua, Wei; Xu, Ming; Zhong, Ping; Yu, Shuangquan; Chen, Di; Ding, Xiaojie; Zhang, Yi; Zheng, Xiujuan; Yang, Jiao; Qian, Jiawen; Deng, Yuting; Hoon, Dave S B; Hu, Jian; Chu, Yiwei; Zhou, Liangfu
Dendritic cell (DC)-based vaccination is a promising approach for active-specific immunotherapy, but is currently of limited efficacy. The safety and effectiveness of a DC vaccine (DCV) loaded with glioblastoma stem cell-like (GSC) antigens was assessed in glioblastoma multiforme (GBM) patients. In this double-blind, placebo-controlled phase II clinical trial, 43 GBM patients were randomized after surgery at a 1:1 ratio to receive either DCV (n = 22) or normal saline placebo (n = 21). Overall survival (OS) and progression-free survival (PFS) were analysed. Participants were stratified into different molecular subgroups based on the mutation (MT) status of isocitrate dehydrogenase (IDH1/2) and telomerase reverse transcriptase (TERT). Plasma cytokine levels, tumor-infiltrating lymphocyte numbers and immune co-inhibitory molecules PD-L1 and B7-H4 were also assessed. Multivariate Cox regression analysis revealed that DCV treatment significantly prolonged OS (p = 0.02) after adjusting for IDH1 and TERT promoter MT and B7-H4 expression, primary vs recurrent GBM. Among IDH1 TERT patients, DCV treatment significantly prolonged OS (p < 0.01) and PFS (p = 0.03) and increased plasma levels of cytokines CCL22 and IFN-γ compared with placebo. Patients with low B7-H4 expression showed significantly prolonged OS (p = 0.02) after DCV treatment. Therefore, IDH1TERT and low B7-H4 expression identified subgroups of GBM patients more responsive to GSC DCV-based specific active-immunotherapy. PMID 30159779

Dendritic cell vaccines for high-grade gliomas.
Aug 2018 | Eagles, Matthew E; Nassiri, Farshad; Badhiwala, Jetan H; Suppiah, Suganth; Almenawer, Saleh A; Zadeh, Gelareh; Aldape, Kenneth D
Glioblastoma (GBM) is the most common and fatal primary adult brain tumor. To date, various promising chemotherapeutic regimens have been trialed for use in GBM; however, temozolomide (TMZ) therapy remains the only US Food and Drug Administration-approved first-line chemotherapeutic option for newly diagnosed GBM. Despite maximal therapy with surgery and combined concurrent chemoradiation and adjuvant TMZ therapy, the median overall survival remains approximately 14 months. Given the failure of conventional chemotherapeutic strategies in GBM, there has been renewed interest in the role of immunotherapy in GBM. Dendritic cells are immune antigen-presenting cells that play a role in both the innate and adaptive immune system, thereby making them prime vehicles for immunotherapy via dendritic cell vaccinations (DCVs) in various cancers. There is great enthusiasm surrounding the use of DCVs for GBM with multiple ongoing trials. In this review, we comprehensively summarize the safety, efficacy, and quality of life results from 33 trials reporting on DCV for high-grade gliomas. PMID 30100728

Dendritic cells loaded with the lysate of tumor cells infected with Newcastle Disease Virus trigger potent anti-tumor immunity by promoting the secretion of IFN-γ and IL-2 from T cells.
Aug 2018 | Zhao, Lianjing; Niu, Chao; Shi, Xiumin; Xu, Dongsheng; Li, Min; Cui, Jiuwei; Li, Wei; Xu, Jianting; Jin, Haofan
Dendritic cells (DCs) are professional antigen-presenting cells that are pivotal in the generation and sustainability of antitumor immune responses. Whole tumor cell lysates (TCLs) have been used as sources of tumor antigens for the development of DC vaccines. However, the clinical outcomes of the use of TCL-based DC vaccines have so far been unsatisfactory because of the weak immunogenicity of tumor cells. To improve the efficacy of TCL-based DC vaccines, viruses have been used to enhance the immunity of TCLs and to further enhance the antigen delivery and antigen-presenting ability of DCs. The aim of the present study was to improve the antigen-presenting ability of DCs and to use them to effectively activate T lymphocytes. The present study demonstrated that DCs loaded with the lysate of Newcastle Disease Virus (NDV)-infected tumor cells (NDV-TCL) have increased levels of cluster of differentiation 80 (CD80), CD86, CD83 and human leukocyte antigen-antigen D-associated expression, compared with those loaded with TCL alone. The DCs loaded with the NDV-TCL promoted T-cell proliferation and antitumor cytokine secretion from T cells. These results indicated that loading DCs with NDV-TCL could enhance the antigen-presenting ability of the DCs. On the basis of the results of the present study, we hypothesize that this method of loading DCs with NDV-TCL can be used to develop novel DC vaccines for tumor immunotherapy in the future. PMID 30061941

A novel allogeneic off-the-shelf dendritic cell vaccine for post-remission treatment of elderly patients with acute myeloid leukemia.
Jul 2018 | van de Loosdrecht, Arjan A; van Wetering, Sandra; Santegoets, Saskia J A M; Singh, Satwinder Kaur; Eeltink, Corien M; den Hartog, Yvonne; Koppes, Malika; Kaspers, Jorn; Ossenkoppele, Gert J; Kruisbeek, Ada M; de Gruijl, Tanja D
In elderly acute myeloid leukemia (AML) patients post-remission treatment options are associated with high comorbidity rates and poor survival. Dendritic cell (DC)-based immunotherapy is a promising alternative treatment strategy. A novel allogeneic DC vaccine, DCP-001, was developed from an AML-derived cell line that uniquely combines the positive features of allogeneic DC vaccines and expression of multi-leukemia-associated antigens. Here, we present data from a phase I study conducted with DCP-001 in 12 advanced-stage elderly AML patients. Patients enrolled were in complete remission (CR1/CR2) (n = 5) or had smoldering disease (n = 7). All patients were at high risk of relapse and ineligible for post-remission intensification therapies. A standard 3 + 3 dose escalation design with extension to six patients in the highest dose was performed. Patients received four biweekly intradermal DCP-001 injections at different dose levels (10, 25, and 50 million cells DCP-001) and were monitored for clinical and immunological responses. Primary objectives of the study (feasibility and safety) were achieved with 10/12 patients completing the vaccination program. Treatment was well tolerated. A clear-cut distinction between patients with and without detectable circulating leukemic blasts during the vaccination period was noted. Patients with no circulating blasts showed an unusually prolonged survival [median overall survival 36 months (range 7-63) from the start of vaccination] whereas patients with circulating blasts, died within 6 months. Long-term survival was correlated with maintained T cell levels and induction of multi-functional immune responses. It is concluded that DCP-001 in elderly AML patients is safe, feasible and generates both cellular and humoral immune responses. PMID 30039426

Pilot study of WT1 peptide-pulsed dendritic cell vaccination with docetaxel in esophageal cancer.
Jul 2018 | Matsuda, Tatsuo; Takeuchi, Hiroya; Sakurai, Toshiharu; Mayanagi, Shuhei; Booka, Eisuke; Fujita, Tomonobu; Higuchi, Hajime; Taguchi, Junichi; Hamamoto, Yasuo; Takaishi, Hiromasa; Kawakubo, Hirofumi; Okamoto, Masato; Sunamura, Makoto; Kawakami, Yutaka; Kitagawa, Yuko
In the present study, the immune response to Wilms tumor gene 1 (WT1) peptide-pulsed dendritic cell (DC) vaccination combined with docetaxel (DCDOC) in advanced esophageal cancer patients who had already received first-line chemotherapy was investigated. Ten HLA-A*2402 patients were treated with docetaxel (50 mg/m) on day 1 and WT1 peptide-pulsed DC vaccination (1×10 cells) on days 15 and 22 (repeated every 4 weeks for 3 cycles). The delayed-type hypersensitivity skin test, HLA tetramer assay and interferon-γ enzyme-linked immunospot (ELISPOT) assay were used to evaluate the induction of a WT1-specific immune response. Median overall survival was 5 months (range, 1.1-11.6). The clinical effect of DCDOC therapy was not observed and only 1 patient could complete the protocol therapy. Disease progression was observed in 9 patients and 1 patient succumbed to fatality during the second cycle of therapy. As a pilot study, it was not possible to evaluate the safety of WT1 peptide-pulsed DCDOC therapy for esophageal squamous cell cancer. However, a WT1-specific response in 6 patients, as indicated by the ELISPOT or HLA/WT1-tetramer assay, was demonstrated. The results suggested that the positive immune response had significant relevance on the low percentage of CD11b and CD66b granulocytic myeloid-derived suppressor cells in CD15 cells. Furthermore, DCDOC elicited a WT1-specific immune response regardless of the myelosuppression associated with docetaxel. The present findings support future studies and further work to assess DCDOC as an adjuvant therapy for esophageal cancer will be performed. The present clinical trial was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry on November 11th, 2011, no. UMIN000006704. PMID 29963201

Targeting dendritic cells in pancreatic ductal adenocarcinoma.
Jun 2018 | Deicher, Anton; Andersson, Roland; Tingstedt, Bobby; Lindell, Gert; Bauden, Monika; Ansari, Daniel
Dendritic cells (DC) are an integral part of the tumor microenvironment. Pancreatic cancer is characterized by reduced number and function of DCs, which impacts antigen presentation and contributes to immune tolerance. Recent data suggest that exosomes can mediate communication between pancreatic cancer cells and DCs. Furthermore, levels of DCs may serve as prognostic factors. There is also growing evidence for the effectiveness of vaccination with DCs pulsed with tumor antigens to initiate adaptive cytolytic immune responses via T cells. Most experience with DC-based vaccination has been gathered for MUC1 and WT1 antigens, where clinical studies in advanced pancreatic cancer have provided encouraging results. In this review, we highlight the role of DC in the course, prognosis and treatment of pancreatic cancer. PMID 29946224

Predictors of Response to Autologous Dendritic Cell Therapy in Glioblastoma Multiforme.
Jun 2018 | Jan, Chia-Ing; Tsai, Wan-Chen; Harn, Horng-Jyh; Shyu, Woei-Cherng; Liu, Ming-Chao; Lu, Hsin-Man; Chiu, Shao-Chih; Cho, Der-Yang
Glioblastoma (GBM) is the most common and lethal primary malignant glioma in adults. Dendritic cell (DC) vaccines have demonstrated promising results in GBM clinical trials. However, some patients do not respond well to DC therapy, with survival rates similar to those of conventional therapy. We retrospectively analyzed clinical and laboratory data to evaluate the factors affecting vaccine treatment. PMID 29910795

Increased cycles of DC/CIK immunotherapy decreases frequency of Tregs in patients with resected NSCLC.
Jun 2018 | Song, Haiping; Liu, Shujuan; Zhao, Ziyun; Sun, Weihong; Wei, Xiaofang; Ma, Xuezhen; Zhao, Peng; Gao, Daiqing
Regulatory T cells (Tregs) suppress antitumor immune responses. Cycles of Dendritic cells (DC) vaccination combined with cytokine-induced killer (CIK) cells (DC/CIK) treatment were significantly related with good prognosis. Therefore, we investigated whether increased cycles of immunotherapy could decrease frequency of Tregs in patients with resected non-small cell lung cancer (NSCLC). Previous study from our laboratory has determined that the optimal cutoff point of the cycle count was 3cycles. We examined the levels of Tregs and the related cytokines by flow cytometric and cytokine analysis in these patients after more than (≥) 3cycles or less than (<) 3cycles of DC/CIK cell treatment. Significant reduction of Tregs frequency, Treg-generated cytokines level and recurrence rate were presented in patients received with ≥3cycles of DC/CIK cell treatment compared with patients with <3cycles of treatment. Interestingly, Tregs frequency and the related cytokines level were similar between patients suffered tumor recurrence and patients without recurrence in both groups. Together, our findings reveal that increased cycle count of DC/CIK cell immunotherapy contribute to decline of Tregs frequency and cancer recurrence rate in patients with resected NSCLC. PMID 28941416

Vaccination of Urological Cancer Patients With WT1 Peptide-Pulsed Dendritic Cells in Combination With Molecular Targeted Therapy or Conventional Chemotherapy Induces Immunological and Clinical Responses.
Jun 2018 | Ogasawara, Masahiro; Miyashita, Mamiko; Ota, Shuichi
The prognosis of metastatic or relapsed renal cell carcinoma (RCC) or bladder cancer (BC) remains poor despite the introduction of immune checkpoint blockade agents. We aimed to investigate the safety and the feasibility of a vaccination with WT1 peptide-loaded dendritic cells (DCs) and OK-432 adjuvant combined with molecular targeted therapy or conventional chemotherapy. Five eligible patients with metastatic or relapsed RCC and five eligible patients with BC were enrolled. No severe adverse events related to a vaccination were observed. Seven patients with RCC or non-muscle invasive BC had durable stable disease and three other patients had disease progression after DC vaccination. DC vaccination augmented WT1 specific immunity and the reduction of regulatory T cells which might be related to clinical outcome. These results indicate that DC-based immunotherapy combined with a molecular targeted therapy or a conventional chemotherapy is safe and feasible for patients in advanced stage of RCC or BC. PMID 29851270

First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.
May 2018 | Liau, Linda M; Ashkan, Keyoumars; Tran, David D; Campian, Jian L; Trusheim, John E; Cobbs, Charles S; Heth, Jason A; Salacz, Michael; Taylor, Sarah; D'Andre, Stacy D; Iwamoto, Fabio M; Dropcho, Edward J; Moshel, Yaron A; Walter, Kevin A; Pillainayagam, Clement P; Aiken, Robert; Chaudhary, Rekha; Goldlust, Samuel A; Bota, Daniela A; Duic, Paul; Grewal, Jai; Elinzano, Heinrich; Toms, Steven A; Lillehei, Kevin O; Mikkelsen, Tom; Walbert, Tobias; Abram, Steven R; Brenner, Andrew J; Brem, Steven; Ewend, Matthew G; Khagi, Simon; Portnow, Jana; Kim, Lyndon J; Loudon, William G; Thompson, Reid C; Avigan, David E; Fink, Karen L; Geoffroy, Francois J; Lindhorst, Scott; Lutzky, Jose; Sloan, Andrew E; Schackert, Gabriele; Krex, Dietmar; Meisel, Hans-Jorg; Wu, Julian; Davis, Raphael P; Duma, Christopher; Etame, Arnold B; Mathieu, David; Kesari, Santosh; Piccioni, David; Westphal, Manfred; Baskin, David S; New, Pamela Z; Lacroix, Michel; May, Sven-Axel; Pluard, Timothy J; Tse, Victor; Green, Richard M; Villano, John L; Pearlman, Michael; Petrecca, Kevin; Schulder, Michael; Taylor, Lynne P; Maida, Anthony E; Prins, Robert M; Cloughesy, Timothy F; Mulholland, Paul; Bosch, Marnix L
Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax-L) to standard therapy for newly diagnosed glioblastoma. PMID 29843811

Immune Response Generated With the Administration of Autologous Dendritic Cells Pulsed With an Allogenic Tumoral Cell-Lines Lysate in Patients With Newly Diagnosed Diffuse Intrinsic Pontine Glioma.
May 2018 | Benitez-Ribas, Daniel; Cabezón, Raquel; Flórez-Grau, Georgina; Molero, Mari Carmen; Puerta, Patricia; Guillen, Antonio; Paco, Sonia; Carcaboso, Angel M; Santa-Maria Lopez, Vicente; Cruz, Ofelia; de Torres, Carmen; Salvador, Noelia; Juan, Manel; Mora, Jaume; La Madrid, Andres Morales
Diffuse intrinsic pontine glioma (DIPG) is a lethal brainstem tumor in children. Dendritic cells (DCs) have T-cell stimulatory capacity and, therefore, potential antitumor activity for disease control. DCs vaccines have been shown to reactivate tumor-specific T cells in both clinical and preclinical settings. We designed a phase Ib immunotherapy (IT) clinical trial with the use of autologous dendritic cells (ADCs) pulsed with an allogeneic tumors cell-lines lysate in patients with newly diagnosed DIPG after irradiation (radiation therapy). PMID 29755954

Proteomic Identification of Heat Shock-Induced Danger Signals in a Melanoma Cell Lysate Used in Dendritic Cell-Based Cancer Immunotherapy.
May 2018 | González, Fermín E; Chernobrovkin, Alexey; Pereda, Cristián; García-Salum, Tamara; Tittarelli, Andrés; López, Mercedes N; Salazar-Onfray, Flavio; Zubarev, Roman A
Autologous dendritic cells (DCs) loaded with cancer cell-derived lysates have become a promising tool in cancer immunotherapy. During the last decade, we demonstrated that vaccination of advanced melanoma patients with autologous tumor antigen presenting cells (TAPCells) loaded with an allogeneic heat shock- (HS-) conditioned melanoma cell-derived lysate (called TRIMEL) is able to induce an antitumor immune response associated with a prolonged patient survival. TRIMEL provides not only a broad spectrum of potential melanoma-associated antigens but also danger signals that are crucial in the induction of a committed mature DC phenotype. However, potential changes induced by heat conditioning on the proteome of TRIMEL are still unknown. The identification of newly or differentially expressed proteins under defined stress conditions is relevant for understanding the lysate immunogenicity. Here, we characterized the proteomic profile of TRIMEL in response to HS treatment. A quantitative label-free proteome analysis of over 2800 proteins was performed, with 91 proteins that were found to be regulated by HS treatment: 18 proteins were overexpressed and 73 underexpressed. Additionally, 32 proteins were only identified in the HS-treated TRIMEL and 26 in non HS-conditioned samples. One protein from the overexpressed group and two proteins from the HS-exclusive group were previously described as potential damage-associated molecular patterns (DAMPs). Some of the HS-induced proteins, such as haptoglobin, could be also considered as DAMPs and candidates for further immunological analysis in the establishment of new putative danger signals with immunostimulatory functions. PMID 29744371

Vaccine therapy in hematologic malignancies.
May 2018 | Avigan, David; Rosenblatt, Jacalyn
Immune-based therapy has emerged as a paradigm shift in cancer therapy with dramatic responses observed in previously incurable disease. Cancer vaccines are being developed to disrupt tumor-associated tolerance and activate and selectively expand tumor-specific lymphocytes within the native effector cell repertoire while maintaining immune-regulatory protection against autoimmunity. Although individual antigen approaches result in immune response with a suggestion of clinical effect in some settings, broader efficacy may be dependent on presentation of multiple antigens that capture clonal diversity presented in the context of functionally potent antigen-presenting cells. The use of whole cell-based strategies such as dendritic cell/tumor fusions have yielded provocative results in single-arm studies and are currently being explored in multicenter randomized trials. The posttransplant setting is a potentially promising platform for vaccination due to cytoreduction and relative depletion of inhibitory accessory cells fostering greater immune responsiveness. Integration of these efforts with other immunotherapeutic strategies and agents that target the tumor microenvironment is being studied in an effort to generate durable immunologic responses with clinically meaningful impact on disease. PMID 29728403

Initial phase I/IIa trial results of an autologous tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine in patients with solid tumors.
May 2018 | Herbert, Garth S; Vreeland, Timothy J; Clifton, Guy T; Greene, Julia M; Jackson, Doreen O; Hardin, Mark O; Hale, Diane F; Berry, John S; Nichol, Pauline; Yin, Sook; Yu, Xianzhong; Wagner, Thomas E; Peoples, George E
Tumor vaccines use various strategies to generate immune responses, commonly targeting generic tumor-associated antigens. The tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is produced from DC loaded with autologous tumor antigens, creating a patient-specific vaccine. Here, we describe initial phase I/IIa trial results. PMID 29724512

Expression of CD14, IL10, and Tolerogenic Signature in Dendritic Cells Inversely Correlate with Clinical and Immunologic Response to TARP Vaccination in Prostate Cancer Patients.
May 2018 | Castiello, Luciano; Sabatino, Marianna; Ren, Jiaqiang; Terabe, Masaki; Khuu, Hanh; Wood, Lauren V; Berzofsky, Jay A; Stroncek, David F
Despite the vast number of clinical trials conducted so far, dendritic cell (DC)-based cancer vaccines have mostly shown unsatisfactory results. Factors and manufacturing procedures essential for these therapeutics to induce effective antitumor immune responses have yet to be fully characterized. We here aimed to identify DC markers correlating with clinical and immunologic response in a prostate carcinoma vaccination regimen. We performed an extensive characterization of DCs used to vaccinate 18 patients with prostate carcinoma enrolled in a pilot trial of T-cell receptor gamma alternate reading frame protein (TARP) peptide vaccination (NCT00908258). Peptide-pulsed DC preparations (114) manufactured were analyzed by gene expression profiling, cell surface marker expression and cytokine release secretion, and correlated with clinical and immunologic responses. DCs showing lower expression of tolerogenic gene signature induced strong antigen-specific immune response and slowing in PSA velocity, a surrogate for clinical response. These DCs were also characterized by lower surface expression of CD14, secretion of IL10 and MCP-1, and greater secretion of MDC. When combined, these four factors were able to remarkably discriminate DCs that were sufficiently potent to induce strong immunologic response. DC factors essential for the activation of immune responses associated with TARP vaccination in prostate cancer patients were identified. This study highlights the importance of in-depth characterization of DC vaccines and other cellular therapies, to understand the critical factors that hinder potency and potential efficacy in patients. . PMID 28073842

Molecular signatures associated with tumor-specific immune response in melanoma patients treated with dendritic cell-based immunotherapy.
Apr 2018 | García-Salum, Tamara; Villablanca, Andrea; Matthäus, Franziska; Tittarelli, Andrés; Baeza, Mauricio; Pereda, Cristián; Gleisner, M Alejandra; González, Fermín E; López, Mercedes N; Hoheisel, Jörg D; Norgauer, Johannes; Gebicke-Haerter, Peter J; Salazar-Onfray, Flavio
We previously showed that autologous dendritic cells (DCs) loaded with an allogeneic heat shock (HS)-conditioned melanoma cell-derived lysate, called TRIMEL, induce T-cell-mediated immune responses in stage IV melanoma patients. Importantly, a positive delayed-type hypersensitivity (DTH) reaction against TRIMEL after vaccination, correlated with patients prolonged survival. Furthermore, we observed that DTH reaction was associated with a differential response pattern reflected in the presence of distinct cell subpopulations in peripheral blood. Detected variations in patient responses encouraged molecular studies aimed to identify gene expression profiles induced after vaccination in treated patients, allowing the identification of new molecular predictive markers. PMID 29682201

Recent developments in immunotherapy of acute myeloid leukemia.
Apr 2018 | Lichtenegger, Felix S; Krupka, Christina; Haubner, Sascha; Köhnke, Thomas; Subklewe, Marion
The advent of new immunotherapeutic agents in clinical practice has revolutionized cancer treatment in the past decade, both in oncology and hematology. The transfer of the immunotherapeutic concepts to the treatment of acute myeloid leukemia (AML) is hampered by various characteristics of the disease, including non-leukemia-restricted target antigen expression profile, low endogenous immune responses, and intrinsic resistance mechanisms of the leukemic blasts against immune responses. However, considerable progress has been made in this field in the past few years.Within this manuscript, we review the recent developments and the current status of the five currently most prominent immunotherapeutic concepts: (1) antibody-drug conjugates, (2) T cell-recruiting antibody constructs, (3) chimeric antigen receptor (CAR) T cells, (4) checkpoint inhibitors, and (5) dendritic cell vaccination. We focus on the clinical data that has been published so far, both for newly diagnosed and refractory/relapsed AML, but omitting immunotherapeutic concepts in conjunction with hematopoietic stem cell transplantation. Besides, we have included important clinical trials that are currently running or have recently been completed but are still lacking full publication of their results.While each of the concepts has its particular merits and inherent problems, the field of immunotherapy of AML seems to have taken some significant steps forward. Results of currently running trials will reveal the direction of further development including approaches combining two or more of these concepts. PMID 28743264

Personalized cancer vaccine effectively mobilizes antitumor T cell immunity in ovarian cancer.
Apr 2018 | Tanyi, Janos L; Bobisse, Sara; Ophir, Eran; Tuyaerts, Sandra; Roberti, Annalisa; Genolet, Raphael; Baumgartner, Petra; Stevenson, Brian J; Iseli, Christian; Dangaj, Denarda; Czerniecki, Brian; Semilietof, Aikaterini; Racle, Julien; Michel, Alexandra; Xenarios, Ioannis; Chiang, Cheryl; Monos, Dimitri S; Torigian, Drew A; Nisenbaum, Harvey L; Michielin, Olivier; June, Carl H; Levine, Bruce L; Powell, Daniel J; Gfeller, David; Mick, Rosemarie; Dafni, Urania; Zoete, Vincent; Harari, Alexandre; Coukos, George; Kandalaft, Lana E
We conducted a pilot clinical trial testing a personalized vaccine generated by autologous dendritic cells (DCs) pulsed with oxidized autologous whole-tumor cell lysate (OCDC), which was injected intranodally in platinum-treated, immunotherapy-naïve, recurrent ovarian cancer patients. OCDC was administered alone (cohort 1, = 5), in combination with bevacizumab (cohort 2, = 10), or bevacizumab plus low-dose intravenous cyclophosphamide (cohort 3, = 10) until disease progression or vaccine exhaustion. A total of 392 vaccine doses were administered without serious adverse events. Vaccination induced T cell responses to autologous tumor antigen, which were associated with significantly prolonged survival. Vaccination also amplified T cell responses against mutated neoepitopes derived from nonsynonymous somatic tumor mutations, and this included priming of T cells against previously unrecognized neoepitopes, as well as novel T cell clones of markedly higher avidity against previously recognized neoepitopes. We conclude that the use of oxidized whole-tumor lysate DC vaccine is safe and effective in eliciting a broad antitumor immunity, including private neoantigens, and warrants further clinical testing. PMID 29643231

WT1-pulsed Dendritic Cell Vaccine Combined with Chemotherapy for Resected Pancreatic Cancer in a Phase I Study.
Apr 2018 | Yanagisawa, Ryu; Koizumi, Tomonobu; Koya, Terutsugu; Sano, Kenji; Koido, Shigeo; Nagai, Kazuhiro; Kobayashi, Masanori; Okamoto, Masato; Sugiyama, Haruo; Shimodaira, Shigetaka
Wilms' tumor 1 (WT1) is a tumor-associated antigen highly expressed in cancer. We examined the safety of WT1-peptide pulsed dendritic cell (WT1-DC) vaccine in combination with chemotherapy in patients with surgically resected pancreatic cancer. PMID 29599342

Survival gain in glioblastoma patients treated with dendritic cell immunotherapy is associated with increased NK but not CD8 T cell activation in the presence of adjuvant temozolomide.
Apr 2018 | Pellegatta, Serena; Eoli, Marica; Cuccarini, Valeria; Anghileri, Elena; Pollo, Bianca; Pessina, Sara; Frigerio, Simona; Servida, Maura; Cuppini, Lucia; Antozzi, Carlo; Cuzzubbo, Stefania; Corbetta, Cristina; Paterra, Rosina; Acerbi, Francesco; Ferroli, Paolo; DiMeco, Francesco; Fariselli, Laura; Parati, Eugenio A; Bruzzone, Maria Grazia; Finocchiaro, Gaetano
In a two-stage phase II study, 24 patients with first diagnosis of glioblastoma (GBM) were treated with dendritic cell (DC) immunotherapy associated to standard radiochemotherapy with temozolomide (TMZ) followed by adjuvant TMZ. Three intradermal injections of mature DC loaded with autologous GBM lysate were administered before adjuvant TMZ, while 4 injections were performed during adjuvant TMZ. According to a two-stage Simon design, to proceed to the second stage progression-free survival (PFS) 12 months after surgery was expected in at least 8 cases enrolled in the first stage. Evidence of immune response and interaction with chemotherapy were investigated. After a median follow up of 17.4 months, 9 patients reached PFS12. In these patients (responders, 37.5%), DC vaccination induced a significant, persistent activation of NK cells, whose increased response was significantly associated with prolonged survival. CD8 T cells underwent rapid expansion and priming but, after the first administration of adjuvant TMZ, failed to generate a memory status. Resistance to TMZ was associated with robust expression of the multidrug resistance protein ABCC3 in NK but not CD8 T cells. The negative effect of TMZ on the formation of T cell-associated antitumor memory deserves consideration in future clinical trials including immunotherapy. PMID 29632727

Dendritic Cells and Programmed Death-1 Blockade: A Joint Venture to Combat Cancer.
Mar 2018 | Versteven, Maarten; Van den Bergh, Johan M J; Marcq, Elly; Smits, Evelien L J; Van Tendeloo, Viggo F I; Hobo, Willemijn; Lion, Eva
Two decades of clinical cancer research with dendritic cell (DC)-based vaccination have proved that this type of personalized medicine is safe and has the capacity to improve survival, but monotherapy is unlikely to cure the cancer. Designed to empower the patient's antitumor immunity, huge research efforts are set to improve the efficacy of next-generation DC vaccines and to find synergistic combinations with existing cancer therapies. Immune checkpoint approaches, aiming to breach immune suppression and evasion to reinforce antitumor immunity, have been a revelation in the immunotherapy field. Early success of therapeutic antibodies blocking the programmed death-1 (PD-1) pathway has sparked the development of novel inhibitors and combination therapies. Hence, merging immunoregulatory tumor-specific DC strategies with PD-1-targeted approaches is a promising path to explore. In this review, we focus on the role of PD-1-signaling in DC-mediated antitumor immunity. In the quest of exploiting the full potential of DC therapy, different strategies to leverage DC immunopotency by impeding PD-1-mediated immune regulation are discussed, including the most advanced research on targeted therapeutic antibodies, lessons learned from chemotherapy-induced immune activation, and more recent developments with soluble molecules and gene-silencing techniques. An overview of DC/PD-1 immunotherapy combinations that are currently under preclinical and clinical investigation substantiates the clinical potential of such combination strategies. PMID 29599770

Combined immunotherapy encompassing intratumoral poly-ICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients.
Mar 2018 | Rodríguez-Ruiz, M E; Perez-Gracia, J L; Rodríguez, I; Alfaro, C; Oñate, C; Pérez, G; Gil-Bazo, I; Benito, A; Inogés, S; López-Diaz de Cerio, A; Ponz-Sarvise, M; Resano, L; Berraondo, P; Barbés, B; Martin-Algarra, S; Gúrpide, A; Sanmamed, M F; de Andrea, C; Salazar, A M; Melero, I
Combination immunotherapy has the potential to achieve additive or synergistic effects. Combined local injections of dsRNA analogues (mimicking viral RNA) and repeated vaccinations with tumor-lysate loaded dendritic cells shows efficacy against colon cancer mouse models. In the context of immunotherapy, radiotherapy can exert beneficial abscopal effects. PMID 29554212

A phase-1/2 study of adenovirus-p53 transduced dendritic cell vaccine in combination with indoximod in metastatic solid tumors and invasive breast cancer.
Mar 2018 | Soliman, Hatem; Khambati, Fatema; Han, Hyo S; Ismail-Khan, Roohi; Bui, Marilyn M; Sullivan, Daniel M; Antonia, Scott
Indoleamine 2, 3-dioxygenase is an enzyme that causes immunosuppression in tumors. Indoximod inhibits the indoleamine 2, 3-dioxygenase pathway and enhances immunologic responses to dendritic cell (DC) vaccines preclinically. Adenovirus p53 (Ad.p53) is used to generate DC vaccines against p53. A phase-1/2 trial of indoximod with Ad.p53-DC vaccine was conducted. PMID 29515795

Randomized phase II trial of autologous dendritic cell vaccines versus autologous tumor cell vaccines in metastatic melanoma: 5-year follow up and additional analyses.
Mar 2018 | Dillman, Robert O; Cornforth, Andrew N; Nistor, Gabriel I; McClay, Edward F; Amatruda, Thomas T; Depriest, Carol
Despite improved survival following checkpoint inhibitors, there is still a potential role for anti-cancer therapeutic vaccines. Because of biological heterogeneity and neoantigens resulting from each patient's mutanome, autologous tumor may be the best source of tumor-associated antigens (TAA) for vaccines. Ex vivo loading of autologous dendritic cells with TAA may be associated with superior clinical outcome compared to injecting irradiated autologous tumor cells. We conducted a randomized phase II trial to compare autologous tumor cell vaccines (TCV) and autologous dendritic cell vaccines (DCV) loaded with autologous TAA. PMID 29510745

Anti-cancer vaccine therapy for hematologic malignancies: An evolving era.
Feb 2018 | Nahas, Myrna R; Rosenblatt, Jacalyn; Lazarus, Hillard M; Avigan, David
The potential promise of therapeutic vaccination as effective therapy for hematologic malignancies is supported by the observation that allogeneic hematopoietic cell transplantation is curative for a subset of patients due to the graft-versus-tumor effect mediated by alloreactive lymphocytes. Tumor vaccines are being explored as a therapeutic strategy to re-educate host immunity to recognize and target malignant cells through the activation and expansion of effector cell populations. Via several mechanisms, tumor cells induce T cell dysfunction and senescence, amplifying and maintaining tumor cell immunosuppressive effects, resulting in failure of clinical trials of tumor vaccines and adoptive T cell therapies. The fundamental premise of successful vaccine design involves the introduction of tumor-associated antigens in the context of effective antigen presentation so that tolerance can be reversed and a productive response can be generated. With the increasing understanding of the role of both the tumor and tumor microenvironment in fostering immune tolerance, vaccine therapy is being explored in the context of immunomodulatory therapies. The most effective strategy may be to use combination therapies such as anti-cancer vaccines with checkpoint blockade to target critical aspects of this environment in an effort to prevent the re-establishment of tumor tolerance while limiting toxicity associated with autoimmunity. PMID 29475779

Re-Emergence of Dendritic Cell Vaccines for Cancer Treatment.
Feb 2018 | Saxena, Mansi; Bhardwaj, Nina
Dendritic cells (DCs) are essential in immunity owing to their role in activating T cells, thereby promoting antitumor responses. Tumor cells, however, hijack the immune system, causing T cell exhaustion and DC dysfunction. Tumor-induced T cell exhaustion may be reversed through immune checkpoint blockade (ICB); however, this treatment fails to show clinical benefit in many patients. While ICB serves to reverse T cell exhaustion, DCs are still necessary to prime, activate, and direct the T cells to target tumor cells. In this review we provide a brief overview of DC function, describe mechanisms by which DC functions are disrupted by the tumor microenvironment, and highlight recent developments in DC cancer vaccines. PMID 29458962

Dendritic cells as cancer therapeutics.
Feb 2018 | Bryant, Christian E; Sutherland, Sarah; Kong, Benjamin; Papadimitrious, Michael S; Fromm, Phillip D; Hart, Derek N J
The ability of immune therapies to control cancer has recently generated intense interest. This therapeutic outcome is reliant on T cell recognition of tumour cells. The natural function of dendritic cells (DC) is to generate adaptive responses, by presenting antigen to T cells, hence they are a logical target to generate specific anti-tumour immunity. Our understanding of the biology of DC is expanding, and they are now known to be a family of related subsets with variable features and function. Most clinical experience to date with DC vaccination has been using monocyte-derived DC vaccines. There is now growing experience with alternative blood-derived DC derived vaccines, as well as with multiple forms of tumour antigen and its loading, a wide range of adjuvants and different modes of vaccine delivery. Key insights from pre-clinical studies, and lessons learned from early clinical testing drive progress towards improved vaccines. The potential to fortify responses with other modalities of immunotherapy makes clinically effective "second generation" DC vaccination strategies a priority for cancer immune therapists. PMID 29454038

EpCAM peptide-primed dendritic cell vaccination confers significant anti-tumor immunity in hepatocellular carcinoma cells.
Feb 2018 | Choi, Yoo Jin; Park, Seong-Joon; Park, You-Soo; Park, Hee Sung; Yang, Kwang Mo; Heo, Kyu
Cancer stem-like cells (CSCs) may play a key role in tumor initiation, self-renewal, differentiation, and resistance to current treatments. Dendritic cells (DCs) play a vital role in host immune reactions as well as antigen presentation. In this study, we explored the suitability of using CSC peptides as antigen sources for DC vaccination against human breast cancer and hepatocellular carcinoma (HCC) with the aim of achieving CSC targeting and enhancing anti-tumor immunity. CD44 is used as a CSC marker for breast cancer and EpCAM is used as a CSC marker for HCC. We selected CD44 and EpCAM peptides that bind to HLA-A2 molecules on the basis of their binding affinity, as determined by a peptide-T2 binding assay. Our data showed that CSCs express high levels of tumor-associated antigens (TAAs) as well as major histocompatibility complex (MHC) molecules. Pulsing DCs with CD44 and EpCAM peptides resulted in the efficient generation of mature DCs (mDCs), thus enhancing T cell stimulation and generating potent cytotoxic T lymphocytes (CTLs). The activation of CSC peptide-specific immune responses by the DC vaccine in combination with standard chemotherapy may provide better clinical outcomes in advanced carcinomas. PMID 29298343

Poly(I:C) enhanced anti-cervical cancer immunities induced by dendritic cells-derived exosomes.
Feb 2018 | Chen, Shisheng; Lv, Mingfen; Fang, Shan; Ye, Wenxia; Gao, Yu; Xu, Yunsheng
Dendritic cell (DC)-derived exosomes (Dexo) has been confirmed to be able to induce the specific anti-tumor immune response ex vivo and in vivo. Here, the aim of this study was to evaluate the application of the antigen-pulsed Dexo as a new vaccination platform in immunotherapy for cervical cancer. The immunogenic profile of the different Dexo was assessed by the cell proliferation, cytokines secretion and effector functions of CD8 T cells and the splenocytes from Dexo-vaccinated mice. Furthermore, the anti-tumor immunity elicited by Dexo was further compared in cervical cancer-bearing mice. Dexo from DCs loaded with E7 peptide could efficiently induce the cytotoxic activity of CD8 T cells on TC-1 tumor cells ex vivo, the proliferation and IFN-γ excretion of CD8 T cells. Moreover, Dexo vaccine promoted the immune responses of vaccinated mice splenocytes induced by antigen E7 in vitro restimulation. Of note, poly(I:C) was significantly more potent inducer of the antigen-loaded Dexo mediated protective immunity responses for cervical cancer and further evidenced by that Dexo(E7+pIC) markedly inhibited the tumor growth and improved the survival rate of the tumor-bearing mice. We provided evidence that poly(I:C) dramatically increased the potent antitumoral immunity induced by antigen-pulsed Dexo for ameliorating cervical cancer. PMID 29427678

Efficacy of intracellular immune checkpoint-silenced DC vaccine.
Feb 2018 | Wang, Danhong; Huang, Xue F; Hong, Bangxing; Song, Xiao-Tong; Hu, Liangding; Jiang, Min; Zhang, Bin; Ning, Hongmei; Li, Yuhang; Xu, Chen; Lou, Xiao; Li, Botao; Yu, Zhiyong; Hu, Jiangwei; Chen, Jianlin; Yang, Fan; Gao, Haiyan; Ding, Guoliang; Liao, Lianming; Rollins, Lisa; Jones, Lindsey; Chen, Si-Yi; Chen, Hu
DC-based tumor vaccines have had limited clinical success thus far. SOCS1, a key inhibitor of inflammatory cytokine signaling, is an immune checkpoint regulator that limits DC immunopotency. PMID 29415891

Radiation and Anti-Cancer Vaccines: A Winning Combination.
Feb 2018 | Cadena, Alexandra; Cushman, Taylor R; Anderson, Clark; Barsoumian, Hampartsoum B; Welsh, James W; Cortez, Maria Angelica
The emerging combination of radiation therapy with vaccines is a promising new treatment plan in the fight against cancer. While many cancer vaccines such as MUC1, p53 CpG oligodeoxynucleotide, and SOX2 may be great candidates for antitumor vaccination, there still remain many investigations to be done into possible vaccine combinations. One fruitful partnership that has emerged are anti-tumor vaccines in combination with radiation. Radiation therapy was previously thought to be only a tool for directly or indirectly damaging DNA and therefore causing cancer cell death. Now, with much preclinical and clinical data, radiation has taken on the role of an in situ vaccine. With both cancer vaccines and radiation at our disposal, more and more studies are looking to combining vaccine types such as toll-like receptors, viral components, dendritic-cell-based, and subunit vaccines with radiation. While the outcomes of these combinatory efforts are promising, there is still much work to be covered. This review sheds light on the current state of affairs in cancer vaccines and how radiation will bring its story into the future. PMID 29385680

Phase I clinical trial of a novel autologous modified-DC vaccine in patients with resected NSCLC.
Dec 2017 | Ge, Chunlei; Li, Ruilei; Song, Haifeng; Geng, Tao; Yang, Jinyan; Tan, Qinghua; Song, Linfeng; Wang, Ying; Xue, Yuanbo; Li, Zhen; Dong, Suwei; Zhang, Zhiwei; Zhang, Na; Guo, Jiyin; Hua, Lin; Chen, Siyi; Song, Xin
The primary aim of this study was to evaluate the safety of a novel dendritic cell (DC) vaccine pulsed with survivin and MUC1, silenced with suppressor of cytokine signaling 1 (SOCS1), and immune stimulated with flagellin for patients with stage I to IIIA non-small cell lung cancer (NSCLC) in a phase I open-label, uncontrolled, and dose-escalation trial. Moreover, we evaluate the potential efficacy of this modified DC vaccine as secondary aim. PMID 29268708

Tumor Vaccines for Malignant Gliomas.
Dec 2017 | Srinivasan, Visish M; Ferguson, Sherise D; Lee, Sungho; Weathers, Shiao-Pei; Kerrigan, Brittany C Parker; Heimberger, Amy B
Despite continued research efforts, glioblastoma multiforme (GBM) remains the deadliest brain tumor. Immunotherapy offers a novel way to treat this disease, the genetic signature of which is not completely elucidated. Additionally, these tumors are known to induce immunosuppression in the surrounding tumor microenvironment via an array of mechanisms, making effective treatment all the more difficult. The immunotherapeutic strategy of using tumor vaccines offers a way to harness the activity of the host immune system to potentially control tumor progression. GBM vaccines can react to a variety of tumor-specific antigens, which can be harvested from the patient's unique pathological condition using selected immunotherapy techniques. This article reviews the rationale behind and development of GBM vaccines, the relevant clinical trials, and the challenges involved in this treatment strategy. PMID 28389997

Autologous Dendritic Cells Pulsed with Allogeneic Tumor Cell Lysate in Mesothelioma: From Mouse to Human.
Dec 2017 | Aerts, Joachim G J V; de Goeje, Pauline L; Cornelissen, Robin; Kaijen-Lambers, Margaretha E H; Bezemer, Koen; van der Leest, Cor H; Mahaweni, Niken M; Kunert, André; Eskens, Ferry A L M; Waasdorp, Cynthia; Braakman, Eric; van der Holt, Bronno; Vulto, Arnold G; Hendriks, Rudi W; Hegmans, Joost P J J; Hoogsteden, Henk C
Mesothelioma has been regarded as a nonimmunogenic tumor, which is also shown by the low response rates to treatments targeting the PD-1/PD-L1 axis. Previously, we demonstrated that autologous tumor lysate-pulsed dendritic cell (DC) immunotherapy increased T-cell response toward malignant mesothelioma. However, the use of autologous tumor material hampers implementation in large clinical trials, which might be overcome by using allogeneic tumor cell lines as tumor antigen source. The purpose of this study was to investigate whether allogeneic lysate-pulsed DC immunotherapy is effective in mice and safe in humans. First, in two murine mesothelioma models, mice were treated with autologous DCs pulsed with either autologous or allogeneic tumor lysate or injected with PBS (negative control). Survival and tumor-directed T-cell responses of these mice were monitored. Results were taken forward in a first-in-human clinical trial, in which 9 patients were treated with 10, 25, or 50 million DCs per vaccination. DC vaccination consisted of autologous monocyte-derived DCs pulsed with tumor lysate from five mesothelioma cell lines. In mice, allogeneic lysate-pulsed DC immunotherapy induced tumor-specific T cells and led to an increased survival, to a similar extent as DC immunotherapy with autologous tumor lysate. In the first-in-human clinical trial, no dose-limiting toxicities were established and radiographic responses were observed. Median PFS was 8.8 months [95% confidence interval (CI), 4.1-20.3] and median OS not reached (median follow-up = 22.8 months). DC immunotherapy with allogeneic tumor lysate is effective in mice and safe and feasible in humans. . PMID 29233904

Hematologic neoplasms: Dendritic cells vaccines in motion.
Dec 2017 | Galati, Domenico; Zanotta, Serena
Dendritic cells (DCs) are bone-marrow-derived immune cells accounted for a key role in cancer vaccination as potent antigen-presenting cells within the immune system. Cancer microenvironment can modulate DCs maturation resulting in their accumulation into functional states associated with a reduced antitumor immune response. In this regard, a successful cancer vaccine needs to mount a potent antitumor immune response able to overcome the immunosuppressive tumor milieu. As a consequence, DCs-based approaches are a safe and promising strategy for improving the therapeutic efficacy in hematological malignancies, particularly in combinations with additional treatments. This review summarizes the most significant evidence about the immunotherapeutic strategies performed to target hematologic neoplasms including the tumoral associated antigens (TAA) pulsed on DCs, whole tumor cell vaccines or leukemia-derived DCs. PMID 28870867

Advances in immunotherapeutic research for glioma therapy.
Dec 2017 | Miyauchi, Jeremy Tetsuo; Tsirka, Stella E
Gliomas are primary malignancies of the brain. Tumors are staged based on malignancy, nuclear atypia, and infiltration of the surrounding brain parenchyma. Tumors are often diagnosed once patients become symptomatic, at which time the lesion is sizable. Glioblastoma (grade IV glioma) is highly aggressive and difficult to treat. Most tumors are diagnosed de novo. The gold standard of therapy, implemented over a decade ago, consists of fractionated radiotherapy and temozolomide, but unfortunately, chemotherapeutic resistance arises. Recurrence is common after initial therapy. The tumor microenvironment plays a large role in cancer progression and its manipulation can repress progression. The advent and implementation of immunotherapy, via manipulation and activation of cytotoxic T cells, have had an outstanding impact on reducing morbidity and mortality associated with peripheral cancers under certain clinical circumstances. An arsenal of immunotherapeutics is currently under clinical investigation for safety and efficacy in the treatment of newly diagnosed and recurrent high grade gliomas. These immunotherapeutics encompass antibody-drug conjugates, autologous infusions of modified chimeric antigen receptor expressing T cells, peptide vaccines, autologous dendritic cell vaccines, immunostimulatory viruses, oncolytic viruses, checkpoint blockade inhibitors, and drugs which alter the behavior of innate immune cells. Effort is focusing on determining which patient populations will benefit the most from these treatments and why. Research addressing synergism between treatment options is gaining attention. While advances in the treatment of glioma stagnated in the past, we may see a considerable evolution in the management of the disease in the upcoming years. PMID 29209782

MtHsp70-CLIC1-pulsed dendritic cells enhance the immune response against ovarian cancer.
Nov 2017 | Yu, Wentao; Qu, Hong; Cao, Guangming; Liu, Chongdong; Deng, Haiteng; Zhang, Zhenyu
Approximately 80% of ovarian cancer (OC) is diagnosed at late stages, and most patients die within 5 years of diagnosis due to recurrence or drug resistance. Novel treatments are required to improve patient survival. Immune therapy against cancer is promising; however, therapeutic vaccination has been limited by the inability of tumor antigens to induce effective immune responses. Chloride intracellular channel 1 (CLIC1) was previously identified as a possible tumor marker for OC. In this study, we constructed a recombinant protein by conjugating the extracellular domain of CLIC1 to the carboxyl terminus of Mycobacterium tuberculosis heat shock protein 70 (MtHsp70). Human dendritic cells (DCs) derived from cortical blood were pulsed with the fusion protein, and the antitumor effect of human cytotoxic T lymphocytes (CTLs) stimulated by autologous DCs was assessed in NOG mice. MtHsp70-CLIC1 promoted the phenotypic maturation of human DCs and the secretion of Th1-associated cytokines in vitro. MtHsp70-CLIC1-stimulated CTLs generated a CLIC1-specific immune response both in vitro and in vivo. These results indicate that DCs pulsed with MtHsp70-CLIC1 can enhance antitumor immunity against OC, providing a novel immune therapeutic strategy. PMID 29061300

Dendritic cells based immunotherapy.
Nov 2017 | Shang, Na; Figini, Matteo; Shangguan, Junjie; Wang, Bin; Sun, Chong; Pan, Liang; Ma, Quanhong; Zhang, Zhuoli
Dendritic cells (DCs) are the most potent antigen-presenting cells, and tumor antigen-loaded DCs (DC-vaccines) can activate tumor-specific cytotoxic T lymphocytes (CTLs) in lymphatic tissues. DC vaccination is a newly emerging and potent form of cancer immunotherapy and has clinically relevant mechanisms of action with great potential for the systemic treatment of cancers. However, clinical trials have demonstrated relatively poor therapeutic efficacy. The efficacy of DC-vaccines is strongly influenced by various techniques for the priming antigen loading onto DCs and their ability to migrate to the draining lymph nodes (LNs). Therefore, it is critical to improve DC-vaccines homing to draining LNs after administration in order to optimize DC-based therapy for individual patients. This review underlines 1) appropriate strategy to load tumor antigens onto DCs and 2) to optimize vaccine administration methods to ensure loaded DCs can migrate to LNs, in particular, Intraperitoneal (IP) injection. IP injection of DC-based vaccine may be a potential regimen for gastrointestinal tumors including hepatocellular carcinoma (HCC) and pancreatic adenocarcinoma (PDAC) since huge populations of LNs are present throughout the gastrointestinal track. Which might improve the subsequent migration to LNs. PMID 29119057

Dendritic cell therapy in melanoma.
Nov 2017 | Alvarez-Dominguez, Carmen; Calderón-Gonzalez, Ricardo; Terán-Navarro, Hector; Salcines-Cuevas, David; Garcia-Castaño, Almudena; Freire, Javier; Gomez-Roman, Javier; Rivera, Fernando
Dendritic cell (DC) vaccines are cancer vaccines used currently as melanoma therapies. They act as adjuvants initiating the immune responses, but not only as they can also have effector activities redirecting cytotoxic CD8 T cells against melanoma. Ex vivo preparation of monocyte derived DCs has been implemented to produce large numbers of DCs for clinical therapy, highlighting the necessity of activate DC s to produce Th1 cytokines, especially TNF-a and IL-12 with potent anti-tumour actions. Several clinical trials both in the European Union and USA are open currently using DC vaccines, alone or in combination with other immunotherapies. The type of antigen is also an active area of investigation involving tumour antigens and bacterial epitopes, both providing good responses. Bacterial epitopes presented the advantage versus tumour antigens that they can prepare the vaccination site as they induce innate and specific immune responses as they are potent recall antigens that expand cytotoxic responses. PMID 29114544

A phase I vaccination study with dendritic cells loaded with NY-ESO-1 and α-galactosylceramide: induction of polyfunctional T cells in high-risk melanoma patients.
Nov 2017 | Gasser, Olivier; Sharples, Katrina J; Barrow, Catherine; Williams, Geoffrey M; Bauer, Evelyn; Wood, Catherine E; Mester, Brigitta; Dzhelali, Marina; Caygill, Graham; Jones, Jeremy; Hayman, Colin M; Hinder, Victoria A; Macapagal, Jerome; McCusker, Monica; Weinkove, Robert; Painter, Gavin F; Brimble, Margaret A; Findlay, Michael P; Dunbar, P Rod; Hermans, Ian F
Vaccines that elicit targeted tumor antigen-specific T-cell responses have the potential to be used as adjuvant therapy in patients with high risk of relapse. However, the responses induced by vaccines in cancer patients have generally been disappointing. To improve vaccine function, we investigated the possibility of exploiting the immunostimulatory capacity of type 1 Natural killer T (NKT) cells, a cell type enriched in lymphoid tissues that can trigger improved antigen-presenting function in dendritic cells (DCs). In this phase I dose escalation study, we treated eight patients with high-risk surgically resected stage II-IV melanoma with intravenous autologous monocyte-derived DCs loaded with the NKT cell agonist α-GalCer and peptides derived from the cancer testis antigen NY-ESO-1. Two synthetic long peptides spanning defined immunogenic regions of the NY-ESO-1 sequence were used. This therapy proved to be safe and immunologically effective, inducing increases in circulating NY-ESO-1-specific T cells that could be detected directly ex vivo in seven out of eight patients. These responses were achieved using as few as 5 × 10 peptide-loaded cells per dose. Analysis after in vitro restimulation showed increases in polyfunctional CD4 and CD8 T cells that were capable of manufacturing two or more cytokines simultaneously. Evidence of NKT cell proliferation and/or NKT cell-associated cytokine secretion was seen in most patients. In light of these strong responses, the concept of including NKT cell agonists in vaccine design requires further investigation. PMID 29094183

Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia.
Oct 2017 | Anguille, Sébastien; Van de Velde, Ann L; Smits, Evelien L; Van Tendeloo, Viggo F; Juliusson, Gunnar; Cools, Nathalie; Nijs, Griet; Stein, Barbara; Lion, Eva; Van Driessche, Ann; Vandenbosch, Irma; Verlinden, Anke; Gadisseur, Alain P; Schroyens, Wilfried A; Muylle, Ludo; Vermeulen, Katrien; Maes, Marie-Berthe; Deiteren, Kathleen; Malfait, Ronald; Gostick, Emma; Lammens, Martin; Couttenye, Marie M; Jorens, Philippe; Goossens, Herman; Price, David A; Ladell, Kristin; Oka, Yoshihiro; Fujiki, Fumihiro; Oji, Yusuke; Sugiyama, Haruo; Berneman, Zwi N
Relapse is a major problem in acute myeloid leukemia (AML) and adversely affects survival. In this phase 2 study, we investigated the effect of vaccination with dendritic cells (DCs) electroporated with Wilms' tumor 1 () messenger RNA (mRNA) as postremission treatment in 30 patients with AML at very high risk of relapse. There was a demonstrable antileukemic response in 13 patients. Nine patients achieved molecular remission as demonstrated by normalization of transcript levels, 5 of which were sustained after a median follow-up of 109.4 months. Disease stabilization was achieved in 4 other patients. Five-year overall survival (OS) was higher in responders than in nonresponders (53.8% vs 25.0%; = .01). In patients receiving DCs in first complete remission (CR1), there was a vaccine-induced relapse reduction rate of 25%, and 5-year relapse-free survival was higher in responders than in nonresponders (50% vs 7.7%; < .0001). In patients age ≤65 and >65 years who received DCs in CR1, 5-year OS was 69.2% and 30.8% respectively, as compared with 51.7% and 18% in the Swedish Acute Leukemia Registry. Long-term clinical response was correlated with increased circulating frequencies of polyepitope WT1-specific CD8 T cells. Long-term OS was correlated with interferon-γ and tumor necrosis factor-α WT1-specific responses in delayed-type hypersensitivity-infiltrating CD8 T lymphocytes. In conclusion, vaccination of patients with AML with mRNA-electroporated DCs can be an effective strategy to prevent or delay relapse after standard chemotherapy, translating into improved OS rates, which are correlated with the induction of WT1-specific CD8 T-cell response. This trial was registered at as #NCT00965224. PMID 28830889

Co-delivery of tumor-derived exosomes with alpha-galactosylceramide on dendritic cell-based immunotherapy for glioblastoma.
Sep 2017 | Liu, Hongyu; Chen, Ling; Liu, Jialin; Meng, Hengxing; Zhang, Rong; Ma, Lin; Wu, Liangliang; Yu, Songyan; Shi, Fei; Li, Ying; Zhang, Lijun; Wang, Lingxiong; Feng, Shiyu; Zhang, Qi; Peng, Yaojun; Wu, Qiyan; Liu, Chunxi; Chang, Xin; Yang, Lin; Uemura, Yasushi; Yu, Xinguang; Liu, Tianyi
Dendritic cell (DC) vaccine-based immunotherapy for glioblastoma multiforme (GBM) has shown apparent benefit in animal experiments and early-phase clinical trials, but the survival benefit is variable. In this work, we analyzed the mechanism of the potent antitumor immune response induced in vivo by tumor-associated antigen (TAA)-specific DCs with an invariant natural killer T (iNKT) cell adjuvant in orthotopic glioblastoma-bearing rats vaccinated with tumor-derived exosomes and α-galactosylceramide (α-GalCer) -pulsed DCs. Compared with traditional tumor lysate, exosomes were utilized as a more potent antigen to load DCs. iNKT cells, as an effective cellular adjuvant activated by α-GalCer, strengthened TAA presentation through their interaction with DCs. Co-delivery of tumor-derived exosomes with α-GalCer on a DC-based vaccine showed powerful effects in glioblastoma immunotherapy. This vaccine induced strong activation and proliferation of tumor-specific cytotoxic T lymphocytes, synergistically breaking the immune tolerance and improving the immunosuppressive environment. PMID 28947140

Trial watch: Dendritic cell-based anticancer immunotherapy.
Aug 2017 | Garg, Abhishek D; Vara Perez, Monica; Schaaf, Marco; Agostinis, Patrizia; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo
Dendritic cell (DC)-based vaccines against cancer have been extensively developed over the past two decades. Typically DC-based cancer immunotherapy entails loading patient-derived DCs with an appropriate source of tumor-associated antigens (TAAs) and efficient DC stimulation through a so-called "maturation cocktail" (typically a combination of pro-inflammatory cytokines and Toll-like receptor agonists), followed by DC reintroduction into patients. DC vaccines have been documented to (re)activate tumor-specific T cells in both preclinical and clinical settings. There is considerable clinical interest in combining DC-based anticancer vaccines with T cell-targeting immunotherapies. This reflects the established capacity of DC-based vaccines to generate a pool of TAA-specific effector T cells and facilitate their infiltration into the tumor bed. In this Trial Watch, we survey the latest trends in the preclinical and clinical development of DC-based anticancer therapeutics. We also highlight how the emergence of immune checkpoint blockers and adoptive T-cell transfer-based approaches has modified the clinical niche for DC-based vaccines within the wide cancer immunotherapy landscape. PMID 28811970

Efficacy of vaccination with tumor-exosome loaded dendritic cells combined with cytotoxic drug treatment in pancreatic cancer.
Jul 2017 | Xiao, Li; Erb, Ulrike; Zhao, Kun; Hackert, Thilo; Zöller, Margot
Pancreatic cancer (PaCa) has a dismal prognosis and adjuvant immunotherapy frequently is of low efficacy due to immunosuppressive features of PaCa and PaCa-stroma. We here explored, whether the efficacy of vaccination with tumor-exosome (TEX)-loaded dendritic cells (DC) can be improved by combining with drugs affecting myeloid-derived suppressor cells (MDSC). Experiments were performed with the UNKC6141 PaCa line. UNKC6141 TEX-loaded DC were weekly intravenously injected, mice additionally receiving Gemcitabine (GEM) and/or ATRA and/or Sunitinib (Sun). UNKC6141 grow aggressively after subcutaneous and orthotopic application and are consistently recovered in peripheral blood, bone marrow, lung and frequently liver. Vaccination with DC-TEX significantly prolonged the survival time, the efficacy of DC-TEX exceeding that of the cytotoxic drugs. However, ATRA, Sun and most efficiently GEM, sufficed for a pronounced reduction of MDSC including tumor-infiltrating MDSC, which was accompanied by a decrease in migrating and metastasizing tumor cells. When combined with DC-TEX vaccination, a higher number of activated T cells was recovered in the tumor and the survival time was prolonged compared with only DC-TEX vaccinated mice. As ATRA, GEM and Sun affect MDSC at distinct maturation and activation stages, a stronger support for DC-TEX vaccination was expected by the drug combination. Intrapancreatic tumor growth was prevented beyond the death of control mice. However, tumors developed after a partial breakdown of the immune system by the persisting drug application. Nonetheless, in combination with optimized drug tuning to prevent MDSC maturation and activation, vaccination with TEX-loaded DC appears a most promising option in PaCa therapy. PMID 28680753

A comprehensive review of immunotherapies in prostate cancer.
Jun 2017 | Maia, Manuel Caitano; Hansen, Aaron R
Prostate cancer is the second most common malignant neoplasm in men worldwide and the fifth cause of cancer-related death. Although multiple new agents have been approved for metastatic castration resistant prostate cancer over the last decade, it is still an incurable disease. New strategies to improve cancer control are needed and agents targeting the immune system have shown encouraging results in many tumor types. Despite being attractive for immunotherapies due to the expression of various tumor associated antigens, the microenvironment in prostate cancer is relatively immunosuppressive and may be responsible for the failures of various agents targeting the immune system in this disease. To date, sipuleucel-T is the only immunotherapy that has shown significant clinical efficacy in this setting, although the high cost and potential trial flaws have precluded its widespread incorporation into clinical practice. Issues with patient selection and trial design may have contributed to the multiple failures of immunotherapy in prostate cancer and provides an opportunity to tailor future studies to evaluate these agents more accurately. We have reviewed all the completed immune therapy trials in prostate cancer and highlight important considerations for the next generation of clinical trials. PMID 28427519

Prospect of Immunotherapy for Glioblastoma: Tumor Vaccine, Immune Checkpoint Inhibitors and Combination Therapy.
May 2017 | Ishikawa, Eiichi; Yamamoto, Tetsuya; Matsumura, Akira
To date, clinical trials of various vaccine therapies using autologous tumor antigens or tumor-associated/specific antigen peptide with adjuvants have been performed to treat patients with high-grade gliomas (HGG). Furthermore, immune checkpoint pathway-targeted therapies including anti- programmed cell death 1 (PD-1) antibody have been remarkably effective in other neoplasms, and various clinical trials with anti-PD-1 antibody in patients with HGG have started to date. It is possible that up-regulation of immune checkpoint molecules in tumor tissues after vaccine therapy may be one of the mechanisms of vaccine failure. Multiple preclinical studies indicate that combination therapy with vaccination and immune checkpoint blockade is effective for the treatment of malignant tumors including HGG. Thus, immunotherapy, especially combination therapy with vaccine and immune checkpoint inhibitors, may be a promising strategy for treatment of patients with HGG. PMID 28539528

A phase II trial of autologous dendritic cell vaccination and radiochemotherapy following fluorescence-guided surgery in newly diagnosed glioblastoma patients.
May 2017 | Inogés, Susana; Tejada, Sonia; de Cerio, Ascensión López-Díaz; Gállego Pérez-Larraya, Jaime; Espinós, Jaime; Idoate, Miguel Angel; Domínguez, Pablo Daniel; de Eulate, Reyes García; Aristu, Javier; Bendandi, Maurizio; Pastor, Fernando; Alonso, Marta; Andreu, Enrique; Cardoso, Felipe Prósper; Valle, Ricardo Díez
Prognosis of patients with glioblastoma multiforme (GBM) remains dismal, with median overall survival (OS) of about 15 months. It is therefore crucial to search alternative strategies that improve these results obtained with conventional treatments. In this context, immunotherapy seems to be a promising therapeutic option. We hypothesized that the addition of tumor lysate-pulsed autologous dendritic cells (DCs) vaccination to maximal safe resection followed by radiotherapy and concomitant and adjuvant temozolomide could improve patients' survival. PMID 28499389

Vaccine-based immunotherapeutic approaches to gliomas and beyond.
May 2017 | Weller, Michael; Roth, Patrick; Preusser, Matthias; Wick, Wolfgang; Reardon, David A; Platten, Michael; Sampson, John H
Astrocytic and oligodendroglial gliomas are intrinsic brain tumours characterized by infiltrative growth and resistance to classic cancer therapies, which renders them inevitably lethal. Glioblastoma, the most common type of glioma, also exhibits neoangiogenesis and profound immunosuppressive properties. Accordingly, strategies to revert glioma-associated immunosuppression and promote tumour-directed immune responses have been extensively explored in rodent models and in large clinical trials of tumour immunotherapy. This Review describes vaccination approaches investigated for the treatment of glioma. Several strategies have reached phase III clinical trials, including vaccines targeting epidermal growth factor receptor variant III, and the use of either immunogenic peptides or tumour lysates to stimulate autologous dendritic cells. Other approaches in early phases of clinical development employ multipeptide vaccines such as IMA-950, cytomegalovirus-derived peptides, or tumour-derived peptides such as heat shock protein-96 peptide complexes and the Arg132His mutant form of isocitrate dehydrogenase. However, some preclinical trial data suggest that addition of immunomodulatory reagents such as immune checkpoint inhibitors, transforming growth factor-β inhibitors, signal transducer and activator of transcription 3 inhibitors, or modifiers of tryptophan metabolism could augment the therapeutic activity of vaccination and overcome glioma-associated immunosuppression. PMID 28497804

Phase I trial of intratumoral injection of CCL21 gene modified dendritic cells in lung cancer elicits tumor-specific immune responses and CD8+ T cell infiltration.
May 2017 | Lee, Jay Moon M; Lee, Mi-Heon; Garon, Edward; Goldman, Jonathan W; Salehi-Rad, Ramin; Baratelli, Felicita E; Schaue, Dorthe; Wang, Gerald; Rosen, Fran; Yanagawa, Jane; Walser, Tonya C; Lin, Ying; Park, Stacy J; Adams, Sharon; Marincola, Francesco M; Tumeh, Paul C; Abtin, Fereidoun; Suh, Robert; Reckamp, Karen L; Lee, Gina; Wallace, William D; Lee, Sarah; Zeng, Gang; Elashoff, David A; Sharma, Sherven; Dubinett, Steven M
A phase I study was conducted to determine safety, clinical efficacy, and anti-tumor immune responses in patients with advanced non-small cell lung carcinoma (NSCLC) following intratumoral (IT) administration of autologous dendritic cells (DC) transduced with an adenoviral (Ad) vector expressing the CCL21 gene (Ad-CCL21-DC). We evaluated safety and tumor antigen-specific immune responses following in situ vaccination ( NCT01574222). PMID 28468947

Combination therapy with dendritic cells and lenalidomide is an effective approach to enhance antitumor immunity in a mouse colon cancer model.
May 2017 | Vo, Manh-Cuong; Nguyen-Pham, Thanh-Nhan; Lee, Hyun-Ju; Jaya Lakshmi, Thangaraj; Yang, Seoyun; Jung, Sung-Hoon; Kim, Hyeoung-Joon; Lee, Je-Jung
In this study, we investigated efficacy of lenalidomide in combination with tumor antigen-loaded dendritic cells (DCs) in murine colon cancer model. MC-38 cell lines were injected subcutaneously to establish colon cancer-bearing mice. After tumor growth, lenalidomide (50 mg/kg/day) was injected intraperitoneally on 3 consecutive days in combination with tumor antigen-loaded DC vaccination on days 8, 12, 16, and 20. The tumor antigen-loaded DCs plus lenalidomide combination treatment exhibited a significant inhibition of tumor growth compared with the other groups. These effects were associated with a reduction in immune suppressor cells, such as myeloid-derived suppressor cells and regulatory T cells, with the induction of immune effector cells, such as natural killer cells, CD4+ T cells and CD8+ T cells in spleen, and with the activation of cytotoxic T lymphocytes and NK cells. This study suggests that a combination of tumor antigen-loaded DC vaccination and lenalidomide synergistically enhanced antitumor immune response in the murine colon cancer model, by inhibiting the generation of immune suppressive cells and recovery of effector cells, and demonstrated superior polarization of Th1/Th2 balance in favor of Th1 immune response. This combination approach with DCs and lenalidomide may provide a new therapeutic option to improve the treatment of colon cancer. PMID 28460478

Dendritic cell based vaccination strategy: an evolving paradigm.
Apr 2017 | Filley, Anna C; Dey, Mahua
Malignant gliomas (MG), tumors of glial origin, are the most commonly diagnosed primary intracranial malignancies in adults. Currently available treatments have provided only modest improvements in overall survival and remain limited by inevitable local recurrence, necessitating exploration of novel therapies. Among approaches being investigated, one of the leading contenders is immunotherapy, which aims to modulate immune pathways to stimulate the selective destruction of malignant cells. Dendritic cells (DCs) are potent initiators of adaptive immune responses and therefore crucial players in the development and success of immunotherapy. Clinical trials of various DC-based vaccinations have demonstrated the induction of anti-tumor immune responses and prolonged survival in the setting of many cancers. In this review, we summarize current literature regarding DCs and their role in the tumor microenvironment, their application and current clinical use in immunotherapy, current challenges limiting their efficacy in anti-cancer therapy, and future avenues for developing successful anti-tumor DC-based vaccines. PMID 28434112

Twelve-year survival and immune correlates in dendritic cell-vaccinated melanoma patients.
Apr 2017 | Gross, Stefanie; Erdmann, Michael; Haendle, Ina; Voland, Steve; Berger, Thomas; Schultz, Erwin; Strasser, Erwin; Dankerl, Peter; Janka, Rolf; Schliep, Stefan; Heinzerling, Lucie; Sotlar, Karl; Coulie, Pierre; Schuler, Gerold; Schuler-Thurner, Beatrice
Reports on long-term (≥10 years) effects of cancer vaccines are missing. Therefore, in 2002, we initiated a phase I/II trial in cutaneous melanoma patients to further explore the immunogenicity of our DC vaccine and to establish its long-term toxicity and clinical benefit after a planned 10-year followup. PMID 28422751

Immunotherapeutic approaches for hepatocellular carcinoma.
Apr 2017 | Longo, Vito; Gnoni, Antonio; Casadei Gardini, Andrea; Pisconti, Salvatore; Licchetta, Antonella; Scartozzi, Mario; Memeo, Riccardo; Palmieri, Vincenzo Ostilio; Aprile, Giuseppe; Santini, Daniele; Nardulli, Patrizia; Silvestris, Nicola; Brunetti, Oronzo
Hepatocellular carcinoma (HCC) is a cancer with a high mortality rate due to the fact that the diagnosis usually occurs at anadvanced stage. Even in case of curative surgical treatment, recurrence is common. Sorafenib and regorafenib are the only therapeutic agents that have been demonstrated to be effective in advanced HCC, thus novel curative approaches are urgently needed. Recent studies focus on the role of immune system in HCC. In fact, the unique immune response in the liver favors tolerance, which can represent a real challenge for conventional immunotherapy in these patients. Spontaneous immune responses against tumor antigens have been detected, and new immune therapies are under investigation: dendritic cell vaccination, immune-modulator strategy, and immune checkpoint inhibition. In recent years different clinical trials examining the use of immunotherapy to treat HCC have been conducted with initial promising results. This review article will summarize the literature data concerning the potential immunotherapeutic approaches in HCC patients. PMID 28420805

Immune responses and long-term disease recurrence status after telomerase-based dendritic cell immunotherapy in patients with acute myeloid leukemia.
Apr 2017 | Khoury, Hanna J; Collins, Robert H; Blum, William; Stiff, Patrick S; Elias, Laurence; Lebkowski, Jane S; Reddy, Anita; Nishimoto, Kevin P; Sen, Debasish; Wirth, Edward D; Case, Casey C; DiPersio, John F
Telomerase activity in leukemic blasts frequently is increased among patients with high-risk acute myeloid leukemia (AML). In the current study, the authors evaluated the feasibility, safety, immunogenicity, and therapeutic potential of human telomerase reverse transcriptase (hTERT)-expressing autologous dendritic cells (hTERT-DCs) in adult patients with AML. PMID 28411378

Long-term Survival in Glioblastoma with Cytomegalovirus pp65-Targeted Vaccination.
Apr 2017 | Batich, Kristen A; Reap, Elizabeth A; Archer, Gary E; Sanchez-Perez, Luis; Nair, Smita K; Schmittling, Robert J; Norberg, Pam; Xie, Weihua; Herndon, James E; Healy, Patrick; McLendon, Roger E; Friedman, Allan H; Friedman, Henry S; Bigner, Darell; Vlahovic, Gordana; Mitchell, Duane A; Sampson, John H
Purpose: Patients with glioblastoma have less than 15-month median survival despite surgical resection, high-dose radiation, and chemotherapy with temozolomide. We previously demonstrated that targeting cytomegalovirus pp65 using dendritic cells (DC) can extend survival and, in a separate study, that dose-intensified temozolomide (DI-TMZ) and adjuvant granulocyte macrophage colony-stimulating factor (GM-CSF) potentiate tumor-specific immune responses in patients with glioblastoma. Here, we evaluated pp65-specific cellular responses following DI-TMZ with pp65-DCs and determined the effects on long-term progression-free survival (PFS) and overall survival (OS).Experimental Design: Following standard-of-care, 11 patients with newly diagnosed glioblastoma received DI-TMZ (100 mg/m(2)/d × 21 days per cycle) with at least three vaccines of pp65 lysosome-associated membrane glycoprotein mRNA-pulsed DCs admixed with GM-CSF on day 23 ± 1 of each cycle. Thereafter, monthly DI-TMZ cycles and pp65-DCs were continued if patients had not progressed.Results: Following DI-TMZ cycle 1 and three doses of pp65-DCs, pp65 cellular responses significantly increased. After DI-TMZ, both the proportion and proliferation of regulatory T cells (Tregs) increased and remained elevated with serial DI-TMZ cycles. Median PFS and OS were 25.3 months [95% confidence interval (CI), 11.0-∞] and 41.1 months (95% CI, 21.6-∞), exceeding survival using recursive partitioning analysis and matched historical controls. Four patients remained progression-free at 59 to 64 months from diagnosis. No known prognostic factors [age, Karnofsky performance status (KPS), IDH-1/2 mutation, and MGMT promoter methylation] predicted more favorable outcomes for the patients in this cohort.Conclusions: Despite increased Treg proportions following DI-TMZ, patients receiving pp65-DCs showed long-term PFS and OS, confirming prior studies targeting cytomegalovirus in glioblastoma. Clin Cancer Res; 23(8); 1898-909. ©2017 AACR. PMID 28411277

Vaccination with poly(IC:LC) and peptide-pulsed autologous dendritic cells in patients with pancreatic cancer.
Apr 2017 | Mehrotra, Shikhar; Britten, Carolyn D; Chin, Steve; Garrett-Mayer, Elizabeth; Cloud, Colleen A; Li, Mingli; Scurti, Gina; Salem, Mohamed L; Nelson, Michelle H; Thomas, Melanie B; Paulos, Chrystal M; Salazar, Andres M; Nishimura, Michael I; Rubinstein, Mark P; Li, Zihai; Cole, David J
Dendritic cells (DCs) enhance the quality of anti-tumor immune response in patients with cancer. Thus, we posit that DC-based immunotherapy, in conjunction with toll-like receptor (TLR)-3 agonist poly-ICLC, is a promising approach for harnessing immunity against metastatic or locally advanced unresectable pancreatic cancer (PC). PMID 28388966

Dynamic and specific immune responses against multiple tumor antigens were elicited in patients with hepatocellular carcinoma after cell-based immunotherapy.
Mar 2017 | Han, Yanyan; Wu, Yeting; Yang, Chou; Huang, Jing; Guo, Yabing; Liu, Li; Chen, Ping; Wu, Dongyun; Liu, Junyun; Li, Jin; Zhou, Xiangjun; Hou, Jinlin
Hepatocellular carcinoma (HCC) is one of the most common cancers in China and frequently occurs with chronic hepatitis B virus infection. To investigate whether cell-based cancer immunotherapy induces tumor specific immune responses in patients with HCC and provides clinical benefits, as well as to elucidate the most immunogenic tumor associated antigens (TAAs), multiple antigen stimulating cellular therapy (MASCT) was applied in addition to standard of care. PMID 28330473

Immunomonitoring reveals interruption of anergy after vaccination in a case of type-2-papillary renal cell carcinoma.
Mar 2017 | Clavijo-Salomon, Maria A; Bergami-Santos, Patricia C; M Barbuto, José Alexandre
With the enormous and growing interest in the clinical application of immunotherapy, we are currently facing the need to accurately monitor the immune function of cancer patients. Here, we describe changes in the immune status of a patient with metastatic type-2-papillary renal cell carcinoma, before and after surgery and subsequent immunotherapy with a dendritic cell-tumor cell hybrid vaccine. Through the accurate assessment of monocyte-derived dendritic cells (Mo-DCs) function, we show that Mo-DCs were freed from tumor-induced maturation blockage by tumor resection surgery, while Mo-DCs-tumor induced suppression and anergy were only interrupted by the vaccination treatment. Our data suggest that the evaluation of Mo-DCs' function may provide a powerful and precise tool to monitor immune restoration in cancer patients. PMID 28303767

Immune and viral therapies for malignant primary brain tumors.
Mar 2017 | Gardeck, Andrew M; Sheehan, Jordan; Low, Walter C
Glioblastoma multiforme (GBM) is a primary brain tumor with great lethality. Current standard of care with surgery, radiation therapy, and chemotherapy are ineffective in curing this disease. Recent advancements in biological therapies show promise in treating brain tumors. Areas covered: This article provides a review of: the peripheral activation of antigen presenting cells such as dendritic cells to stimulate T cells to recognize and destroy tumor cells within the brain; the ex vivo expansion and transfer of dendritic cells, T cells, and engineered T cells expressing chimeric antigen receptors to target cells bearing specific tumor antigens as well as monoclonal antibodies as immune check point inhibitors. Gene therapy approaches have also been utilized to employ viral vectors in transducing cells to express cytokines for activating immune responses to brain tumors. Finally, the article reviews engineering of viruses for oncolytic targeting and destruction of malignant tumors within the brain. Expert opinion: The ultimate goal of immune and viral approaches for treating malignant brain tumors is to cure this disease. Preclinical and clinical studies utilizing these biological therapeutic approaches for treating brain tumors have the potential to augment the current standard of care to provide potential curative therapies. PMID 28274139

Immunotherapy for the treatment of multiple myeloma.
Mar 2017 | Jung, Sung-Hoon; Lee, Hyun-Ju; Vo, Manh-Cuong; Kim, Hyeoung-Joon; Lee, Je-Jung
Immunotherapy has recently emerged as a promising treatment for multiple myeloma (MM). There are now several monoclonal antibodies that target specific surface antigens on myeloma cells or the checkpoints of immune and myeloma cells. Elotuzumab (targeting SLAMF7), daratumumab (targeting CD38), and pembrolizumab (targeting PD-1) have shown clinical activity in clinical studies with relapsed/refractory MM. Dendritic cell vaccination is a safe strategy that has shown some efficacy in a subset of myeloma patients and may become a crucial part of MM treatment when combined with immunomodulatory drugs or immune check-point blockade. Genetically engineered T cells, such as chimeric antigen receptor T cells or T cell receptor-engineered T cells, have also shown encouraging results in recent clinical studies of patients with MM. In this paper, we discuss recent progress in immunotherapy for the treatment of MM. PMID 28259300

Dendritic cell vaccination in combination with docetaxel for patients with metastatic castration-resistant prostate cancer: A randomized phase II study.
Feb 2017 | Kongsted, Per; Borch, Troels Holz; Ellebaek, Eva; Iversen, Trine Zeeberg; Andersen, Rikke; Met, Özcan; Hansen, Morten; Lindberg, Henriette; Sengeløv, Lisa; Svane, Inge Marie
We investigated whether the addition of an autologous dendritic cell-based cancer vaccine (DCvac) induces an immune response in patients with metastatic castration-resistant prostate cancer treated with docetaxel. PMID 28215654

Targeting the immune niche within the bone marrow microenvironment: The rise of immunotherapy in Multiple Myeloma.
Feb 2017 | Podar, Klaus; Jäger, D
Multiple Myeloma (MM) cells inhibit the development of an effective anti-MM immune response via defects in T cell function, ineffective antigen presentation; reduced phagocytic capacity; natural killer and dendritic cell dysfunction; decreased responsiveness to IL-2 and defects in B cell immunity; upregulation of inhibitory pathways; and production of excessive pro-inflammatory cytokines. Moreover, immune cells including plasmacytoid dendritic cells and macrophages trigger tumor cell proliferation, survival, and drug resistance. The usefulness of immunotherapies in MM patients has first been supported by the identification of the graft-versus-myeloma effect in the context of allogeneic bone marrow (BM) transplantation. Subsequently, the inclusion of thalidomide and its derivatives, the Immunomodulatory Drugs (IMiDs) as well as of (immuno) proteasome inhibitors into MM regimens dramatically improved MM patients&#039; outcome during the last 15 years. Despite these unprecedented therapeutic advances MM remains an incurable disease. Novel immunotherapeutic approaches aim to restore the balance within the immunologic niche of the MM BM microenvironment. Indeed, the inclusion of monoclonal antibodies, immune checkpoint inhibitors, chimeric antigen receptor-engineered (CAR) T cells, genetically engineered T cells, and vaccination, dendritic cell- based cancer vaccines in particular, into existing regimens is likely to significantly improve MM patient outcome in the near future. PMID 28201977

A Dendritic Cell Vaccine Combined With Radiotherapy Activates the Specific Immune Response in Patients With Esophageal Cancer.
Jan 2017 | Wang, Chengshi; Pu, Juan; Yu, Hanxu; Liu, Yanyan; Yan, Honghuan; He, Zhongxiang; Feng, Xin
Dendritic cells (DC) are highly efficient antigen-presenting cells. DC may be used to create DC vaccines against cancer, but the optimal strategies remain to be elucidated. This study aimed to examine the benefits and adverse effects of using esophageal cancer cell antigens to stimulate DC to trigger the specific immune response in patients with esophageal cancer undergoing radiotherapy. This was an observational cohort study performed at Lianshui County People's Hospital between September 2010 and June 2012. Forty patients with esophageal cancer planned to receive radiotherapy were selected, and 28 received the DC vaccine. DC were isolated, loaded with antigens, and intradermally injected after being cultured for 1 week. One week after injection, the patients underwent a delayed-type hypersensitivity test. Serum Th1 cytokines [interleukin (IL)-2, IL-12, and interferon (IFN)-γ] and antigen-specific IFN-γCD8 T cells were tested before and after vaccination. Patients were followed up for 2 years. Adverse events were monitored. Patients in the vaccine group tolerated the DC vaccine. Levels of serum IL-2 (+92.4%), IL-12 (+70.9%), and IFN-γ (+214.3%) as well as the proportion of IFN-γCD8 T cells (3.0-16.4-fold) were significantly increased compared with baseline and the control group (all P<0.05). The 1- (82.1% vs. 50.0%, P=0.04) and 2-year survival (67.8% vs. 33.3%, P=0.04) was improved by vaccination. Only 2 patients showed mild fever. In conclusion, the DC vaccine triggered the specific immune response and induced the secretion of Th1 cytokines. The vaccine may lead to better survival, but this have to be confirmed. Adverse events were rare and mild. PMID 28125513

Immunosuppressive tumor-infiltrating myeloid cells mediate adaptive immune resistance via a PD-1/PD-L1 mechanism in glioblastoma.
Jan 2017 | Antonios, Joseph P; Soto, Horacio; Everson, Richard G; Moughon, Diana; Orpilla, Joey R; Shin, Namjo P; Sedighim, Shaina; Treger, Janet; Odesa, Sylvia; Tucker, Alexander; Yong, William H; Li, Gang; Cloughesy, Timothy F; Liau, Linda M; Prins, Robert M
Adaptive immune resistance in the tumor microenvironment appears to attenuate the immunotherapeutic targeting of glioblastoma (GBM). In this study, we identified a tumor-infiltrating myeloid cell (TIM) population that expands in response to dendritic cell (DC) vaccine treatment. The aim of this study was to understand how this programmed death ligand 1 (PD-L1)-expressing population restricts activation and tumor-cytolytic function of vaccine-induced tumor-infiltrating lymphocytes (TILs). PMID 28115578

Prostate cancer immunotherapy, particularly in combination with androgen deprivation or radiation treatment. Customized pharmacogenomic approaches to overcome immunotherapy cancer resistance.
Jan 2017 | Alberti, C
Conventional therapeutic approaches for advanced prostate cancer - such as androgen deprivation, chemotherapy, radiation - come up often against lack of effectiveness because of possible arising of correlative cancer cell resistance and/or inadequate anti-tumor immune conditions. Whence the timeliness of resorting to immune-based treatment strategies including either therapeutic vaccination-based active immunotherapy or anti-tumor monoclonal antibody-mediated passive immunotherapy. Particularly attractive, as for research studies and clinical applications, results to be the cytotoxic T-lymphocyte check point blockade by the use of anti-CTLA-4 and PD-1 monoclonal antibodies, particularly when combined with androgen deprivation therapy or radiation. Unlike afore said immune check point inhibitors, both cell-based (by the use of prostate specific antigen carriers autologous dendritic cells or even whole cancer cells) and recombinant viral vector vaccines are able to induce immune-mediated focused killing of specific antigen-presenting prostate cancer cells. Such vaccines, either used alone or concurrently/sequentially combined with above-mentioned conventional therapies, led to generally reach, in the field of various clinical trials, reasonable results particularly as regards the patient's overall survival. Adoptive trasferred T-cells, as adoptive T-cell passive immunotherapy, and monoclonal antibodies against specific antigen-endowed prostate cancer cells can improve immune micro-environmental conditions. On the basis of a preliminary survey about various immunotherapy strategies, are here also outlined their effects when combined with androgen deprivation therapy or radiation. What's more, as regard the immune-based treatment effectiveness, it has to be pointed out that suitable personalized epigenetic/gene profile-achieved pharmacogenomic approaches to target identified gene aberrations, may lead to overcome - as well as for conventional therapies - possible prostate cancer resistance to immunotherapy. PMID 28098061

A phase I clinical study of autologous dendritic cell therapy in patients with relapsed or refractory multiple myeloma.
Jan 2017 | Jung, Sung-Hoon; Lee, Hyun-Ju; Lee, Youn-Kyung; Yang, Deok-Hwan; Kim, Hyeoung-Joon; Rhee, Joon Haeng; Emmrich, Frank; Lee, Je-Jung
Cellular immunotherapy is emerging as a potential immunotherapeutic modality in multiple myeloma (MM). We have developed potent immunotherapeutic agent (VAX-DC/MM) generated by dendritic cells (DCs) loaded with autologous myeloma cells irradiated with ultraviolet B. In this study, we evaluated the safety and efficacy of VAX-DC/MM in patients with relapsed or refractory MM. This trial enrolled relapsed or refractory MM patients who had received both thalidomide- and bortezomib-based therapies. Patients received the intradermal VAX-DC/MM injection every week for 4 weeks. Patients were treated with 5 × 106 or 10 × 106 cells, with nine patients treated at a higher dose. The median time from diagnosis to VAX-DC/MM therapy was 56.6 months (range, 28.5-130.5). Patients had received a median of five prior treatments, and 75% had received autologous stem cell transplantation. VAX-DC therapy was well-tolerated, and the most frequent adverse events were local reactions at the injection site and infusion-related reactions. In seven of nine patients who received 10×106 cells, an immunological response (77.8%) was observed by interferon-gamma ELISPOT assay or a mixed lymphocyte reaction assay for T-cell proliferation. The clinical benefit rate was 66.7% including one (11.1%) with minor response and five (55.6%) with stable disease; three (33.3%) patients showed disease progression. In conclusion, VAX-DC/MM therapy was well-tolerated, and had disease-stabilizing activity in heavily pretreated MM cases. Further studies are needed to increase the efficacy of VAX-DC/MM in patients with MM. PMID 28088784

Feasibility study of DCs/CIKs combined with thoracic radiotherapy for patients with locally advanced or metastatic non-small-cell lung cancer.
Jan 2017 | Zhang, Luping; Xu, Yanmei; Shen, Jie; He, Feng; Zhang, Dan; Chen, Zhengtang; Duan, Yuzhong; Sun, Jianguo
The combination of dendritic cells (DCs) and cytokine-induced killer cells (CIKs) can induce the anti-tumor immune response and radiotherapy may promote the activity. We aimed to explore the feasibility of DCs/CIKs combined with thoracic radiotherapy (TRT) for patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). PMID 27097970

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of prostate carcinoma.
Dec 2016 | McNeel, Douglas G; Bander, Neil H; Beer, Tomasz M; Drake, Charles G; Fong, Lawrence; Harrelson, Stacey; Kantoff, Philip W; Madan, Ravi A; Oh, William K; Peace, David J; Petrylak, Daniel P; Porterfield, Hank; Sartor, Oliver; Shore, Neal D; Slovin, Susan F; Stein, Mark N; Vieweg, Johannes; Gulley, James L
Prostate cancer is the most commonly diagnosed malignancy and second leading cause of cancer death among men in the United States. In recent years, several new agents, including cancer immunotherapies, have been approved or are currently being investigated in late-stage clinical trials for the management of advanced prostate cancer. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel, including physicians, nurses, and patient advocates, to develop consensus recommendations for the clinical application of immunotherapy for prostate cancer patients. To do so, a systematic literature search was performed to identify high-impact papers from 2006 until 2014 and was further supplemented with literature provided by the panel. Results from the consensus panel voting and discussion as well as the literature review were used to rate supporting evidence and generate recommendations for the use of immunotherapy in prostate cancer patients. Sipuleucel-T, an autologous dendritic cell vaccine, is the first and currently only immunotherapeutic agent approved for the clinical management of metastatic castrate resistant prostate cancer (mCRPC). The consensus panel utilized this model to discuss immunotherapy in the treatment of prostate cancer, issues related to patient selection, monitoring of patients during and post treatment, and sequence/combination with other anti-cancer treatments. Potential immunotherapies emerging from late-stage clinical trials are also discussed. As immunotherapy evolves as a therapeutic option for the treatment of prostate cancer, these recommendations will be updated accordingly. PMID 28031820

Dendritic cell-based immunotherapy.
Dec 2016 | Sabado, Rachel L; Balan, Sreekumar; Bhardwaj, Nina
Immunotherapy using dendritic cell (DC)-based vaccination is an approved approach for harnessing the potential of a patient's own immune system to eliminate tumor cells in metastatic hormone-refractory cancer. Overall, although many DC vaccines have been tested in the clinic and proven to be immunogenic, and in some cases associated with clinical outcome, there remains no consensus on how to manufacture DC vaccines. In this review we will discuss what has been learned thus far about human DC biology from clinical studies, and how current approaches to apply DC vaccines in the clinic could be improved to enhance anti-tumor immunity. PMID 28025976

Immune response and long-term clinical outcome in advanced melanoma patients vaccinated with tumor-mRNA-transfected dendritic cells.
Dec 2016 | Kyte, Jon Amund; Aamdal, Steinar; Dueland, Svein; Sæbøe-Larsen, Stein; Inderberg, Else Marit; Madsbu, Ulf Erik; Skovlund, Eva; Gaudernack, Gustav; Kvalheim, Gunnar
The most effective anticancer immune responses are probably directed against patient-specific neoantigens. We have developed a melanoma vaccine targeting this individual mutanome based on dendritic cells (DCs) loaded with autologous tumor-mRNA. Here, we report a phase I/II trial evaluating toxicity, immune response and clinical outcome in 31 metastatic melanoma patients. The first cohort (n = 22) received the vaccine without any adjuvant; the next cohort (n = 9) received adjuvant IL2. Each subject received four weekly intranodal or intradermal injections, followed by optional monthly vaccines. Immune response was evaluated by delayed-type hypersensitivity (DTH), T cell proliferation and cytokine assays. Data were collected for 10 y after inclusion of the last patient. No serious adverse events were detected. In the intention-to-treat-cohort, we demonstrated significantly superior survival compared to matched controls from a benchmark meta-analysis (1 y survival 43% vs. 24%, 2 y 23% vs. 6.6%). A tumor-specific immune response was demonstrated in 16/31 patients. The response rate was higher after intradermal than intranodal vaccination (80% vs. 38%). Immune responders had improved survival compared to non-responders (median 14 mo vs. 6 mo; p = 0.030), and all eight patients surviving >20 mo were immune responders. In addition to the tumor-specific response, most patients developed a response against autologous DC antigens. The cytokine profile was polyfunctional and did not follow a Th1/Th2 dichotomy. We conclude that the favorable safety profile and evidence of a possible survival benefit warrant further studies of the RNA/DC vaccine. The vaccine appears insufficient as monotherapy, but there is a strong rationale for combination with checkpoint modulators. PMID 27999747

Novel vaccines for glioblastoma: clinical update and perspective.
Dec 2016 | Winograd, Evan K; Ciesielski, Michael J; Fenstermaker, Robert A
Glioblastoma is the most common primary brain cancer. Aggressive treatment with surgery, radiation therapy and chemotherapy provides limited overall survival benefit. Glioblastomas have a formidable tumor microenvironment that is hostile to immunological effector cells and these cancers produce profound systemic immunosuppression. However, surgical resection of these tumors creates conditions that favor the use of immunotherapeutic strategies. Therefore, extensive surgical resection, when feasible, will remain part of the equation to provide an environment in which active specific immunotherapy has the greatest chance of working. Toward that end, a number of vaccination protocols are under investigation. Vaccines studied to date have produced cellular and humoral antitumor responses, but unequivocal clinical efficacy has yet to be demonstrated. In addition, focus is shifting toward the prospect of therapies involving vaccines in combination with immune checkpoint inhibitors and other immunomodulatory agents so that effector cells remain active against their targets systemically and within the tumor microenvironment. PMID 27993092

Dendritic Cell Vaccination Enhances Immune Responses and Induces Regression of HER2pos DCIS Independent of Route: Results of Randomized Selection Design Trial.
Dec 2016 | Lowenfeld, Lea; Mick, Rosemarie; Datta, Jashodeep; Xu, Shuwen; Fitzpatrick, Elizabeth; Fisher, Carla S; Fox, Kevin R; DeMichele, Angela; Zhang, Paul; Weinstein, Susan; Roses, Robert E; Czerniecki, Brian J
Vaccination with HER2 peptide-pulsed DC1s stimulates a HER2 specific T-cell response. This randomized trial aimed to establish safety and evaluate immune and clinical responses to vaccination via intralesional (IL), intranodal (IN), or both intralesional and intranodal (ILN) injection. PMID 27965306

Individualized vaccination of AML patients in remission is associated with induction of antileukemia immunity and prolonged remissions.
Dec 2016 | Rosenblatt, Jacalyn; Stone, Richard M; Uhl, Lynne; Neuberg, Donna; Joyce, Robin; Levine, James D; Arnason, Jon; McMasters, Malgorzata; Luptakova, Katarina; Jain, Salvia; Zwicker, Jeffrey I; Hamdan, Ayad; Boussiotis, Vassiliki; Steensma, David P; DeAngelo, Daniel J; Galinsky, Ilene; Dutt, Poorvi Somaiya; Logan, Emma; Bryant, Mary Paty; Stroopinsky, Dina; Werner, Lillian; Palmer, Kristen; Coll, Max; Washington, Abigail; Cole, Leandra; Kufe, Donald; Avigan, David
We developed a personalized cancer vaccine in which patient-derived acute myeloid leukemia (AML) cells are fused with autologous dendritic cells, generating a hybridoma that potently stimulates broad antitumor responses. We report results obtained from the first 17 AML patients, who achieved remission after chemotherapy and were then serially vaccinated to target minimal residual disease and prevent relapse. Vaccination was well tolerated and induced inflammatory responses at the site of administration, characterized by the dense infiltration of T cells. Vaccination was also associated with a marked rise in circulating T cells recognizing whole AML cells and leukemia-specific antigens that persisted for more than 6 months. Twelve of 17 vaccinated patients (71%; 90% confidence interval, 52 to 89%) remain alive without recurrence at a median follow-up of 57 months. The results demonstrate that personalized vaccination of AML patients in remission induces the expansion of leukemia-specific T cells and may be protective against disease relapse. PMID 27928025

Lenalidomide enhances the function of dendritic cells generated from patients with multiple myeloma.
Nov 2016 | Vo, Manh-Cuong; Anh-NguyenThi, Truc; Lee, Hyun-Ju; Nguyen-Pham, Thanh-Nhan; Jaya Lakshmi, Thangaraj; Jung, Sung-Hoon; Kim, Hyeoung-Joon; Lee, Je-Jung
Lenalidomide (LEN) has been used as an immunomodulatory drug with direct and indirect anti-tumor effects. In this study, we evaluated the effect of LEN on the differentiation, maturation, and function of dendritic cells (DCs) in patients with multiple myeloma in vitro. Various doses of LEN were added after the monocytes had differentiated into immature DCs and were activated into mature DCs. LEN (5 μg/mL) was the optimal concentration to promote differentiation and maturation of DCs. Immature DCs treated with LEN exhibited enhanced endocytic capacity. Mature DCs treated with LEN produced higher levels of interleukin-12p70, possessed stronger allogeneic T-cell stimulation capacity, reduced the number of suppressor cells, and generated antigen-specific cytotoxic T lymphocytes more potently compared with control DCs. These results suggest that LEN enhanced the function of DCs generated from patients with multiple myeloma by stimulating the capacity of allogeneic T cells, inhibiting the generation of immunosuppressive cells, inducing naïve T cells toward Th1 polarization, and generating potent myeloma-specific cytotoxic T lymphocytes. PMID 27889516

Role of Immunotherapy in Targeting the Bone Marrow Microenvironment in Multiple Myeloma: An Evolving Therapeutic Strategy.
Nov 2016 | Chung, Clement
Multiple myeloma (referred to henceforth as myeloma) is a B-cell malignancy characterized by unregulated growth of plasma cells in the bone marrow. The treatment paradigm for myeloma underwent significant evolution in the last decade, with an improved understanding of the pathogenesis of the disease as well as the development of therapeutic agents that target not only the tumor cells but also their microenvironment. Despite these therapeutic advances, the prognosis of patients with relapsed or refractory myeloma remains poor. Accordingly, a need exists for new therapeutic avenues that can overcome resistance to current therapies and improve survival outcomes. In addition, myeloma is associated with progressive immune dysregulation, with defects in T-cell immunity, natural killer cell function, and the antigen-presenting capacity of dendritic cells, resulting in a tumor microenvironment that promotes disease tolerance and progression. Together, the immunosuppressive microenvironment and oncogenic mutations activate signaling networks that promote myeloma cell survival. Immunotherapy incorporates novel treatment options (e.g., monoclonal antibodies, antibody-drug conjugates, chimeric antigen receptor T-cell therapy, immune checkpoint inhibitors, bispecific antibodies, and tumor vaccines) either alone or in combination with existing lines of therapies (e.g., immunomodulatory agents, proteasome inhibitors, and histone deacetylase inhibitors) to enhance the host anti myeloma immunity within the bone marrow microenvironment and improve clinical response. Following the U.S. Food and Drug Administration approval of daratumumab and elotuzumab in 2015, more immunotherapeutic agents are expected to be become available as valuable treatment options in the near future. This review provides a basic understanding of the role of immunotherapy in modulating the bone marrow tumor microenvironment and its role in the treatment of myeloma. Clinical efficacy and safety of recently approved therapeutic monoclonal antibodies (daratumumab, elotuzumab) are discussed, along with the therapeutic potential of emerging immunotherapies (antibody-drug conjugates, chimeric antigen receptor T-cell therapy, tumor vaccines, and immune checkpoint inhibitors). PMID 27870103

Efficacy of host-dendritic cell vaccinations with or without minor histocompatibility antigen loading, combined with donor lymphocyte infusion in multiple myeloma patients.
Nov 2016 | Oostvogels, R; Kneppers, E; Minnema, M C; Doorn, R C; Franssen, L E; Aarts, T; Emmelot, M E; Spierings, E; Slaper-Cortenbach, I; Westinga, K; Goulmy, E; Lokhorst, H M; Mutis, T
Donor lymphocyte infusions (DLI) can induce durable remissions in multiple myeloma (MM) patients, but this occurs rather infrequently. As the graft-versus-tumor (GvT) effect of DLI depends on the presence of host-dendritic cells (DCs), we tested in a phase I/II trial whether the efficacy of DLI could be improved by simultaneous vaccination with host-DCs. We also analyzed the possibility of further improving the GvT effect by loading the DCs with peptides of mismatched hematopoietic cell-specific minor histocompatibility antigens (mHags). Fifteen MM patients not responding to a first DLI were included. Eleven patients could be treated with a second equivalent dose DLI combined with DC vaccinations, generated from host monocytes (moDC). For four patients, the DC products did not meet the quality criteria. In four of the treated patients the DCs were loaded with host mHag peptides. Toxicity was limited and no acute GvHD occurred. Most patients developed objective anti-host T-cell responses and in one patient a distinct mHag-specific T-cell response accompanied a temporary clinical response. These findings confirm that DLI combined with host-DC vaccination, either unloaded or loaded with mHag peptides, is feasible, safe and capable of inducing host-specific T-cell responses. The limited clinical effects may be improved by developing more immunogenic DC products or by combining this therapy with immune potentiating modalities like checkpoint inhibitors. PMID 27841858

Dendritic Cells and Cancer Immunity.
Oct 2016 | Gardner, Alycia; Ruffell, Brian
Dendritic cells (DCs) are central regulators of the adaptive immune response, and as such are necessary for T-cell-mediated cancer immunity. In particular, antitumoral responses depend on a specialized subset of conventional DCs that transport tumor antigens to draining lymph nodes and cross-present antigen to activate cytotoxic T lymphocytes. DC maturation is necessary to provide costimulatory signals to T cells, but while DC maturation occurs within tumors, it is often insufficient to induce potent immunity, particularly in light of suppressive mechanisms within tumors. Bypassing suppressive pathways or directly activating DCs can unleash a T-cell response, and although clinical efficacy has proven elusive, therapeutic targeting of DCs continues to hold translational potential in combinatorial approaches. PMID 27793569

Phase I/II trial of combination of temozolomide chemotherapy and immunotherapy with fusions of dendritic and glioma cells in patients with glioblastoma.
Sep 2016 | Akasaki, Yasuharu; Kikuchi, Tetsuro; Homma, Sadamu; Koido, Shigeo; Ohkusa, Toshifumi; Tasaki, Tetsunori; Hayashi, Kazumi; Komita, Hideo; Watanabe, Nobuyuki; Suzuki, Yuta; Yamamoto, Yohei; Mori, Ryosuke; Arai, Takao; Tanaka, Toshihide; Joki, Tatsuhiro; Yanagisawa, Takaaki; Murayama, Yuichi
This trial was designed to evaluate the safety and clinical responses to a combination of temozolomide (TMZ) chemotherapy and immunotherapy with fusions of DCs and glioma cells in patients with glioblastoma (GBM). PMID 27688162

Adjuvant Dendritic Cell Vaccination in High-Risk Uveal Melanoma.
Sep 2016 | Bol, Kalijn F; van den Bosch, Thomas; Schreibelt, Gerty; Mensink, Hanneke W; Keunen, Jan E E; Kiliç, Emine; Japing, Wouter J; Geul, Kaspar W; Westdorp, Harm; Boudewijns, Steve; Croockewit, Sandra A J; van Rossum, Michelle M; de Goede, Anna L; Naus, Nicole C; van der Graaf, Winette T A; Gerritsen, Winald R; de Klein, Annelies; Punt, Cornelis J A; Figdor, Carl G; Cohen, Victoria M; Paridaens, Dion; de Vries, I Jolanda M
PMID 27476772

Induction of Immune Response after Allogeneic Wilms' Tumor 1 Dendritic Cell Vaccination and Donor Lymphocyte Infusion in Patients with Hematologic Malignancies and Post-Transplantation Relapse.
Sep 2016 | Shah, Nirali N; Loeb, David M; Khuu, Hahn; Stroncek, David; Ariyo, Tolu; Raffeld, Mark; Delbrook, Cindy; Mackall, Crystal L; Wayne, Alan S; Fry, Terry J
Relapse of hematologic malignancies is the primary cause of treatment failure after allogeneic hematopoietic stem cell transplantation (HCT). Treatment for post-HCT relapse using donor lymphocyte infusion (DLI) has limited utility, particularly in the setting of acute leukemia, and can result in the development of graft-versus-host disease (GVHD). The Wilms' tumor 1 (WT1) gene product is a tumor-associated antigen that is expressed in acute leukemia and other hematologic malignancies, with limited expression in normal tissues. In this pilot trial, we assessed safety and feasibility of a WT1 peptide-loaded donor-derived dendritic cell (DC) vaccine given with DLI designed to enhance and direct the graft-versus-leukemia effect. Secondary objectives were to evaluate immunologic and clinical responses. A total of 5 subjects, median age 17 years (range, 9 to 19 years), with post-HCT relapse were enrolled. Disease subtypes included acute lymphoblastic leukemia (n = 3), acute myelogenous leukemia (n = 1), and Hodgkin lymphoma (n = 1). Successful vaccine production was feasible from all donors. DC vaccination and DLI were well tolerated. One recipient developed grade 1 skin GVHD not requiring systemic therapy. The most common adverse events included grade 1 reversible pain and pruritus at the vaccine injection and delayed-type hypersensitivity (DTH) skin testing sites. There were no grade 3 or higher adverse events related to the research. Immune responses consisted of ELISpot response in 3 recipients and positive DTH tests to WT1 peptide cocktail in 2 subjects. Our study provides 1 of the first attempts to apply tumor-specific vaccine therapy to the allogeneic setting. Preliminary results show the DC-based vaccination is safe and feasible after allogeneic HCT, with a suggestion that this approach can be used to sensitize the repopulated allogeneic-donor immune system to WT1. Future directions may include testing of vaccination strategies in the early post-transplantation setting for relapse prevention. PMID 27634018

Recent advances in immuno-oncology and its application to urological cancers.
Sep 2016 | Mataraza, Jennifer M; Gotwals, Philip
Recent advances in immuno-oncology have the potential to transform the practice of medical oncology. Antibodies directed against negative regulators of T-cell function (checkpoint inhibitors), engineered cell therapies and innate immune stimulators, such as oncolytic viruses, are effective in a wide range of cancers. Immune'based therapies have had a clinically meaningful impact on the treatment of advanced melanoma, and the lessons regarding use of single agents and combinations in melanoma may be applicable to the treatment of urological cancers. Checkpoint inhibitors, cytokine therapy and therapeutic vaccines are already showing promise in urothelial bladder cancer, renal cell carcinoma and prostate cancer. Critical areas of future immuno-oncology research include the prospective identification of patients who will respond to current immune-based cancer therapies and the identification of new therapeutic agents that promote immune priming in tumours, and increase the rate of durable clinical responses. PMID 27123757

Adjuvant dendritic cell vaccination induces tumor-specific immune responses in the majority of stage III melanoma patients.
Sep 2016 | Boudewijns, Steve; Bol, Kalijn F; Schreibelt, Gerty; Westdorp, Harm; Textor, Johannes C; van Rossum, Michelle M; Scharenborg, Nicole M; de Boer, Annemiek J; van de Rakt, Mandy W M M; Pots, Jeanne M; van Oorschot, Tom G M; Duiveman-de Boer, Tjitske; Olde Nordkamp, Michel A; van Meeteren, Wilmy S E C; van der Graaf, Winette T A; Bonenkamp, Johannes J; de Wilt, Johannes H W; Aarntzen, Erik H J G; Punt, Cornelis J A; Gerritsen, Winald R; Figdor, Carl G; de Vries, I Jolanda M
To determine the effectiveness of adjuvant dendritic cell (DC) vaccination to induce tumor-specific immunological responses in stage III melanoma patients. PMID 27622047

A phase I clinical study of immunotherapy for advanced colorectal cancers using carcinoembryonic antigen-pulsed dendritic cells mixed with tetanus toxoid and subsequent IL-2 treatment.
Aug 2016 | Liu, Ko-Jiunn; Chao, Tsu-Yi; Chang, Jang-Yang; Cheng, Ann-Lii; Ch'ang, Hui-Ju; Kao, Woei-Yau; Wu, Yu-Chen; Yu, Wei-Lan; Chung, Tsai-Rong; Whang-Peng, Jacqueline
To better evaluate and improve the efficacy of dendritic cell (DC)-based cancer immunotherapy, we conducted a clinical study of patients with advanced colorectal cancer using carcinoembryonic antigen (CEA)-pulsed DCs mixed with tetanus toxoid and subsequent interleukin-2 treatment. The tetanus toxoid in the vaccine preparation serves as an adjuvant and provides a non-tumor specific immune response to enhance vaccine efficacy. The aims of this study were to (1) evaluate the toxicity of this treatment, (2) observe the clinical responses of vaccinated patients, and (3) investigate the immune responses of patients against CEA before and after treatment. PMID 27558635

Lung adenocarcinoma may be a more susceptive subtype to a dendritic cell-based cancer vaccine than other subtypes of non-small cell lung cancers: a multicenter retrospective analysis.
Aug 2016 | Takahashi, Hidenori; Shimodaira, Shigetaka; Ogasawara, Masahiro; Ota, Shuichi; Kobayashi, Masanori; Abe, Hirofumi; Morita, Yuji; Nagai, Kazuhiro; Tsujitani, Shunichi; Okamoto, Masato; Suzuki, Yukio; Nakanishi, Yoichi; Yonemitsu, Yoshikazu; ,
The J-SICT DC Vaccine Study Group provides dendritic cell (DC) vaccines for compassionate use under unified cell production and patient treatment regimens. We previously reported beneficial effects of DC vaccines on the overall survival of 62 patients with advanced non-small cell lung cancer (NSCLC) in a single-center analysis. Here, we extended analysis to 260 patients with NSCLC who were treated at six centers. PMID 27448677

Immunotherapy in atypical teratoid-rhabdoid tumors: Data from a survey of the HGG-Immuno Group.
Aug 2016 | van Gool, Stefaan W; Holm, Stefan; Rachor, Johannes; Adamson, Lars; Technau, Antje; Maass, Eberhard; Frühwald, Michael C; Schlegel, Paul G; Eyrich, Matthias
Atypical rhabdoid/teratoid tumors (AT/RT) are the most common brain tumors in infants and associated with a dismal prognosis. Although intensification of first-line therapy has resulted in improvement of overall survival, novel treatment strategies are needed. Because immunotherapy has resulted in remarkable results in several adult tumor entities, incorporation of immunotherapy into AT/RT treatment offers a novel alternative. PMID 27421737

Diversification of Antitumour Immunity in a Patient with Metastatic Melanoma Treated with Ipilimumab and an IDO-Silenced Dendritic Cell Vaccine.
Aug 2016 | Sioud, Mouldy; Nyakas, Marta; Sæbøe-Larssen, Stein; Mobergslien, Anne; Aamdal, Steinar; Kvalheim, Gunnar
Indoleamine 2,3-dioxygenase (IDO) expression in dendritic cells (DCs) inhibits T-cell activation and promotes T-cell differentiation into regulatory T-cells. Moreover, IDO expression promotes resistance to immunotherapies targeting immune checkpoints such as the cytotoxic T lymphocyte antigen-4 (CTLA-4). Here, a patient with metastatic melanoma pretreated with ipilimumab, an anti-CTLA-4 blocking antibody, was vaccinated with IDO-silenced DCs cotransfected with mRNA for survivin or hTERT tumour antigens. During vaccination, T-cell responses to survivin and hTERT tumour antigens were generated, and a certain degree of clinical benefit was achieved, with a significant reduction in lung, liver, and skin metastases, along with a better performance status. T-cell responses against MART-1 and NY-ESO-1 tumour antigens were also detected in the peripheral blood. The patient also mounted an antibody response to several melanoma proteins, indicating diversification of the antitumour immunity in this patient. The identification of such serum antibody-reacting proteins could facilitate the discovery of tumour neoantigens. PMID 27504122

Targeting breast cancer stem cells by dendritic cell vaccination in humanized mice with breast tumor: preliminary results.
Aug 2016 | Pham, Phuc Van; Le, Hanh Thi; Vu, Binh Thanh; Pham, Viet Quoc; Le, Phong Minh; Phan, Nhan Lu-Chinh; Trinh, Ngu Van; Nguyen, Huyen Thi-Lam; Nguyen, Sinh Truong; Nguyen, Toan Linh; Phan, Ngoc Kim
Breast cancer (BC) is one of the leading cancers in women. Recent progress has enabled BC to be cured with high efficiency. However, late detection or metastatic disease often renders the disease untreatable. Additionally, relapse is the main cause of death in BC patients. Breast cancer stem cells (BCSCs) are considered to cause the development of BC and are thought to be responsible for metastasis and relapse. This study aimed to target BCSCs using dendritic cells (DCs) to treat tumor-bearing humanized mice models. PMID 27499638

Dendritic cell vaccination in melanoma patients: From promising results to future perspectives.
Jul 2016 | Boudewijns, Steve; Bloemendal, Martine; Gerritsen, Winald R; de Vries, I Jolanda M; Schreibelt, Gerty
Dendritic cells (DCs) play an important role in the induction of antitumor immunity. Therefore, they are used as anti-cancer vaccines in clinical studies in various types of cancer. DC vaccines are generally well tolerated and able to induce antigen-specific T cell responses in melanoma patients. After DC vaccinations, functional tumor-specific T cells are more frequently detected in stage III melanoma patients, as compared to patients with advanced melanoma, indicating that the tumor load influences immunological responses. Furthermore, long-lasting clinical responses were rarely seen in metastatic melanoma patients after DC vaccination. Since more potent treatment options are available, e.g. immune checkpoint inhibitors and targeted therapy, DC vaccination as monotherapy may not be preferred in the treatment of advanced melanoma. However, encouraging results of DC vaccines combined with ipilimumab have been reported in advanced melanoma patients with an objective response rate of 38%. DC vaccines show promising clinical results in stage III patients, although clinical efficacy still needs to be proven in a phase 3 trial. The clinical and immunological results of DC vaccination in stage III melanoma patients might be further improved by using naturally circulating DCs (myeloid DCs and plasmacytoid DCs) and neoantigens to load DCs. PMID 27322496

PD-1 blockade enhances the vaccination-induced immune response in glioma.
Jul 2016 | Antonios, Joseph P; Soto, Horacio; Everson, Richard G; Orpilla, Joey; Moughon, Diana; Shin, Namjo; Sedighim, Shaina; Yong, William H; Li, Gang; Cloughesy, Timothy F; Liau, Linda M; Prins, Robert M
DC vaccination with autologous tumor lysate has demonstrated promising results for the treatment of glioblastoma (GBM) in preclinical and clinical studies. While the vaccine appears capable of inducing T cell infiltration into tumors, the effectiveness of active vaccination in progressively growing tumors is less profound. In parallel, a number of studies have identified negative costimulatory pathways, such as programmed death 1/programmed death ligand 1 (PD-1/PD-L1), as relevant mediators of the intratumoral immune responses. Clinical responses to PD-1 pathway inhibition, however, have also been varied. To evaluate the relevance to established glioma, the effects of PD-1 blockade following DC vaccination were tested in intracranial (i.c.) glioma tumor- bearing mice. Treatment with both DC vaccination and PD-1 mAb blockade resulted in long-term survival, while neither agent alone induced a survival benefit in animals with larger, established tumors. This survival benefit was completely dependent on CD8(+) T cells. Additionally, DC vaccine plus PD-1 mAb blockade resulted in the upregulation of integrin homing and immunologic memory markers on tumor-infiltrating lymphocytes (TILs). In clinical samples, DC vaccination in GBM patients was associated with upregulation of PD-1 expression in vivo, while ex vivo blockade of PD-1 on freshly isolated TILs dramatically enhanced autologous tumor cell cytolysis. These findings strongly suggest that the PD-1/PD-L1 pathway plays an important role in the adaptive immune resistance of established GBM in response to antitumor active vaccination and provide us with a rationale for the clinical translation of this combination therapy. PMID 27453950

PI3K/Akt/mTOR Signaling and Plasma Membrane Proteins Are Implicated in Responsiveness to Adjuvant Dendritic Cell Vaccination for Metastatic Colorectal Cancer.
Jul 2016 | Qian, David C; Xiao, Xiangjun; Byun, Jinyoung; Suriawinata, Arief A; Her, Stephanie C; Amos, Christopher I; Barth, Richard J
We have previously demonstrated that patients with metastatic colorectal cancer who exhibit immune responses to a dendritic cell (DC) vaccine have superior recurrence-free survival following surgery, compared with patients in whom responses do not occur. We sought to characterize the patterns of T-lymphocyte infiltration and somatic mutations in metastases that are associated with and predictive of response to the DC vaccine. PMID 27435399

NK Cell Activation in the Antitumor Response Induced by IFN-α Dendritic Cells Loaded with Apoptotic Cells from Follicular Lymphoma Patients.
Jul 2016 | Lapenta, Caterina; Donati, Simona; Spadaro, Francesca; Castaldo, Paolo; Belardelli, Filippo; Cox, Maria C; Santini, Stefano M
Follicular lymphoma (FL) is the most common form of indolent non-Hodgkin lymphoma. This malignancy is considered virtually incurable, with high response rates to therapy but frequent relapses. We investigated the ability of monocyte-derived dendritic cells generated in the presence of IFN-α and GM-CSF (IFN-DC) and loaded with apoptotic lymphoma cells to activate immune responses against FL cells, with the ultimate goal of designing novel patient-specific vaccination strategies for the treatment of FL. In this article, we show that apoptotic tumor cell-loaded IFN-DC from FL patients, which were cultured for 2 wk with autologous lymphocytes, led to Th1 response skewing, based on significantly higher levels of IFN-γ production and a remarkable increase in CD8(+) and NK cell frequency, consistent with the detection of enhanced cytotoxic effector function toward autologous FL cells. IFN-DC were found to promote efficient NK cell activation, increased expression of cytotoxicity receptors, and extensive IFN-γ production in the virtual absence of IL-10. Moreover, direct recognition and killing of primary autologous lymphoma cells by activated NK cells from FL patients was also demonstrated. A critical role was demonstrated for MHC class I-related chain A and B and membrane-bound IL-15 in IFN-DC-mediated NK cell activation and early IFN-γ production. The overall results indicate that IFN-DC loaded with autologous apoptotic FL cells represent a valuable tool for improving the potency of therapeutic cancer vaccines through the efficient induction of NK cell activation and promotion of CD8(+) T cell antitumor immunity. PMID 27357153

A Perspective of Immunotherapy for Prostate Cancer.
Jul 2016 | Silvestri, Ida; Cattarino, Susanna; Giantulli, Sabrina; Nazzari, Cristina; Collalti, Giulia; Sciarra, Alessandro
In cancer patients, the immune system is often altered with an excess of inhibitory factors, such as immunosuppressive cytokines, produced by regulatory T cells (Treg) or myeloid-derived suppressor cells (MDSC). The manipulation of the immune system has emerged as one of new promising therapies for cancer treatment, and also represents an attractive strategy to control prostate cancer (PCa). Therapeutic cancer vaccines and immune checkpoint inhibitors have been the most investigated in clinical trials. Many trials are ongoing to define the effects of immune therapy with established treatments: androgen deprivation therapy (ADT) and chemotherapy (CT) or radiotherapy (RT). This article discusses some of these approaches in the context of future treatments for PCa. PMID 27399780

Immunotherapy for human papillomavirus-associated disease and cervical cancer: review of clinical and translational research.
Jul 2016 | Lee, Sung Jong; Yang, Andrew; Wu, T C; Hung, Chien Fu
Cervical cancer is the fourth most lethal women's cancer worldwide. Current treatments against cervical cancer include surgery, radiotherapy, chemotherapy, and anti-angiogenic agents. However, despite the various treatments utilized for the treatment of cervical cancer, its disease burden remains a global issue. Persistent infection of human papillomavirus (HPV) has been identified as an essential step of pathogenesis of cervical cancer and many other cancers, and nation-wide HPV screening as well as preventative HPV vaccination program have been introduced globally. However, even though the commercially available prophylactic HPV vaccines, Gardasil (Merck) and Cervarix (GlaxoSmithKline), are effective in blocking the entry of HPV into the epithelium of cervix through generation of HPV-specific neutralizing antibodies, they cannot eliminate the pre-existing HPV infection. For these reason, other immunotherapeutic options against HPV-associated diseases, including therapeutic vaccines, have been continuously explored. Therapeutic HPV vaccines enhance cell-mediated immunity targeting HPV E6 and E7 antigens by modulating primarily dendritic cells and cytotoxic T lymphocyte. Our review will cover various therapeutic vaccines in development for the treatment of HPV-associated lesions and cancers. Furthermore, we will discuss the potential of immune checkpoint inhibitors that have recently been adopted and tested for their treatment efficacy against HPV-induced cervical cancer. PMID 27329199

Immunological Aspects of Malignant Gliomas.
Jun 2016 | Cohen-Inbar, Or; Zaaroor, Menashe
Glioblastoma Multiforme (GBM) is the most common malignant primary brain neoplasm having a mean survival time of <24 months. This figure remains constant, despite significant progress in medical research and treatment. The lack of an efficient anti-tumor immune response and the micro-invasive nature of the glioma malignant cells have been explained by a multitude of immune-suppressive mechanisms, proven in different models. These immune-resistant capabilities of the tumor result in a complex interplay this tumor shares with the immune system. We present a short review on the immunology of GBM, discussing the different unique pathological and molecular features of GBM, current treatment modalities, the principles of cancer immunotherapy and the link between GBM and melanoma. Current knowledge on immunological features of GBM, as well as immunotherapy past and current clinical trials, is discussed in an attempt to broadly present the complex and formidable challenges posed by GBM. PMID 27324313

Progress of dendritic cell-based cancer vaccines for patients with hematological malignancies.
Jun 2016 | Ni, Ming; Hoffmann, Jean-Marc; Schmitt, Michael; Schmitt, Anita
Dendritic cells (DCs) are the most professional antigen-presenting cells eliciting cellular and humoral immune responses against cancer cells by expressing these antigens on MHC class I/II complexes to T cells. Therefore, they have been employed in many clinical trials as cancer vaccines for patients with cancer. This review focuses on the use of DCs in leukemia patients expressing leukemia-associated antigens (LAAs). PMID 27238400

T cell landscape in a primary melanoma predicts the survival of patients with metastatic disease after their treatment with dendritic cell vaccines.
May 2016 | Vasaturo, Angela; Halilovic, Altuna; Bol, Kalijn F; Verweij, Dagmar I; Blokx, Willeke A M; Punt, Cornelis J A; Groenen, Patricia J T A; van Krieken, Han J H J M; Textor, Johannes; de Vries, I Jolanda M; Figdor, Carl G
Tumor infiltrating lymphocytes appear to be a predictor of survival in many cancers, including cutaneous melanoma. We applied automated multispectral imaging to determine whether density and distribution of T cells within primary cutaneous melanoma tissue correlate with survival of metastatic melanoma patients after dendritic cell (DC) vaccination. CD3+ T cells infiltration in primary tumors from 77 metastatic melanoma patients was quantified using the ratio of intratumoral versus peritumoral T cell densities (I/P ratio). Patients with longer survival after DC vaccination had stronger T cell infiltration than patients with shorter survival in a discovery cohort of 19 patients (p=0.000026) and a validation cohort of 39 patients (p=0.000016). I/P ratio was the strongest predictor of survival in a multivariate analysis including M substage and serum LDH level. To evaluate I/P ratio as a predictive biomarker, we analyzed 19 chemotherapy-treated patients. Longer survival times of DC-vaccinated compared to chemotherapy-treated patients was observed for high (p=0.000566), but not low (p=0.154) I/P ratios. In conclusion, T cell infiltration into primary melanoma is a strong predictor of survival after DC vaccination in metastatic melanoma patients who, on average, started this therapy several years after primary tumor resection. The infiltration remains predictive even after adjustment for late-stage prognostic markers. Our findings suggest that the I/P ratio is a potential predictive biomarker for treatment selection. PMID 27197179

Dendritic cell-based cancer immunotherapy for colorectal cancer.
May 2016 | Kajihara, Mikio; Takakura, Kazuki; Kanai, Tomoya; Ito, Zensho; Saito, Keisuke; Takami, Shinichiro; Shimodaira, Shigetaka; Okamoto, Masato; Ohkusa, Toshifumi; Koido, Shigeo
Colorectal cancer (CRC) is one of the most common cancers and a leading cause of cancer-related mortality worldwide. Although systemic therapy is the standard care for patients with recurrent or metastatic CRC, the prognosis is extremely poor. The optimal sequence of therapy remains unknown. Therefore, alternative strategies, such as immunotherapy, are needed for patients with advanced CRC. This review summarizes evidence from dendritic cell-based cancer immunotherapy strategies that are currently in clinical trials. In addition, we discuss the possibility of antitumor immune responses through immunoinhibitory PD-1/PD-L1 pathway blockade in CRC patients. PMID 27158196

Dendritic Cell-Based Immunotherapy: State of the Art and Beyond.
Apr 2016 | Bol, Kalijn F; Schreibelt, Gerty; Gerritsen, Winald R; de Vries, I Jolanda M; Figdor, Carl G
Dendritic cell (DC) vaccination in cancer patients aims to induce or augment an effective antitumor immune response against tumor antigens and was first explored in a clinical trial in the 1990s. More than two decades later, numerous clinical trials have been performed or are ongoing with a wide variety of DC subsets, culture protocols, and treatment regimens. The safety of DC vaccination and its ability to induce antitumor responses have clearly been established; however, although scattered patients with long-term benefit were reported, DC vaccines have not yet fulfilled their promise, perhaps mainly due to the lack of large-scale well-conducted phase II/III trials. To allow meaningful multicenter phase III trials, the production of DC vaccines should be standardized between centers which is now becoming feasible. To improve the efficacy of DC-based immunotherapy, it could be combined with other treatments.Clin Cancer Res; 22(8); 1897-906. ©2016 AACR SEE ALL ARTICLES IN THIS CCR FOCUS SECTION, "OPPORTUNITIES AND CHALLENGES IN CANCER IMMUNOTHERAPY". PMID 27084743

Dendritic cell vaccine and cytokine-induced killer cell therapy for the treatment of advanced non-small cell lung cancer.
Apr 2016 | Zhang, Lihong; Yang, Xuejing; Sun, Zhen; Li, Jiali; Zhu, Hui; Li, Jing; Pang, Yan
The present study aimed to evaluate the survival time, immune response and safety of a dendritic cell (DC) vaccine and cytokine-induced killer (CIK) cell therapy (DC-CIK) in advanced non-small cell lung cancer (NSCLC). The present retrospective study enrolled 507 patients with advanced NSCLC; 99 patients received DC-CIK [immunotherapy group (group I)] and 408 matched patients did not receive DC-CIK, and acted as the control [non-immunotherapy group (group NI)]. Delayed-type hypersensitivity (DTH), quality of life (QOL) and safety were analyzed in group I. The follow-up period for the two groups was 489.2±160.4 days. The overall survival (OS) time was calculated using the Kaplan-Meier method. DTH was observed in 59 out of 97 evaluated patients (60.8%) and 67 out of 98 evaluated patients (68.4%) possessed an improved QOL. Fever and a skin rash occurred in 36 out of 98 patients (36.7%) and 7 out of 98 patients (7.1%) in group I. DTH occurred more frequently in patients with squamous cell carcinoma compared with patients with adenocarcinoma (77.1 vs. 40.4%; P=0.0013). Radiotherapy was not associated with DC-CIK-induced DTH (72.7 vs. 79.6%; P=0.18), but chemotherapy significantly reduced the rate of DTH (18.2 vs. 79.6%; P=0.00). The OS time was significantly increased in group I compared with group NI (P=0.03). In conclusion, DC-CIK may induce an immune response against NSCLC, improve the QOL, and prolong the OS time of patients, without adverse effects. Therefore, the present study recommends DC-CIK for the treatment of patients with advanced NSCLC. PMID 27073525

Irradiation of necrotic cancer cells, employed for pulsing dendritic cells (DCs), potentiates DC vaccine-induced antitumor immunity against high-grade glioma.
Apr 2016 | Vandenberk, Lien; Garg, Abhishek D; Verschuere, Tina; Koks, Carolien; Belmans, Jochen; Beullens, Monique; Agostinis, Patrizia; De Vleeschouwer, Steven; Van Gool, Stefaan W
Dendritic cell (DC)-based immunotherapy has yielded promising results against high-grade glioma (HGG). However, the efficacy of DC vaccines is abated by HGG-induced immunosuppression and lack of attention toward the immunogenicity of the tumor lysate/cells used for pulsing DCs. A literature analysis of DC vaccination clinical trials in HGG patients delineated the following two most predominantly applied methods for tumor lysate preparation: freeze-thaw (FT)-induced necrosis or FT-necrosis followed by X-ray irradiation. However, from the available clinical evidence, it is unclear which of both methodologies has superior immunogenic potential. Using an orthotopic HGG murine model (GL261-C57BL/6), we observed that prophylactic vaccination with DCs pulsed with irradiated FT-necrotic cells (compared to FT-necrotic cells only) prolonged overall survival by increasing tumor rejection in glioma-challenged mice. This was associated, both in prophylactic and curative vaccination setups, with an increase in brain-infiltrating Th1 cells and cytotoxic T lymphocytes (CTL), paralleled by a reduced accumulation of regulatory T cells, tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC). Further analysis showed that irradiation treatment of FT-necrotic cells considerably increased the levels of carbonylated proteins - a surrogate-marker of oxidation-associated molecular patterns (OAMPs). Through further application of antioxidants and hydrogen peroxide, we found a striking correlation between the amount of lysate-associated protein carbonylation/OAMPs and DC vaccine-mediated tumor rejection capacity thereby suggesting for the first time a role for protein carbonylation/OAMPs in at least partially mediating antitumor immunity. Together, these data strongly advocate the use of protein oxidation-inducing modalities like irradiation for increasing the immunogenicity of tumor lysate/cells used for pulsing DC vaccines. PMID 27057467

Antigen-specific T cell response from dendritic cell vaccination using side population cell-associated antigens targets hepatocellular carcinoma.
Mar 2016 | Li, Xiao; Zhang, Zhuochao; Lin, Guoying; Gao, Yuanxing; Yan, Zhen; Yin, Heliang; Sun, Bingyi; Wang, Fangyuan; Zhang, Haijun; Chen, Hong; Cao, Dayong
Dendritic cell (DC) vaccination targeting cancer stem cells is an effective way to suppress tumor progression and reduce the metastasis and recurrence. In the present study, we explored the suitability of side population (SP) cells as source of antigens for DC vaccination against hepatocellular carcinoma (HCC) in a mouse model. In this study, we identified the "stem-like" characteristics of SP cells in the MHCC97 and Hepa 1-6 HCC cell lines. We found that SP cells express high levels of tumor-associated antigens and MHC class I molecules. Although loading with cell lysates did not change the characteristics of DCs, SP cell lysate-pulsed DCs induced antigen-specific T cell responses, including T cell proliferation and increased IFN-γ production by stimulated CD8(+) T cells. We investigated the cytotoxicity of T cells stimulated by SP cell lysate-pulsed DCs in nude mice co-injected with MHCC97 cells. To mimic the in vivo environment, we also confirmed the result in mouse HCC cell line Hepa 1-6 induced tumor-bearing C57/BL6 immune competent mice, and we demonstrated that vaccination with DCs loaded with Hepa 1-6 SP cell lysates could induce a T cell response in vivo and suppress the tumor growth. Our results may have applications for anti-HCC immunotherapy by targeting the cancer stem cells and may provide new insight for cancer vaccines. PMID 26951511

Prophylactic vaccines are potent activators of monocyte-derived dendritic cells and drive effective anti-tumor responses in melanoma patients at the cost of toxicity.
Mar 2016 | Bol, Kalijn F; Aarntzen, Erik H J G; Pots, Jeanette M; Olde Nordkamp, Michel A M; van de Rakt, Mandy W M M; Scharenborg, Nicole M; de Boer, Annemiek J; van Oorschot, Tom G M; Croockewit, Sandra A J; Blokx, Willeke A M; Oyen, Wim J G; Boerman, Otto C; Mus, Roel D M; van Rossum, Michelle M; van der Graaf, Chantal A A; Punt, Cornelis J A; Adema, Gosse J; Figdor, Carl G; de Vries, I Jolanda M; Schreibelt, Gerty
Dendritic cell (DC)-based immunotherapy is explored worldwide in cancer patients, predominantly with DC matured with pro-inflammatory cytokines and prostaglandin E2. We studied the safety and efficacy of vaccination with monocyte-derived DC matured with a cocktail of prophylactic vaccines that contain clinical-grade Toll-like receptor ligands (BCG, Typhim, Act-HIB) and prostaglandin E2 (VAC-DC). Stage III and IV melanoma patients were vaccinated via intranodal injection (12 patients) or combined intradermal/intravenous injection (16 patients) with VAC-DC loaded with keyhole limpet hemocyanin (KLH) and mRNA encoding tumor antigens gp100 and tyrosinase. Tumor antigen-specific T cell responses were monitored in blood and skin-test infiltrating-lymphocyte cultures. Almost all patients mounted prophylactic vaccine- or KLH-specific immune responses. Both after intranodal injection and after intradermal/intravenous injection, tumor antigen-specific immune responses were detected, which coincide with longer overall survival in stage IV melanoma patients. VAC-DC induce local and systemic CTC grade 2 and 3 toxicity, which is most likely caused by BCG in the maturation cocktail. The side effects were self-limiting or resolved upon a short period of systemic steroid therapy. We conclude that VAC-DC can induce functional tumor-specific responses. Unfortunately, toxicity observed after vaccination precludes the general application of VAC-DC, since in DC maturated with prophylactic vaccines BCG appears to be essential in the maturation cocktail. PMID 26861670

Dendritic cell vaccines based on immunogenic cell death elicit danger signals and T cell-driven rejection of high-grade glioma.
Mar 2016 | Garg, Abhishek D; Vandenberk, Lien; Koks, Carolien; Verschuere, Tina; Boon, Louis; Van Gool, Stefaan W; Agostinis, Patrizia
The promise of dendritic cell (DC)-based immunotherapy has been established by two decades of translational research. Of the four malignancies most targeted with clinical DC immunotherapy, high-grade glioma (HGG) has shown the highest susceptibility. HGG-induced immunosuppression is a roadblock to immunotherapy, but may be overcome by the application of T helper 1 (TH1) immunity-biased, next-generation, DC immunotherapy. To this end, we combined DC immunotherapy with immunogenic cell death (ICD; a modality shown to induce TH1 immunity) induced by hypericin-based photodynamic therapy. In an orthotopic HGG mouse model involving prophylactic/curative setups, both biologically and clinically relevant versions of ICD-based DC vaccines provided strong anti-HGG survival benefit. We found that the ability of DC vaccines to elicit HGG rejection was significantly blunted if cancer cell-associated reactive oxygen species and emanating danger signals were blocked either singly or concomitantly, showing hierarchical effect on immunogenicity, or if DCs, DC-associated MyD88 signal, or the adaptive immune system (especially CD8(+) T cells) were depleted. In a curative setting, ICD-based DC vaccines synergized with standard-of-care chemotherapy (temozolomide) to increase survival of HGG-bearing mice by ~300%, resulting in ~50% long-term survivors. Additionally, DC vaccines also induced an immunostimulatory shift in the brain immune contexture from regulatory T cells to TH1/cytotoxic T lymphocyte/TH17 cells. Analysis of the The Cancer Genome Atlas glioblastoma cohort confirmed that increased intratumor prevalence of TH1/cytotoxic T lymphocyte/TH17 cells linked genetic signatures was associated with good patient prognosis. Therefore, pending final preclinical checks, ICD-based vaccines can be clinically translated for glioma treatment. PMID 26936504

Effective Clinical Responses in Metastatic Melanoma Patients after Vaccination with Primary Myeloid Dendritic Cells.
Feb 2016 | Schreibelt, Gerty; Bol, Kalijn F; Westdorp, Harm; Wimmers, Florian; Aarntzen, Erik H J G; Duiveman-de Boer, Tjitske; van de Rakt, Mandy W M M; Scharenborg, Nicole M; de Boer, Annemiek J; Pots, Jeanette M; Olde Nordkamp, Michel A M; van Oorschot, Tom G M; Tel, Jurjen; Winkels, Gregor; Petry, Katja; Blokx, Willeke A M; van Rossum, Michelle M; Welzen, Marieke E B; Mus, Roel D M; Croockewit, Sandra A J; Koornstra, Rutger H T; Jacobs, Joannes F M; Kelderman, Sander; Blank, Christian U; Gerritsen, Winald R; Punt, Cornelis J A; Figdor, Carl G; de Vries, I Jolanda M
Thus far, dendritic cell (DC)-based immunotherapy of cancer was primarily based on in vitro-generated monocyte-derived DCs, which require extensive in vitro manipulation. Here, we report on a clinical study exploiting primary CD1c(+) myeloid DCs, naturally circulating in the blood. PMID 26712687

Immunization of HIV-1-Infected Persons With Autologous Dendritic Cells Transfected With mRNA Encoding HIV-1 Gag and Nef: Results of a Randomized, Placebo-Controlled Clinical Trial.
Feb 2016 | Gandhi, Rajesh T; Kwon, Douglas S; Macklin, Eric A; Shopis, Janet R; McLean, Anna P; McBrine, Nicole; Flynn, Theresa; Peter, Lauren; Sbrolla, Amy; Kaufmann, Daniel E; Porichis, Filippos; Walker, Bruce D; Bhardwaj, Nina; Barouch, Dan H; Kavanagh, Daniel G
HIV-1 eradication may require reactivation of latent virus along with stimulation of HIV-1-specific immune responses to clear infected cells. Immunization with autologous dendritic cells (DCs) transfected with viral mRNA is a promising strategy for eliciting HIV-1-specific immune responses. We performed a randomized controlled clinical trial to evaluate the immunogenicity of this approach in HIV-1-infected persons on antiretroviral therapy. PMID 26379068

HIV immunotherapy comes of age: implications for prevention, treatment and cure.
Feb 2016 | Routy, Jean-Pierre; Mehraj, Vikram; Cao, Wei
Antiretroviral therapy (ART) has reshaped the lives of millions of individuals infected with human immunodeficiency virus (HIV). Patients initiating ART early in the course of infection benefit from a considerable reduction in the risks of acquired immune deficiency syndrome (AIDS) and HIV-related inflammatory events. However, the absence of cure and lifelong requirements of treatment highlight the need of a vaccine and an immunotherapeutic strategy. Like for cancer, a paradigm shift has occurred with the contribution of immune activation and microbial translocation priming aberrant systemic immunity in restricting the ability of the host to mount an effective immune response. The approaches of implementing an effective vaccine to prevent infection and inhibition of immune activation with breakage of viral latency followed by vaccination should lead to an HIV-free generation. PMID 26629806

Exploiting the Immunogenic Potential of Cancer Cells for Improved Dendritic Cell Vaccines.
Feb 2016 | Vandenberk, Lien; Belmans, Jochen; Van Woensel, Matthias; Riva, Matteo; Van Gool, Stefaan W
Cancer immunotherapy is currently the hottest topic in the oncology field, owing predominantly to the discovery of immune checkpoint blockers. These promising antibodies and their attractive combinatorial features have initiated the revival of other effective immunotherapies, such as dendritic cell (DC) vaccinations. Although DC-based immunotherapy can induce objective clinical and immunological responses in several tumor types, the immunogenic potential of this monotherapy is still considered suboptimal. Hence, focus should be directed on potentiating its immunogenicity by making step-by-step protocol innovations to obtain next-generation Th1-driving DC vaccines. We review some of the latest developments in the DC vaccination field, with a special emphasis on strategies that are applied to obtain a highly immunogenic tumor cell cargo to load and to activate the DCs. To this end, we discuss the effects of three immunogenic treatment modalities (ultraviolet light, oxidizing treatments, and heat shock) and five potent inducers of immunogenic cell death [radiotherapy, shikonin, high-hydrostatic pressure, oncolytic viruses, and (hypericin-based) photodynamic therapy] on DC biology and their application in DC-based immunotherapy in preclinical as well as clinical settings. PMID 26834740

Eliciting cytotoxic T lymphocytes against human laryngeal cancer-derived antigens: evaluation of dendritic cells pulsed with a heat-treated tumor lysate and other antigen-loading strategies for dendritic-cell-based vaccination.
Jan 2016 | Wei, Fan-Qin; Sun, Wei; Wong, Thian-Sze; Gao, Wei; Wen, Yi-Hui; Wei, Jia-Wei; Wei, Yi; Wen, Wei-Ping
Dendritic cells (DCs) have been used successfully in clinical pilot studies. However, tumor-specific immunity and clinical responses were only induced in certain cancer patients. It has been well documented that immunotherapy efficacy can be optimized for responses using antigen pulsing. PMID 26795730

Current status and perspectives of immune-based therapies for hepatocellular carcinoma.
Jan 2016 | Aerts, Maridi; Benteyn, Daphné; Van Vlierberghe, Hans; Thielemans, Kris; Reynaert, Hendrik
Hepatocellular carcinoma (HCC) is a frequent cancer with a high mortality. For early stage cancer there are potentially curative treatments including local ablation, resection and liver transplantation. However, for more advanced stage disease, there is no optimal treatment available. Even in the case of a "curative" treatment, recurrence or development of a new cancer in the precancerous liver is common. Thus, there is an urgent need for novel and effective (adjuvant) therapies to treat HCC and to prevent recurrence after local treatment in patients with HCC. The unique immune response in the liver favors tolerance, which remains a genuine challenge for conventional immunotherapy in patients with HCC. However, even in this "immunotolerant" organ, spontaneous immune responses against tumor antigens have been detected, although they are insufficient to achieve significant tumor death. Local ablation therapy leads to immunogenic tumor cell death by inducing the release of massive amounts of antigens, which enhances spontaneous immune response. New immune therapies such as dendritic cell vaccination and immune checkpoint inhibition are under investigation. Immunotherapy for cancer has made huge progress in the last few years and clinical trials examining the use of immunotherapy to treat hepatocellular carcinoma have shown some success. In this review, we discuss the current status of and offer some perspectives on immunotherapy for hepatocellular carcinoma, which could change disease progression in the near future. PMID 26755874

Therapeutic Vaccination With Dendritic Cells Loaded With Autologous HIV Type 1-Infected Apoptotic Cells.
Jan 2016 | Macatangay, Bernard J C; Riddler, Sharon A; Wheeler, Nicole D; Spindler, Jonathan; Lawani, Mariam; Hong, Feiyu; Buffo, Mary J; Whiteside, Theresa L; Kearney, Mary F; Mellors, John W; Rinaldo, Charles R
 We report the results of a phase I/II, open-label, single-arm clinical trial to evaluate the safety and anti-human immunodeficiency virus type 1 (HIV-1) efficacy of an autologous dendritic cell (DC)-based HIV-1 vaccine loaded with autologous HIV-1-infected apoptotic cells. PMID 26647281

A phase I/IIa study of adjuvant immunotherapy with tumour antigen-pulsed dendritic cells in patients with hepatocellular carcinoma.
Dec 2015 | Lee, Jeong-Hoon; Lee, Yoon; Lee, Minjong; Heo, Min Kyu; Song, Jae-Sung; Kim, Ki-Hwan; Lee, Hyunah; Yi, Nam-Joon; Lee, Kwang-Woong; Suh, Kyung-Suk; Bae, Yong-Soo; Kim, Yoon Jun
To date, no adjuvant treatment has been shown to have a clear benefit in patients with hepatocellular carcinoma (HCC). In this prospective phase I/IIa study, we evaluated the safety and efficacy of adjuvant dendritic cell (DC) therapy in HCC patients who received primary treatment for HCC. PMID 26657650

Dendritic Cell-Based Adjuvant Vaccination Targeting Wilms' Tumor 1 in Patients with Advanced Colorectal Cancer.
Dec 2015 | Shimodaira, Shigetaka; Sano, Kenji; Hirabayashi, Koichi; Koya, Terutsugu; Higuchi, Yumiko; Mizuno, Yumiko; Yamaoka, Naoko; Yuzawa, Miki; Kobayashi, Takashi; Ito, Kenichi; Koizumi, Tomonobu
Despite significant recent advances in the development of immune checkpoint inhibitors, the treatment of advanced colorectal cancer involving metastasis to distant organs remains challenging. We conducted a phase I study to investigate the safety and immunogenicity of Wilms' tumor (WT1) class I/II peptides-pulsed dendritic cell DC vaccination for patients with advanced colorectal cancer. Standard treatment comprising surgical resection and chemotherapy was followed by one course of seven biweekly administrations of 1-2 × 10⁷ DCs with 1-2 KE of OK-432 (streptococcal preparation) in three patients. Clinical efficacy was confirmed based on WT1 expression using immunohistochemistry on paraffin-embedded tissues and immune monitoring using tetramer analysis and enzyme-linked immunosorbent spot (ELISPOT) assays. WT1 expression with human leukocyte antigen (HLA)-class I molecules was detected in surgical resected tissues. Adverse reactions to DC vaccinations were tolerable under an adjuvant setting. WT1-specific cytotoxic T cells were detected by both modified WT1-peptide/HLA-A*24:02 tetramer analysis and/or interferon-γ-producing cells through the use of ELISPOT assays after the first DC vaccination. Immunity acquired from DC vaccination persisted for two years with prolonged disease-free and overall survival. The present study indicated that DC vaccination targeting WT1 demonstrated the safety and immunogenicity as an adjuvant therapy in patients with resectable advanced colorectal cancer. PMID 26690485

Extended Tumor Control After Dendritic Cell Vaccination With Low Dose Cyclophosphamide as Adjuvant Treatment in Patients With Malignant Pleural Mesothelioma.
Dec 2015 | Cornelissen, Robin; Hegmans, Joost P J J; Maat, Alexander P W M; Kaijen-Lambers, Margaretha E H; Bezemer, Koen; Hendriks, Rudi W; Hoogsteden, Henk C; Aerts, Joachim G J V
We demonstrated before that autologous tumor lysate-pulsed dendritic cell-based immunotherapy in patients with malignant pleural mesothelioma is feasible, well-tolerated, and capable of inducing immunological responses against tumors. In our murine model we found that reduction of regulatory T cells with metronomic cyclophosphamide increased the efficacy of immunotherapy. PMID 26652184

Vaccination of multiple myeloma: Current strategies and future prospects.
Oct 2015 | Allegra, Alessandro; Penna, Giuseppa; Innao, Vanessa; Greve, Bruna; Maisano, Valerio; Russo, Sabina; Musolino, Caterina
Tumor immunotherapy holds great promise in controlling multiple myeloma (MM) and may provide an alternative treatment modality to conventional chemotherapy for MM patients. For this reason, a major area of investigation is the development of cancer vaccines to generate myeloma-specific immunity. Several antigens that are able to induce specific T-cell responses are involved in different critical mechanisms for cell differentiation, inhibition of apoptosis, demethylation and proliferation. Strategies under development include infusion of vaccine-primed and ex vivo expanded/costimulated autologous T cells after high-dose melphalan, genetic engineering of autologous T cells with receptors for myeloma-specific epitopes, administration of dendritic cell/plasma cell fusions and administration expanded marrow-infiltrating lymphocytes. In addition, novel immunomodulatory drugs may synergize with immunotherapies. The task ahead is to evaluate these approaches in appropriate clinical settings, and to couple them with strategies to overcome mechanisms of immunoparesis as a means to induce more robust clinically significant immune responses. PMID 26123319

Improving immunological tumor microenvironment using electro-hyperthermia followed by dendritic cell immunotherapy.
Oct 2015 | Tsang, Yuk-Wah; Huang, Cheng-Chung; Yang, Kai-Lin; Chi, Mau-Shin; Chiang, Hsin-Chien; Wang, Yu-Shan; Andocs, Gabor; Szasz, Andras; Li, Wen-Tyng; Chi, Kwan-Hwa
The treatment of intratumoral dentritic cells (DCs) commonly fails because it cannot evoke immunity in a poor tumor microenvironment (TME). Modulated electro-hyperthermia (mEHT, trade-name: oncothermia) represents a significant technological advancement in the hyperthermia field, allowing the autofocusing of electromagnetic power on a cell membrane to generate massive apoptosis. This approach turns local immunogenic cancer cell death (apoptosis) into a systemic anti-tumor immune response and may be implemented by treatment with intratumoral DCs. PMID 26472466

Pancreatic adenocarcinoma upregulated factor serves as adjuvant by activating dendritic cells through stimulation of TLR4.
Oct 2015 | Kang, Tae Heung; Kim, Young Seob; Kim, Seokho; Yang, Benjamin; Lee, Je-Jung; Lee, Hyun-Ju; Lee, Jaemin; Jung, In Duk; Han, Hee Dong; Lee, Seung-Hyun; Koh, Sang Seok; Wu, T-C; Park, Yeong-Min
Dendritic cell (DC) based cancer vaccines represent a promising immunotherapeutic strategy against cancer. To enhance the modest immunogenicity of DC vaccines, various adjuvants are often incorporated. Particularly, most of the common adjuvants are derived from bacteria. In the current study, we evaluate the use of a human pancreatic cancer derived protein, pancreatic adenocarcinoma upregulated factor (PAUF), as a novel DC vaccine adjuvant. We show that PAUF can induce activation and maturation of DCs and activate NFkB by stimulating the Toll-like receptor signaling pathway. Furthermore, vaccination with PAUF treated DCs pulsed with E7 or OVA peptides leads to generation of E7 or OVA-specific CD8+ T cells and memory T cells, which correlate with long term tumor protection and antitumor effects against TC-1 and EG.7 tumors in mice. Finally, we demonstrated that PAUF mediated DC activation and immune stimulation are dependent on TLR4. Our data provides evidence supporting PAUF as a promising adjuvant for DC based therapies, which can be applied in conjunction with other cancer therapies. Most importantly, our results serve as a reference for future investigation of human based adjuvants. PMID 26336989

Type I-polarized BRAF-pulsed dendritic cells induce antigen-specific CD8+ T cells that impact BRAF-mutant murine melanoma.
Oct 2015 | Cintolo, Jessica A; Datta, Jashodeep; Xu, Shuwen; Gupta, Meera; Somasundaram, Rajasekharan; Czerniecki, Brian J
Existing therapies targeting the mutated BRAF oncodriver (BRAF) successfully treat melanoma but are susceptible to resistance. This study assessed the potential of a dendritic cell-based BRAF vaccine for the treatment of BRAF-mutant melanoma. Type 1-polarized dendritic cells (DC1) pulsed with affinity-modified BRAF peptide were administered to C57Bl/6 mice both before (prevention) and twice weekly after (treatment) the development of established tumor with B16 melanoma transfected to express BRAF (B16). The efficacy of the BRAF-pulsed DC1 vaccine was corroborated in a novel transplantable BRAF-mutant murine melanoma model (BRAF; PTEN; CDK2NA). Three-dimensional tumor measurements and survival were determined. Induction of BRAF-specific CD8 T-cell responses after brief in-vitro sensitization was assessed by interferon-γ enzyme-linked immunosorbent assay and/or enzyme-linked immunospot. Mice receiving BRAF-pulsed DC1 vaccines before B16 tumor challenge demonstrated increased tumor-doubling times (P<0.001) and improved survival (P=0.0186) compared with those that received ovalbumin (control)-pulsed DC1 vaccines. In mice bearing established B16 tumors (mean 32 mm), BRAF-pulsed DC1 vaccines delayed tumor growth (P<0.001) and improved survival (P=0.0008), compared with untreated mice. Likewise, in mice bearing BRAF; PTEN; CDK2NA tumors, compared with controls, BRAF-DC1 vaccination recapitulated these effects by delaying tumor growth (P<0.001) and improving survival (P=0.002). Vaccination elicited specific CD8 T-cell recognition of BRAF-pulsed antigen-presenting cells (P<0.05), as well as BRAF-expressing cancer cells (P<0.001), measured by interferon-γ release in vitro. BRAF-pulsed DC1 vaccines induce oncogene-specific CD8 T-cell immune responses that impact tumor growth and survival in preclinical models of BRAF-mutant melanoma. Exploration of BRAF-targeted vaccines, in combination with BRAF-targeted therapies and checkpoint inhibitors, is warranted. PMID 26451873

Ex vivo generation of dendritic cells from cryopreserved, post-induction chemotherapy, mobilized leukapheresis from pediatric patients with medulloblastoma.
Oct 2015 | Nair, Smita K; Driscoll, Timothy; Boczkowski, David; Schmittling, Robert; Reynolds, Renee; Johnson, Laura A; Grant, Gerald; Fuchs, Herbert; Bigner, Darell D; Sampson, John H; Gururangan, Sridharan; Mitchell, Duane A
Generation of patient-derived, autologous dendritic cells (DCs) is a critical component of cancer immunotherapy with ex vivo-generated, tumor antigen-loaded DCs. An important factor in the ability to generate DCs is the potential impact of prior therapies on DC phenotype and function. We investigated the ability to generate DCs using cells harvested from pediatric patients with medulloblastoma for potential evaluation of DC-RNA based vaccination approach in this patient population. Cells harvested from medulloblastoma patient leukapheresis following induction chemotherapy and granulocyte colony stimulating factor mobilization were cryopreserved prior to use in DC generation. DCs were generated from the adherent CD14+ monocytes using standard procedures and analyzed for cell recovery, phenotype and function. To summarize, 4 out of 5 patients (80 %) had sufficient monocyte recovery to permit DC generation, and we were able to generate DCs from 3 out of these 4 patient samples (75 %). Overall, we successfully generated DCs that met phenotypic requisites for DC-based cancer therapy from 3 out of 5 (60 %) patient samples and met both phenotypic and functional requisites from 2 out of 5 (40 %) patient samples. This study highlights the potential to generate functional DCs for further clinical treatments from refractory patients that have been heavily pretreated with myelosuppressive chemotherapy. Here we demonstrate the utility of evaluating the effect of the currently employed standard-of-care therapies on the ex vivo generation of DCs for DC-based clinical studies in cancer patients. PMID 26311248

Dendritic cell-based immunotherapy targeting Wilms' tumor 1 in patients with recurrent malignant glioma.
Oct 2015 | Sakai, Keiichi; Shimodaira, Shigetaka; Maejima, Shinya; Udagawa, Nobuyuki; Sano, Kenji; Higuchi, Yumiko; Koya, Terutsugu; Ochiai, Takanaga; Koide, Masanori; Uehara, Shunsuke; Nakamura, Midori; Sugiyama, Haruo; Yonemitsu, Yoshikazu; Okamoto, Masato; Hongo, Kazuhiro
OBJECT Dendritic cell (DC)-based vaccination is considered a potentially effective therapy against advanced cancer. The authors conducted a Phase I study to investigate the safety and immunomonitoring of Wilms' tumor 1 (WT1)-pulsed DC vaccination therapy for patients with relapsed malignant glioma. METHODS WT1-pulsed and/or autologous tumor lysate-pulsed DC vaccination therapy was performed in patients with relapsed malignant gliomas. Approximately 1 × 10(7) to 2 × 10(7) pulsed DCs loaded with WT1 peptide antigen and/or tumor lysate were intradermally injected into the axillary areas with OK-432, a streptococcal preparation, at 2-week intervals for at least 5-7 sessions (1 course) during an individual chemotherapy regimen. RESULTS Ten patients (3 men, 7 women; age range 24-64 years [median 39 years]) with the following tumors were enrolled: glioblastoma (6), anaplastic astrocytoma (2), anaplastic oligoastrocytoma (1), and anaplastic oligodendroglioma (1). Modified WT1 peptide-pulsed DC vaccine was administered to 7 patients, tumor lysate-pulsed DC vaccine to 2 patients, and both tumor lysate-pulsed and WT1-pulsed DC vaccine to 1 patient. The clinical response was stable disease in 5 patients with WT1-pulsed DC vaccination. In 2 of 5 patients with stable disease, neurological findings improved, and MR images showed tumor shrinkage. No serious adverse events occurred except Grade 1-2 erythema at the injection sites. WT1 tetramer analysis detected WT1-reactive cytotoxic T cells after vaccination in patients treated with WT1-pulsed therapy. Positivity for skin reaction at the injection sites was 80% (8 of 10 patients) after the first session, and positivity remained for these 8 patients after the final session. CONCLUSIONS This study of WT1-pulsed DC vaccination therapy demonstrated safety, immunogenicity, and feasibility in the management of relapsed malignant gliomas. PMID 26252465

Comparison of cytotoxic T lymphocyte responses against pancreatic cancer induced by dendritic cells transfected with total tumor RNA and fusion hybrided with tumor cell.
Oct 2015 | Chen, Jiang; Guo, Xiao-Zhong; Li, Hong-Yu; Wang, Di; Shao, Xiao-Dong
Pancreatic cancer (PC) is a deadly human malignancy. Dendritic cell (DC)-based immunotherapy with whole tumor antigens demonstrates potential efficiency in cancer treatment. Tumor RNA and tumor fusion hybrid cells are sources of whole tumor antigens for preparing DC tumor vaccines. However, the efficacy of these sources in eliciting immune responses against PC has not yet to be directly compared. In the present study, patient-derived PC cells and DCs were fused (DC-tumor hybrids) and primary cultured PC cell-derived total RNA was electroporated into autologous DCs (DC-tumor RNA). The antitumor immune responses induced by DC-tumor hybrids and DC-tumor RNA were compared directly. The results showed that both RNA and hybrid methodologies could induce tumor-specific cytotoxic T lymphocyte (CTL) responses, but pulsing DCs with total tumor RNA could induce a higher frequency of activated CTLs and T-helper cells than fusing DCs with autologous tumor cells. In addition, DC-tumor RNA triggered stronger autologous tumor cell lysis than DC-tumor hybrids. It could be concluded that DCs pulsed with whole tumor RNA are superior to those fused with tumor cells in priming anti-PC CTL responses. Electroporation with total tumor RNA may be more suitable for DC-based PC vaccination. PMID 25736302

Dendritic cell vaccination with a toll-like receptor agonist derived from mycobacteria enhances anti-tumor immunity.
Sep 2015 | Vo, Manh-Cuong; Lee, Hyun-Ju; Kim, Jong-Seok; Hoang, My-Dung; Choi, Nu-Ri; Rhee, Joon Haeng; Lakshmanan, Vinoth-Kumar; Shin, Sung-Jae; Lee, Je-Jung
Dendritic cell (DC)-based vaccines are considered useful in cancer immunotherapy, and the interaction of DC and adjuvants is important in the design of the next generation vaccines. In this study, whether DC combined with Rv2299c derived from mycobacteria could improve anti-tumor immune responses in a colon cancer mouse model was evaluated. MC38 cell lines were injected subcutaneously to establish colon-cancer-bearing mice and the following four groups were evaluated: PBS control, tumor antigen (TA) loaded-DC, Rv2299c, and a combination of TA-loaded-DC and Rv2299c. The combination treatment with TA-loaded-DC and Rv2299c exhibited greater inhibition of tumor growth compared to other groups. These effects were associated with the reduction of suppressor cells, such as myeloid-derived suppressor cells and regulatory T cells, and the induction of effector cells, such as CD4+ T cells and CD8+ T cells, in spleen, and with the activation of cytotoxic T Lymphocytes and NK cells. These results suggest that TA-loaded-DC vaccination with Rv2299c derived from mycobacteria enhanced anti-tumor immunity in a mouse colon cancer model by inhibiting the generation of immune-suppressive cells and recovering numbers of effector cells, and demonstrated superior polarization of the Th1/Th2 balance in favor of the Th1 immune response. PMID 26418952

Antigen targeting to dendritic cells combined with transient regulatory T cell inhibition results in long-term tumor regression.
Sep 2015 | Unger, Wendy Wj; Mayer, Christian T; Engels, Steef; Hesse, Christina; Perdicchio, Maurizio; Puttur, Franz; Streng-Ouwehand, Ingeborg; Litjens, Manja; Kalay, Hakan; Berod, Luciana; Sparwasser, Tim; van Kooyk, Yvette
Therapeutic vaccinations against cancer are still largely ineffective. Major caveats are inefficient delivery of tumor antigens to dendritic cells (DCs) and excessive immune suppression by Foxp3(+) regulatory T cells (Tregs), resulting in defective T cell priming and failure to induce tumor regression. To circumvent these problems we evaluated a novel combinatorial therapeutic strategy. We show that tumor antigen targeting to DC-SIGN in humanized hSIGN mice via glycans or specific antibodies induces superior T cell priming. Next, this targeted therapy was combined with transient Foxp3(+) Treg depletion employing hSIGNxDEREG mice. While Treg depletion alone slightly delayed B16-OVA melanoma growth, only the combination therapy instigated long-term tumor regression in a substantial fraction of mice. This novel strategy resulted in optimal generation of antigen-specific activated CD8(+) T cells which accumulated in regressing tumors. Notably, Treg depletion also allowed the local appearance of effector T cells specific for endogenous B16 antigens. This indicates that antitumor immune responses can be broadened by therapies aimed at controlling Tregs in tumor environments. Thus, transient inhibition of Treg-mediated immune suppression potentiates DC targeted antigen vaccination and tumor-specific immunity. PMID 26405564

A pancreatic tumor-specific biomarker characterized in humans and mice as an immunogenic onco-glycoprotein is efficient in dendritic cell vaccination.
Sep 2015 | Collignon, Aurélie; Perles-Barbacaru, Adriana Teodora; Robert, Stéphane; Silvy, Françoise; Martinez, Emmanuelle; Crenon, Isabelle; Germain, Sébastien; Garcia, Stéphane; Viola, Angèle; Lombardo, Dominique; Mas, Eric; Béraud, Evelyne
Oncofetal fucose-rich glycovariants of the pathological bile salt-dependent lipase (pBSDL) appear during human pancreatic oncogenesis and are detected by themonoclonal antibody J28 (mAbJ28). We aimed to identify murine counterparts onpancreatic ductal adenocarcinoma (PDAC) cells and tissue and investigate the potential of dendritic cells (DC) loaded with this unique pancreatic tumor antigen to promote immunotherapy in preclinical trials. Pathological BSDLs purified from pancreatic juices of patients with PDAC were cleaved to generate glycosylated C-terminal moieties (C-ter) containing mAbJ28-reactive glycoepitopes. Immunoreactivity of the murine PDAC line Panc02 and tumor tissue to mAbJ28 was detected by immunohistochemistry and flow cytometry. C-ter-J28+ immunization promoted Th1-dominated immune responses. In vitro C-ter-J28+-loaded DCskewed CD3+ T-cells toward Th1 polarization. C-ter-J28+-DC-vaccinations selectively enhanced cell immunoreactivity to Panc02, as demonstrated by CD4+- and CD8+-T-cell activation, increased percentages of CD4+- and CD8+-T-cells and NK1.1+ cells expressing granzyme B, and T-cell cytotoxicity. Prophylactic and therapeutic C-ter-J28+-DC-vaccinations reduced ectopic Panc02-tumor growth, provided long-lasting protection from Panc02-tumor development in 100% of micebut not from melanoma, and attenuated progression of orthotopic tumors as revealed by MRI. Thusmurine DC loaded with pancreatic tumor-specific glycoepitope C-ter-J28+ induce efficient anticancer adaptive immunity and represent a potential adjuvant therapy for patients afflicted with PDAC. PMID 26405163

Re-irradiation or re-operation followed by dendritic cell vaccination? Comparison of two different salvage strategies for relapsed high-grade gliomas by means of a new prognostic model.
Sep 2015 | Müller, Klaus; Henke, Guido; Pietschmann, Sophie; van Gool, Stefaan; De Vleeschouwer, Steven; von Bueren, André O; Compter, Inge; Friedrich, Carsten; Matuschek, Christiane; Klautke, Gunther; Kortmann, Rolf-Dieter; Hundsberger, Thomas; Baumert, Brigitta G
We aimed to compare two different salvage treatment strategies for relapsed high-grade glioma (HGG) patients by means of a new prognostic model. A simplified version of the so-called HGG-Immuno RPA model estimates the prognosis of relapsed HGG patients and distinguishes three different prognostic classes (I = good, II = intermediate, III = poor). The model has been constructed with a cohort of 117 patients whose salvage treatment consisted of re-operation followed by dendritic cell vaccination (ReOP + DCV). However, using only the predictors histology, age and performance status, the simplified HGG-Immuno RPA model is basically independent from treatment. In the present study we applied the simplified model to the cohort used to construct the original HGG-Immuno RPA model and another cohort of 165 patients who underwent re-irradiation (ReRT) at relapse. Then, we compared the outcomes achieved by the two different salvage treatments in each prognostic class. The model predicted good, intermediate and poor prognosis for 11, 31 and 75 patients of the ReOP + DCV cohort and for 20, 39 and 106 patients of the ReRT cohort, respectively. Neither of the two strategies was superior to the other. In the groups with good, intermediate and poor prognosis 12-months survival rates were 73, 59 and 25 % after ReOP + DCV and 72, 36 and 23 % after ReRT, respectively. Being easy to handle and independent from treatment, the aforementioned model is useful for therapeutic decisions. ReRT and ReOP + DVC seem to be equally effective. The choice of salvage treatment should be based on the expected side effects. PMID 26070556

Long-term survival of a breast cancer patient with extensive liver metastases upon immune and virotherapy: a case report.
Sep 2015 | Schirrmacher, Volker; Stücker, Wilfried; Lulei, Maria; Bihari, Akos-Sigmund; Sprenger, Tobias
Liver metastases in breast cancer are associated with a poor prognosis. We report long-term survival of a patient with breast cancer and liver metastases. After operation the patient declined further standard therapy. Instead, she was treated with local hyperthermia, Newcastle disease virus and dendritic cell vaccination at the Immunological and Oncological Center Cologne (IOZK), Germany. A continuous high quality of life was reported and the patient survived more than 66 months after initial diagnosis. No recurrence or further metastases developed under treatment. Following treatment, a long-lasting tumor-reactive memory T-cell responsiveness could be documented. This possibly explains the favorable course of disease. Since this combination of therapies is not restricted to a particular tumor type, further exploration is warranted. PMID 26020523

Immunotherapy of Brain Tumors.
Sep 2015 | Dutoit, Valérie; Migliorini, Denis; Walker, Paul R; Dietrich, Pierre-Yves
Glioma is one of the most devastating cancers, affecting children and young adults, and associated with a very high morbidity and poor prognosis. The propensity of glioma cells to invade normal brain structures makes current treatments poorly efficient and new therapeutic strategies an urgent need. We now know that many of the rules governing immune responses in other tissues are also valid for the brain, providing solid scientific background for developing new strategies exploiting the immune system to fight brain tumors. Some vaccines use tumor-specific mutated peptides (EGFRvIII, IDH1 or personalized peptides), but most are tumor-associated or undefined tumor-derived peptides (tumor-eluted peptides, peptides predicted from tumor-associated proteins or bound to HSPPC-96 complexes), in some cases pulsed on dendritic cells. Cell therapy is less advanced but the first clinical trials exploring the safety of T cells with chimeric antigen receptors incorporating antibodies to EGFRvIII, IL-13Rα2 or Her2 are ongoing. Finally, various strategies designed at reshaping the glioma microenvironment are being tested, including TGFβ inhibition, Treg depletion and immune checkpoint blockade. Altogether, combining vaccines, cell therapy and reshaping of the tumor microenvironment will be the foundation for a new era of therapeutics for brain tumors. PMID 26376741

Prophylactic Dendritic Cell-Based Vaccines Efficiently Inhibit Metastases in Murine Metastatic Melanoma.
Sep 2015 | Markov, Oleg V; Mironova, Nadezhda L; Sennikov, Sergey V; Vlassov, Valentin V; Zenkova, Marina A
Recent data on the application of dendritic cells (DCs) as anti-tumor vaccines has shown their great potential in therapy and prophylaxis of cancer. Here we report on a comparison of two treatment schemes with DCs that display the models of prophylactic and therapeutic vaccination using three different experimental tumor models: namely, Krebs-2 adenocarcinoma (primary tumor), melanoma (B16, metastatic tumor without a primary node) and Lewis lung carcinoma (LLC, metastatic tumor with a primary node). Dendritic cells generated from bone marrow-derived DC precursors and loaded with lysate of tumor cells or transfected with the complexes of total tumor RNA with cationic liposomes were used for vaccination. Lipofectamine 2000 and liposomes consisting of helper lipid DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) and cationic lipid 2D3 (1,26-Bis(1,2-de-O-tetradecyl-rac-glycerol)-7,11,16,20-tetraazahexacosan tetrahydrocloride) were used for RNA transfection. It was shown that DCs loaded with tumor lysate were ineffective in contrast to tumor-derived RNA. Therapeutic vaccination with DCs loaded by lipoplexes RNA/Lipofectamine 2000 was the most efficient for treatment of non-metastatic Krebs-2, where a 1.9-fold tumor growth retardation was observed. Single prophylactic vaccination with DCs loaded by lipoplexes RNA/2D3 was the most efficient to treat highly aggressive metastatic tumors LLC and B16, where 4.7- and 10-fold suppression of the number of lung metastases was observed, respectively. Antimetastatic effect of single prophylactic DC vaccination in metastatic melanoma model was accompanied by the reductions in the levels of Th2-specific cytokines however the change of the levels of Th1/Th2/Th17 master regulators was not found. Failure of double prophylactic vaccination is explained by Th17-response polarization associated with autoimmune and pro-inflammatory reactions. In the case of therapeutic DC vaccine the polarization of Th1-response was found nevertheless the antimetastatic effect was less effective in comparison with prophylactic DC vaccine. PMID 26325576

Lenalidomide Synergistically Enhances the Effect of Dendritic Cell Vaccination in a Model of Murine Multiple Myeloma.
Sep 2015 | Nguyen-Pham, Thanh-Nhan; Jung, Sung-Hoon; Vo, Manh-Cuong; Thanh-Tran, Huong-Thi; Lee, Youn-Kyung; Lee, Hyun-Ju; Choi, Nu-Ri; Hoang, My-Dung; Kim, Hyeoung-Joon; Lee, Je-Jung
We investigated the efficacy of lenalidomide (LEN) in combination with dendritic cell (DC) vaccination in the MOPC-315 murine myeloma model. After tumor growth, LEN was injected intraperitoneally for 4 consecutive days in combination with DC vaccination. The combination of LEN and vaccination efficiently inhibited tumor growth compared with the single agents alone. A cytotoxic assay revealed that the anticancer effects of DC vaccination plus LEN involved not only generation of antigen-specific cytotoxic T lymphocytes but also NK cells. Vaccinated mice had reduced numbers of suppressor cells, including both myeloid-derived suppressor cells and regulatory T cells, in the spleen. The proportions of CD4 and CD8 T cells increased in the spleen, and a Th1 cytokine (interferon-γ) rather than a Th2 cytokine (interleukin-10) was synthesized in response to tumor antigens. LEN enhanced the innate immune response by modulating NK cell numbers and function. In addition, LEN reduced the production levels of angiogenesis-inducing factors in tumor-bearing mice. Together, these results suggest that a combination of LEN and DC vaccination may synergistically enhance anticancer immunity in the murine myeloma model, by inhibiting immunosuppressor cells and stimulating effector cells, as well as effectively polarizing the Th1/Th2 balance in favor of a Th1-specific immune response. PMID 26325377

Enhancement of the Immunostimulatory Functions of Ex Vivo-Generated Dendritic Cells from Early-Stage Colon Cancer Patients by Consecutive Exposure to Low Doses of Sequential-Kinetic-Activated IL-4 and IL-12. A Preliminary Study.
Aug 2015 | Radice, Elisabetta; Bellone, Graziella; Miranda, Vincenzo
Dendritic cells (DCs), specialized antigen-presenting cells bridging innate and adaptive immunity, play a crucial role in determining specific immune response to tumors. Because of their potent immunoregulatory capacities, DCs have been exploited in anticancer vaccination, with limited success thus far. This pilot study compared low-dose interleukin (IL)-4 and IL-12 prepared by sequential kinetic activation (SKA) with standard doses of the same recombinant human cytokines on functional activity of ex vivo-generated monocyte-derived (Mo) DCs from colon carcinoma patients and normal subjects. MoDCs were exposed to medium alone, SKA-IL-4 (0.5 fg/ml), or SKA-IL-12 (2 fg/ml), alone or consecutively combined, in parallel with rhIL-4 (50 ng/ml) and rhIL-12 (1 ng/ml). Primary allogeneic one-way mixed lymphocyte reaction (MLR) was the end point to assess in vitro T-lymphocyte proliferation in response to MoDCs, and secreted IL-12p70 and interferon-γ in MLR supernatants measured by ELISA to assay for T-helper 1-promoting MoDC phenotype. No single agent enhanced the compromised allostimulatory activity of MoDCs from colon cancer patients, unlike healthy donors. However, MoDCs from nonmetastatic colon cancer patients, after sequential exposure to SKA-IL-4 (48 hours) and SKA-IL-12 (24 hours), displayed increased T-cell stimulatory capacity by MLR and acquired driving T-helper 1 polarization activity, although less markedly than the effects induced by recombinant human cytokines or found in normal subjects. These results point to an immunomodulatory capacity of low-dose SKA-IL-4 and SKA-IL-12 and encourage further investigation to provide clues for the rational development of new and more effective immunotherapeutic strategies against cancer. PMID 26310379

Advances in the understanding of cancer immunotherapy.
Aug 2015 | Shore, Neal D
The principal role of the immune system is to prevent and eradicate pathogens and infections. The key characteristics or features of an effective immune response include specificity, trafficking, antigen spread and durability (memory). The immune system is recognised to have a critical role in controlling cancer through a dynamic relationship with tumour cells. Normally, at the early stages of tumour development, the immune system is capable of eliminating tumour cells or keeping tumour growth abated; however, tumour cells may evolve multiple pathways over time to evade immune control. Immunotherapy may be viewed as a treatment designed to boost or restore the ability of the immune system to fight cancer, infections and other diseases. Immunotherapy manifests differently from traditional cancer treatments, eliciting delayed response kinetics and thus may be more effective in patients with lower tumour burden, in whom disease progression may be less rapid, thereby allowing ample time for the immunotherapy to evolve. Because immunotherapies may have a different mechanism of action from traditional cytotoxic or targeted biological agents, immunotherapy techniques have the potential to combine synergistically with traditional therapies. PMID 24612369

Dendritic Cells as Pharmacological Tools for Cancer Immunotherapy.
Aug 2015 | Anguille, Sébastien; Smits, Evelien L; Bryant, Christian; Van Acker, Heleen H; Goossens, Herman; Lion, Eva; Fromm, Phillip D; Hart, Derek N; Van Tendeloo, Viggo F; Berneman, Zwi N
Although the earliest—rudimentary—attempts at exploiting the immune system for cancer therapy can be traced back to the late 18th Century, it was not until the past decade that cancer immunotherapeutics have truly entered mainstream clinical practice. Given their potential to stimulate both adaptive and innate antitumor immune responses, dendritic cells (DCs) have come under intense scrutiny in recent years as pharmacological tools for cancer immunotherapy. Conceptually, the clinical effectiveness of this form of active immunotherapy relies on the completion of three critical steps: 1) the DCs used as immunotherapeutic vehicles must properly activate the antitumor immune effector cells of the host, 2) these immune effector cells must be receptive to stimulation by the DCs and be competent to mediate their antitumor effects, which 3) requires overcoming the various immune-inhibitory mechanisms used by the tumor cells. In this review, following a brief overview of the pivotal milestones in the history of cancer immunotherapy, we will introduce the reader to the basic immunobiological and pharmacological principles of active cancer immunotherapy using DCs. We will then discuss how current research is trying to define the optimal parameters for each of the above steps to realize the full clinical potential of DC therapeutics. Given its high suitability for immune interventions, acute myeloid leukemia was chosen here to showcase the latest research trends driving the field of DC-based cancer immunotherapy. PMID 26240218

Route of antigen delivery impacts the immunostimulatory activity of dendritic cell-based vaccines for hepatocellular carcinoma.
Jul 2015 | Pardee, Angela D; Yano, Hiroshi; Weinstein, Aliyah M; Ponce, Aaron A K; Ethridge, Alexander D; Normolle, Daniel P; Vujanovic, Lazar; Mizejewski, Gerald J; Watkins, Simon C; Butterfield, Lisa H
Dendritic cells (DC) are uniquely equipped to capture, process, and present antigens from their environment. The context in which an antigen is acquired by DC helps to dictate the subsequent immune response. Cancer vaccination promotes antitumor immunity by directing an immune response to antigens expressed by tumors. We have tested the tumor-associated antigen alpha-fetoprotein (AFP) as an immunotherapy target. The majority of hepatocellular carcinomas (HCC) upregulate and secrete this oncofetal antigen. PMID 26199728

Improved Efficacy of a Dendritic Cell-Based Vaccine against a Murine Model of Colon Cancer: The Helper Protein Effect.
Jul 2015 | Zarnani, Amir-Hassan; Torabi-Rahvar, Monireh; Bozorgmehr, Mahmood; Zareie, Mehri; Mojtabavi, Nazanin
Targeted immunotherapy using dendritic cells (DCs) has been employed in numerous investigations aiming at combating neoplasms. We previously showed that copulsing of an antigen with a helper protein could considerably enhance antigen presenting capacity of ex vivo-generated DCs. In this study, we attempted to administer an effective treatment in a murine model of colon cancer with DCs pulsed with the mixture of a tumor-specific gp70-derived peptide (AH1) and a helper protein, ovalbumin (OVA). PMID 25648091

Brain Tumor Immunotherapy: What have We Learned so Far?
Jul 2015 | Van Gool, Stefaan Willy
High grade glioma is a rare brain cancer, incurable in spite of modern neurosurgery, radiotherapy, and chemotherapy. Novel approaches are in research, and immunotherapy emerges as a promising strategy. Clinical experiences with active specific immunotherapy demonstrate feasibility, safety and most importantly, but incompletely understood, prolonged long-term survival in a fraction of the patients. In relapsed patients, we developed an immunotherapy schedule and we categorized patients into clinically defined risk profiles. We learned how to combine immunotherapy with standard multimodal treatment strategies for newly diagnosed glioblastoma multiforme patients. The developmental program allows further improvements related to newest scientific insights. Finally, we developed a mode of care within academic centers to organize cell-based therapies for experimental clinical trials in a large number of patients. PMID 26137448

Engineering monocyte-derived dendritic cells to secrete interferon-α enhances their ability to promote adaptive and innate anti-tumor immune effector functions.
Jun 2015 | Willemen, Yannick; Van den Bergh, Johan M J; Lion, Eva; Anguille, Sébastien; Roelandts, Vicky A E; Van Acker, Heleen H; Heynderickx, Steven D I; Stein, Barbara M H; Peeters, Marc; Figdor, Carl G; Van Tendeloo, Viggo F I; de Vries, I Jolanda; Adema, Gosse J; Berneman, Zwi N; Smits, Evelien L J
Dendritic cell (DC) vaccination has demonstrated potential in clinical trials as a new effective cancer treatment, but objective and durable clinical responses are confined to a minority of patients. Interferon (IFN)-α, a type-I IFN, can bolster anti-tumor immunity by restoring or increasing the function of DCs, T cells and natural killer (NK) cells. Moreover, type-I IFN signaling on DCs was found to be essential in mice for tumor rejection by the innate and adaptive immune system. Targeted delivery of IFN-α by DCs to immune cells could boost the generation of anti-tumor immunity, while avoiding the side effects frequently associated with systemic administration. Naturally circulating plasmacytoid DCs, major producers of type-I IFN, were already shown capable of inducing tumor antigen-specific T cell responses in cancer patients without severe toxicity, but their limited number complicates their use in cancer vaccination. In the present work, we hypothesized that engineering easily generated human monocyte-derived mature DCs to secrete IFN-α using mRNA electroporation enhances their ability to promote adaptive and innate anti-tumor immunity. Our results show that IFN-α mRNA electroporation of DCs significantly increases the stimulation of tumor antigen-specific cytotoxic T cell as well as anti-tumor NK cell effector functions in vitro through high levels of IFN-α secretion. Altogether, our findings mark IFN-α mRNA-electroporated DCs as potent inducers of both adaptive and innate anti-tumor immunity and pave the way for clinical trial evaluation in cancer patients. PMID 25863943

Dendritic Cell-Based Vaccines that Utilize Myeloid Rather than Plasmacytoid Cells Offer a Superior Survival Advantage in Malignant Glioma.
Jun 2015 | Dey, Mahua; Chang, Alan L; Miska, Jason; Wainwright, Derek A; Ahmed, Atique U; Balyasnikova, Irina V; Pytel, Peter; Han, Yu; Tobias, Alex; Zhang, Lingjiao; Qiao, Jian; Lesniak, Maciej S
Dendritic cells (DCs) are professional APCs that are traditionally divided into two distinct subsets, myeloid DC (mDCs) and plasmacytoid DC (pDCs). pDCs are known for their ability to secrete large amounts of IFN-α. Apart from IFN-α production, pDCs can also process Ag and induce T cell immunity or tolerance. In several solid tumors, pDCs have been shown to play a critical role in promoting tumor immunosuppression. We investigated the role of pDCs in the process of glioma progression in the syngeneic murine model of glioma. We show that glioma-infiltrating pDCs are the major APC in glioma and are deficient in IFN-α secretion (p < 0.05). pDC depletion leads to increased survival of the mice bearing intracranial tumor by decreasing the number of regulatory T cells (Tregs) and by decreasing the suppressive capabilities of Tregs. We subsequently compared the ability of mDCs and pDCs to generate effective antiglioma immunity in a GL261-OVA mouse model of glioma. Our data suggest that mature pDCs and mDCs isolated from naive mice can be effectively activated and loaded with SIINFEKL Ag in vitro. Upon intradermal injection in the hindleg, a fraction of both types of DCs migrate to the brain and lymph nodes. Compared to mice vaccinated with pDC or control mice, mice vaccinated with mDCs generate a robust Th1 type immune response, characterized by high frequency of CD4(+)T-bet(+) T cells and CD8(+)SIINFEKEL(+) T cells. This robust antitumor T cell response results in tumor eradication and long-term survival in 60% of the animals (p < 0.001). PMID 26026061

Rationale for a Multimodality Strategy to Enhance the Efficacy of Dendritic Cell-Based Cancer Immunotherapy.
Jun 2015 | Datta, Jashodeep; Berk, Erik; Cintolo, Jessica A; Xu, Shuwen; Roses, Robert E; Czerniecki, Brian J
Dendritic cells (DC), master antigen-presenting cells that orchestrate interactions between the adaptive and innate immune arms, are increasingly utilized in cancer immunotherapy. Despite remarkable progress in our understanding of DC immunobiology, as well as several encouraging clinical applications - such as DC-based sipuleucel-T for metastatic castration-resistant prostate cancer - clinically effective DC-based immunotherapy as monotherapy for a majority of tumors remains a distant goal. The complex interplay between diverse molecular and immune processes that govern resistance to DC-based vaccination compels a multimodality approach, encompassing a growing arsenal of antitumor agents which target these distinct processes and synergistically enhance DC function. These include antibody-based targeted molecular therapies, immune checkpoint inhibitors, therapies that inhibit immunosuppressive cellular elements, conventional cytotoxic modalities, and immune potentiating adjuvants. It is likely that in the emerging era of "precision" cancer therapeutics, tangible clinical benefits will only be realized with a multifaceted - and personalized - approach combining DC-based vaccination with adjunctive strategies. PMID 26082780

Dendritic cell regulation of NK-cell responses involves lymphotoxin-α, IL-12, and TGF-β.
Jun 2015 | Sarhan, Dhifaf; Palma, Marzia; Mao, Yumeng; Adamson, Lars; Kiessling, Rolf; Mellstedt, Håkan; Österborg, Anders; Lundqvist, Andreas
Dendritic cell (DC) vaccines induce T-cell responses in cancer patients. However, there is a paucity of data regarding the role of DC vaccines in shaping natural killer (NK) cell responses. Here, we observe that NK cells are less activated following DC vaccination. In vitro, DC-mediated inhibition of NK cells did not require cell-to-cell contact, but required increased Signal transducer and activator of transcription 3 (STAT3) phosphorylation (pSTAT3) in DCs. When phosphorylation of STAT3 was inhibited in DCs, we found that DCs did not suppress NK cells, and observed an increase in the production of lymphotoxin-alpha (LTα) and interleukin-12 (IL-12) as well as reduced release of transforming growth factor beta (TGF-β). The addition of recombinant LTα or IL-12 to the DC-NK-cell cocultures restored NK-cell activity, and neutralization of TGF-β resulted in elevated production of LTα and IL-12 from DCs. Compared with LPS, DCs matured with a cocktail of R848, poly I:C, and IFN-γ showed reduced levels of pSTAT3 and higher levels of LTα and IL-12 and did not inhibit NK-cell activity. These results show that LTα, IL-12, and TGF-β are involved in the cross-talk between NK cells and DCs. Our findings have important implications for the development of DC-based vaccination strategies to potentiate NK-cell responses in patients with cancer. PMID 25773885

Dendritic cell-based vaccination in cancer: therapeutic implications emerging from murine models.
Jun 2015 | Mac Keon, Soledad; Ruiz, María Sol; Gazzaniga, Silvina; Wainstok, Rosa
Dendritic cells (DCs) play a pivotal role in the orchestration of immune responses, and are thus key targets in cancer vaccine design. Since the 2010 FDA approval of the first cancer DC-based vaccine (Sipuleucel-T), there has been a surge of interest in exploiting these cells as a therapeutic option for the treatment of tumors of diverse origin. In spite of the encouraging results obtained in the clinic, many elements of DC-based vaccination strategies need to be optimized. In this context, the use of experimental cancer models can help direct efforts toward an effective vaccine design. This paper reviews recent findings in murine models regarding the antitumoral mechanisms of DC-based vaccination, covering issues related to antigen sources, the use of adjuvants and maturing agents, and the role of DC subsets and their interaction in the initiation of antitumoral immune responses. The summary of such diverse aspects will highlight advantages and drawbacks in the use of murine models, and contribute to the design of successful DC-based translational approaches for cancer treatment. PMID 26042126

Survivin and PSMA Loaded Dendritic Cell Vaccine for the Treatment of Prostate Cancer.
Jun 2015 | Xi, Hai-Bo; Wang, Gong-Xian; Fu, Bin; Liu, Wei-Peng; Li, Yu
Dendritic cell (DC)-based vaccines are a promising therapeutic modality for cancer. Results from recent trials and approval of the first DC vaccine by the U.S. Food and Drugs Administration for prostate cancer have paved the way for DC-based vaccines. A total of 21 hormone refractory prostate cancer (HRPC) patients with a life expectancy >3 months were randomised into two groups. DC loaded with recombinant Prostate Specific Membrane Antigen (rPSMA) and recombinant Survivin (rSurvivin) peptides was administered as an subcutaneous (s.c.) injection (5×10(6) cells). Docetaxel (75 mg/m(2) intravenous (i.v.)) and prednisone (5 mg, bis in die (b.i.d.)) served as control. Clinical and immunological responses were evaluated. Primary endpoints were safety and feasibility; secondary endpoint was overall survival. Responses were evaluated on day 15, day 30, day 60, and day 90. DC vaccination was well tolerated with no signs of grade 2 toxicity. DC vaccination induced delayed-type hypersensitivity reactivity and an immune response in all patients. Objective Response Rate (ORR) by Response Evaluation Criteria in Solid Tumours (RECIST) was 72.7% (8/11) versus 45.4 (5/11) in the docetaxel arm and immune related response criteria (irRC) was 54.5% (6/11) compared with 27.2% (3/11) in the control arm. The DC arm showed stable disease (SD) in 6 patients, progressive disease (PD) in 3 patients, and partial remission (PR) in two patients compared to SD in 5 patients, PD in 6 patients, and PR in none in the docetaxel arm. There was a cellular response, disease stabilization, no adverse events, and partial remission with the rPSMA and rSurvivin primed DC vaccine. PMID 25787895

Clinical efficacy of tumor antigen-pulsed DC treatment for high-grade glioma patients: evidence from a meta-analysis.
May 2015 | Cao, Jun-Xia; Zhang, Xiao-Yan; Liu, Jin-Long; Li, Duo; Li, Jun-Li; Liu, Yi-Shan; Wang, Min; Xu, Bei-Lei; Wang, Hai-Bo; Wang, Zheng-Xu
The effectiveness of immunotherapy for high-grade glioma (HGG) patients remains controversial. To evaluate the therapeutic efficacy of dendritic cells (DCs) alone in the treatment of HGG, we performed a systematic review and meta-analysis in terms of patient survival with relevant published clinical studies. PMID 25215607

Immunotherapy for castration-resistant prostate cancer: Progress and new paradigms.
May 2015 | Quinn, David I; Shore, Neal D; Egawa, Shin; Gerritsen, Winald R; Fizazi, Karim
The approval of sipuleucel-T in conjunction with data from other immunotherapeutic trials for prostate cancer and other solid tumors demonstrates the potential of harnessing the patients' immune system for long-term survival. Thus, a range of therapeutic approaches are under evaluation. This review describes the rationale for immunotherapy for prostate cancer, summarizes the approaches under evaluation, and discusses sequencing options for immunotherapy in the current treatment paradigm. PMID 25575714

Cancer immunotherapy. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells.
May 2015 | Carreno, Beatriz M; Magrini, Vincent; Becker-Hapak, Michelle; Kaabinejadian, Saghar; Hundal, Jasreet; Petti, Allegra A; Ly, Amy; Lie, Wen-Rong; Hildebrand, William H; Mardis, Elaine R; Linette, Gerald P
T cell immunity directed against tumor-encoded amino acid substitutions occurs in some melanoma patients. This implicates missense mutations as a source of patient-specific neoantigens. However, a systematic evaluation of these putative neoantigens as targets of antitumor immunity is lacking. Moreover, it remains unknown whether vaccination can augment such responses. We found that a dendritic cell vaccine led to an increase in naturally occurring neoantigen-specific immunity and revealed previously undetected human leukocyte antigen (HLA) class I-restricted neoantigens in patients with advanced melanoma. The presentation of neoantigens by HLA-A*02:01 in human melanoma was confirmed by mass spectrometry. Vaccination promoted a diverse neoantigen-specific T cell receptor (TCR) repertoire in terms of both TCR-β usage and clonal composition. Our results demonstrate that vaccination directed at tumor-encoded amino acid substitutions broadens the antigenic breadth and clonal diversity of antitumor immunity. PMID 25837513

Cellular immunotherapy in ovarian cancer: Targeting the stem of recurrence.
May 2015 | Wefers, Christina; Lambert, Laurens J; Torensma, Ruurd; Hato, Stanleyson V
Ovarian cancer is a devastating disease with a high relapse rate. Due to a mostly asymptomatic early stage and lack of early diagnostic tools, the disease is usually diagnosed in a late stage. Surgery and chemotherapy with taxanes and platinum compounds are very effective in reducing tumor burden. However, relapses occur frequently and there is a lack of credible second-line options. Therefore, new treatment modalities are eagerly awaited. The presence and influx of immune cells in the ovarian cancer tumor microenvironment are correlated with survival. High numbers of infiltrating T cells correlate with improved progression free and overall survival, while the presence of regulatory T cells and expression of T cell inhibitory molecules is correlated with a poor prognosis. These data indicate that immunotherapy, especially cell-based immunotherapy could be a promising novel addition to the treatment of ovarian cancer. Here, we review the available data on the immune contexture surrounding ovarian cancer and discuss novel strategies and targets for immunotherapy in ovarian cancer. In the end the addition of immunotherapy to existing therapeutic options could lead to a great improvement in the outcome of ovarian cancer, especially when targeting cancer stem cells. PMID 25727651

Autologous dendritic cell based adoptive immunotherapy of patients with colorectal cancer-A phase I-II study.
Apr 2015 | Hunyadi, János; András, Csilla; Szabó, Imre; Szántó, János; Szluha, Kornélia; Sipka, Sándor; Kovács, Péter; Kiss, Attila; Szegedi, Gyula; Altorjay, István; Sápy, Péter; Antal-Szalmás, Péter; Tóth, László; Fazekas, György; Rajnavölgyi, Éva
Dendritic cell-based active immunotherapies of cancer patients are aimed to provoke the proliferation and differentiation of tumor-specific CD4(+) and CD8(+) T-lymphocytes towards protective effector cells. Isolation and in vitro differentiation of circulating blood monocytes has been established a reasonable platform for adoptively transferred DC-based immunotherapies. In the present study the safety and tolerability of vaccination by autologous tumor cell lysates (oncolysate)- or carcinoembriogenic antigen (CEA)-loaded DCs in patients with colorectal cancer was investigated in a phase I-II trial. The study included 12 patients with histologically confirmed colorectal cancer (Dukes B2-C stages). Six of the patients received oncolysate-pulsed, whereas the other six received recombinant CEA-loaded autologous DCs. The potential of the tumor antigen-loaded DCs to provoke the patient's immune system was studied both in vivo and in vitro. The clinical outcome of the therapy evaluated after 7 years revealed that none of the six patients treated with oncolysate-loaded DCs showed relapse of colorectal cancer, whereas three out of the six patients treated with CEA-loaded DCs died because of tumor relapse. Immunization with both the oncolysate- and the CEA-loaded autologous DCs induced measurable immune responses, which could be detected in vivo by cutaneous reactions and in vitro by lymphocyte proliferation assay. Our results show that vaccination by autologous DCs loaded with autologous oncolysates containing various tumor antigens represents a well tolerated therapeutic modality in patients with colorectal cancer without any detectable adverse effects. Demonstration of the efficacy of such therapy needs further studies with increased number of patients. PMID 24163303

Dendritic Cell-Based Cancer Immunotherapy against Multiple Myeloma: From Bench to Clinic.
Apr 2015 | Hoang, My-Dung; Jung, Sung-Hoon; Lee, Hyun-Ju; Lee, Youn-Kyung; Nguyen-Pham, Thanh-Nhan; Choi, Nu-Ri; Vo, Manh-Cuong; Lee, Seung-Shin; Ahn, Jae-Sook; Yang, Deok-Hwan; Kim, Yeo-Kyeoung; Kim, Hyeoung-Joon; Lee, Je-Jung
Although the introduction of stem cell transplantation and novel agents has improved survival, multiple myeloma (MM) is still difficult to cure. Alternative approaches are clearly needed to prolong the survival of patients with MM. Dendritic cell (DC) therapy is a very promising tool immunologically in MM. We developed a method to generate potent DCs with increased Th1 polarization and migration ability for inducing strong myeloma-specific cytotoxic T lymphocytes. In this review, we discuss how the efficacy of cancer immunotherapy using DCs can be improved in MM. PMID 25914874

Phase I pilot study of Wilms tumor gene 1 peptide-pulsed dendritic cell vaccination combined with gemcitabine in pancreatic cancer.
Apr 2015 | Mayanagi, Shuhei; Kitago, Minoru; Sakurai, Toshiharu; Matsuda, Tatsuo; Fujita, Tomonobu; Higuchi, Hajime; Taguchi, Junichi; Takeuchi, Hiroya; Itano, Osamu; Aiura, Koichi; Hamamoto, Yasuo; Takaishi, Hiromasa; Okamoto, Masato; Sunamura, Makoto; Kawakami, Yutaka; Kitagawa, Yuko
This study aimed to evaluate the feasibility of and immune response to Wilms tumor gene 1 (WT1) peptide-pulsed dendritic cell vaccination combined with gemcitabine (DCGEM) as a first-line therapy among patients with advanced pancreatic cancer. Ten HLA-A*2402 patients were treated with WT1 peptide-pulsed DC vaccination (1 × 10(7) cells) on days 8 and 22 and gemcitabine (1000 mg/m(2) ) on days 1, 8 and 15. Induction of a WT1-specific immune response was evaluated using the delayed-type hypersensitivity (DTH) skin test, interferon-γ enzyme-linked immunospot and HLA tetramer assays, along with assays for various immunological factors. DCGEM was well-tolerated, and the relative dose intensity of gemcitabine was 87%. Disease control associated with a low neutrophil/lymphocyte ratio was observed in all three patients with DTH positivity; it was also correlated with a low percentage of granulocytic myeloid derived suppressor cells in the pretreatment peripheral blood (P = 0.017). Patients with liver metastases and high levels of inflammatory markers such as C-reactive protein and interleukin-8 (IL-8) showed poor survival even though a WT1-specific immune response was induced in them. WT1 peptide-pulsed DCGEM is feasible and effective for inducing anti-tumor T-cell responses. Our results support future investigations for pancreatic cancer patients with non-liver metastases and favorable immunological conditions. This trial was registered with the University hospital Medical Information Network (UMIN) Clinical Trials Registry ( number: UMIN-000004855). PMID 25614082

Clinical outcomes of a novel therapeutic vaccine with Tax peptide-pulsed dendritic cells for adult T cell leukaemia/lymphoma in a pilot study.
Apr 2015 | Suehiro, Youko; Hasegawa, Atsuhiko; Iino, Tadafumi; Sasada, Amane; Watanabe, Nobukazu; Matsuoka, Masao; Takamori, Ayako; Tanosaki, Ryuji; Utsunomiya, Atae; Choi, Ilseung; Fukuda, Tetsuya; Miura, Osamu; Takaishi, Shigeo; Teshima, Takanori; Akashi, Koichi; Kannagi, Mari; Uike, Naokuni; Okamura, Jun
Adult T cell leukaemia/lymphoma (ATL) is a human T cell leukaemia virus type-I (HTLV-I)-infected T cell malignancy with poor prognosis. We herein developed a novel therapeutic vaccine designed to augment an HTLV-I Tax-specific cytotoxic T lymphocyte (CTL) response that has been implicated in anti-ATL effects, and conducted a pilot study to investigate its safety and efficacy. Three previously treated ATL patients, classified as intermediate- to high-risk, were subcutaneously administered with the vaccine, consisting of autologous dendritic cells (DCs) pulsed with Tax peptides corresponding to the CTL epitopes. In all patients, the performance status improved after vaccination without severe adverse events, and Tax-specific CTL responses were observed with peaks at 16-20 weeks. Two patients achieved partial remission in the first 8 weeks, one of whom later achieved complete remission, maintaining their remission status without any additional chemotherapy 24 and 19 months after vaccination, respectively. The third patient, whose tumour cells lacked the ability to express Tax at biopsy, obtained stable disease in the first 8 weeks and later developed slowly progressive disease although additional therapy was not required for 14 months. The clinical outcomes of this pilot study indicate that the Tax peptide-pulsed DC vaccine is a safe and promising immunotherapy for ATL. PMID 25612920

Precision cancer immunotherapy: optimizing dendritic cell-based strategies to induce tumor antigen-specific T-cell responses against individual patient tumors.
Apr 2015 | Osada, Takuya; Nagaoka, Koji; Takahara, Masashi; Yang, Xiao Yi; Liu, Cong-Xiao; Guo, Hongtao; Roy Choudhury, Kingshuk; Hobeika, Amy; Hartman, Zachary; Morse, Michael A; Lyerly, H Kim
Most dendritic cell (DC)-based vaccines have loaded the DC with defined antigens, but loading with autologos tumor-derived antigens would generate DCs that activate personalized tumor-specific T-cell responses. We hypothesized that DC matured with an optimized combination of reagents and loaded with tumor-derived antigens using a clinically feasible electroporation strategy would induce potent antitumor immunity. We first studied the effects on DC maturation and antigen presentation of the addition of picibanil (OK432) to a combination of zoledronic acid, tumor necrosis factor-α, and prostaglandin E2. Using DC matured with the optimized combination, we tested 2 clinically feasible sources of autologous antigen for electroloading, total tumor mRNA or total tumor lysate, to determine which stimulated more potent antigen-specific T cells in vitro and activated more potent antitumor immunity in vivo. The combination of tumor necrosis factor-α/prostaglandin E2/zoledronic acid/OK432 generated DC with high expression of maturation markers and antigen-specific T-cell stimulatory function in vitro. Mature DC electroloaded with tumor-derived mRNA [mRNA electroporated dendritic cell (EPDC)] induced greater expansion of antigen-specific T cells in vitro than DC electroloaded with tumor lysate (lysate EPDC). In a therapeutic model of MC38-carcinoembryonic antigen colon cancer-bearing mice, vaccination with mRNA EPDC induced the most efficient anti-carcinoembryonic antigen cellular immune response, which significantly suppressed tumor growth. In conclusion, mature DC electroloaded with tumor-derived mRNA are a potent cancer vaccine, especially useful when specific tumor antigens for vaccination have not been identified, allowing autologous tumor, and if unavailable, allogeneic cell lines to be used as an unbiased source of antigen. Our data support clinical testing of this strategy. PMID 25839441

Antitumor Responses Stimulated by Dendritic Cells Are Improved by Triiodothyronine Binding to the Thyroid Hormone Receptor β.
Apr 2015 | Alamino, Vanina A; Mascanfroni, Iván D; Montesinos, María M; Gigena, Nicolás; Donadio, Ana C; Blidner, Ada G; Milotich, Sonia I; Cheng, Sheue-Yann; Masini-Repiso, Ana M; Rabinovich, Gabriel A; Pellizas, Claudia G
Bidirectional cross-talk between the neuroendocrine and immune systems orchestrates immune responses in both physiologic and pathologic settings. In this study, we provide in vivo evidence of a critical role for the thyroid hormone triiodothyronine (T3) in controlling the maturation and antitumor functions of dendritic cells (DC). We used a thyroid hormone receptor (TR) β mutant mouse (TRβPV) to establish the relevance of the T3-TRβ system in vivo. In this model, TRβ signaling endowed DCs with the ability to stimulate antigen-specific cytotoxic T-cell responses during tumor development. T3 binding to TRβ increased DC viability and augmented DC migration to lymph nodes. Moreover, T3 stimulated the ability of DCs to cross-present antigens and to stimulate cytotoxic T-cell responses. In a B16-OVA mouse model of melanoma, vaccination with T3-stimulated DCs inhibited tumor growth and prolonged host survival, in part by promoting the generation of IFNγ-producing CD8(+) T cells. Overall, our results establish an adjuvant effect of T3-TRβ signaling in DCs, suggesting an immediately translatable method to empower DC vaccination approaches for cancer immunotherapy. PMID 25672979

Decreased HIV-specific T-regulatory responses are associated with effective DC-vaccine induced immunity.
Mar 2015 | Brezar, Vedran; Ruffin, Nicolas; Richert, Laura; Surenaud, Mathieu; Lacabaratz, Christine; Palucka, Karolina; Thiébaut, Rodolphe; Banchereau, Jacques; Levy, Yves; Seddiki, Nabila
The role of regulatory T cells (Tregs) in vaccination has been poorly investigated. We have reported that vaccination with ex vivo-generated dendritic-cells (DC) loaded with HIV-lipopeptides (LIPO-5-DC vaccine) in HIV-infected patients was well tolerated and highly immunogenic. These responses and their relation to viral replication following analytical treatment interruption (ATI) were variable. Here, we investigated whether the presence of HIV-specific Tregs might explain these differences. Co-expression of CD25, CD134, CD39 and FoxP3 was used to delineate both antigen-specific Tregs and effectors T cells (Teffs). Median LIPO-5 specific-CD25+CD134+ polyfunctional T cells increased from 0.1% (IQR 0-0.3) before vaccination (week -4) to 2.1% (IQR 1.1-3.9) at week 16 following 4 immunizations (p=0.001) and were inversely correlated with maximum viral load following ATI (r=-0.77, p=0.001). Vaccinees who displayed lower levels of HIV-specific CD4+CD134+CD25+CD39+FoxP3+ Tregs responded better to the LIPO-5-DC vaccine. After vaccination, the frequency of HIV-specific Tregs decreased (from 69.3 at week -4 to 31.7% at week 16) and inversely correlated with HIV-specific IFN-γ-producing cells (r=-0.64, p=0.002). We show that therapeutic immunization skewed the HIV-specific response from regulatory to effector phenotype which impacts on the magnitude of viral replication following ATI. PMID 25816350

Immunotherapy for lung cancer: for whom the bell tolls?
Mar 2015 | Madureira, Pedro; de Mello, Ramon Andrade; de Vasconcelos, Alessandro; Zhang, Yan
Lung cancer is the leading cause of cancer-related death and accounts for approximately 30% of all cancer deaths. Despite the recent developments in personalized therapy, the prognosis in lung cancer is still very poor. Immunotherapy is now emerging as a new hope for patients with lung cancer. It is well known that standard chemotherapeutic regimens have devastating effects for the patient's immune system. Therefore, the aim of immunotherapy is to specifically enhance the immune response against the tumour. Recently, many trials addressed the role of such therapies for metastatic non-small cell lung cancer (NSCLC) treatment: ipilimumab, tremelimumab, nivolumab and pembrolizumab are immunotherapeutic agents of high relevance in this field. Anti-tumour vaccines, as well as dendritic cell-based therapies, have emerged as potent inducers of immune response against the tumour. Herein, we will review some of the most promising cancer immunotherapies, highlighting their advantages and try to understand, in an immunological perspective, the missteps associated with the current treatments for cancer. PMID 25736929

A novel cancer immunotherapy based on the combination of a synthetic carbohydrate-pulsed dendritic cell vaccine and glycoengineered cancer cells.
Mar 2015 | Qiu, Lei; Li, Jie; Yu, Shichong; Wang, Qianli; Li, Yinghua; Hu, Zhenlin; Wu, Qiuye; Guo, Zhongwu; Zhang, Junping
Immune tolerance to tumor-associated carbohydrate antigens (TACAs) has severely restricted the usefulness of most TACAs. To overcome this problem, we selected a sialylated trisaccharide TACA, GM3, as a target antigen, and tested a new immunotherapeutic strategy by combining metabolic bioengineering with dendritic cell (DC) vaccination. We engineered cancer cells to express an artificial structure, N-phenylacetyl-D-neuraminic acid, in place of the natural N-acetyl-D-neuraminic acid of GM3 by using N-phenylacetyl-D-mannosamine (ManNPhAc) as a biosynthetic precursor. Next, we selectively targeted the bioengineered cancer cells by vaccination with DCs pulsed with the GM3 N-phenylacetyl derivative. Vaccination with GM3NPhAc-KLH-loaded DCs elicited robust GM3NPhAc-specific T cell-dependent immunity. The results showed that this strategy could significantly inhibit FBL3 tumor growth and prolong the survival of tumor-bearing mice; B16F10 lung metastases could also be reduced. These findings lay out a new strategy for overcoming immune tolerance to TACAs, such as GM3, for the development of effective tumor immunotherapies. PMID 25760071

Dendritic cell immunotherapy combined with cytokine-induced killer cells promotes skewing toward Th2 cytokine profile in patients with metastatic non-small cell lung cancer.
Mar 2015 | Zhao, Peng; Bu, Xiaocui; Wei, Xiaofang; Sun, Weihong; Xie, Xihe; Li, Changyou; Guo, Qingming; Zhu, Danni; Wei, Xiaoqiang; Gao, Daiqing
Dendritic cell (DC) vaccination and cytokine-induced killer (CIK) cell therapy (DC/CIK) have shown limited success in the treatment of advanced non-small cell lung cancer (NSCLC). To investigate the reason for this limited success, the effects of DC/CIK cell therapy on the immune responses of tumor-bearing patients and patients with resected NSCLC were evaluated. In the total 50 patients studied, the serum concentrations of the Th2 cytokines (IL-4 and IL-10) in tumor-bearing patients were significantly higher than those with resected NSCLC before immunotherapy. The post-therapy Th1 cytokine (IFN-γ) level in patients with resected NSCLC significantly increased from the pre-therapy level. In contrast, significantly enhanced post-therapy Th2 cytokine (IL-4 and IL-10) levels were found in tumor-bearing patients. The intracellular staining assay revealed that DC/CIK cell therapy increased the IFN-γ-producing T lymphocyte (CD8(+)IFN-γ(+)) frequency in patients with resected NSCLC, but these lymphocytes were not found in tumor-bearing patients. Furthermore, overproduction of vascular endothelial growth factor (VEGF) in tumor-bearing patients showed a statistically positive correlation with IL-4, suggesting that VEGF might be responsible for the predominance of serum Th2 cytokines. In a word, tumor-bearing patients developed a Th2-dominant status that could not be reversed toward Th1 following immunotherapy. A combined regiment of DC vaccination and CIK cell therapy with other treatments to overcome systemic Th2-dominant immune response might improve the current clinical benefit. PMID 25698555

Dendritic cell-based vaccine efficacy: aiming for hot spots.
Mar 2015 | Pizzurro, Gabriela Andrea; Barrio, María Marcela
Many approaches for cancer immunotherapy have targeted dendritic cells (DCs), directly or indirectly, for the induction of antitumor immune responses. DC-based vaccines have been developed using a wide variety of ex vivo DC culture conditions, antigen (Ag) source and loading strategies, maturation agents, and routes of vaccination. Adjuvants are used to activate innate immune cells at the vaccine injection site, to promote Ag transport to the draining lymph nodes (LNs) and to model adaptive immune responses. Despite years of effort, the effective induction of strong and durable antitumor T-cell responses in vaccinated patients remains a challenge. The study of vaccine interactions with other immune cells in the LNs and, more recently, in the injection site has opened new doors for understanding antitumor effector T-cell licensing and function. In this review, we will briefly discuss the relevant sites and up-to-date facts regarding possible targets for antitumor vaccine refinement. We will focus on the processes taking place at the injection site, adjuvant combinations and their role in DC-based vaccines, LN homing, and modeling vaccine-induced immune responses capable of controlling tumor growth and generating immune memory. PMID 25784913

Matched-pair analysis of dendritic cell versus targeted-therapy in patients with metastatic renal cell carcinoma.
Mar 2015 | Isaak, Alexander; Hauser, Stefan; Rogenhofer, Sebastian; Schmidt-Wolf, Ingo G H
Although targeted-therapy (TT) for patients with metastatic renal cell cancer (mRCC) has shown an improved outcome, their prognosis is still very poor. Immunotherapy with dendritic cells (DC) as one promising new treatment tries to fight cancer by boosting the patient's own immune system. The present analysis matches two different methods of treatment against mRCC, namely sequential TT versus DC vaccine therapy, by comparison of long-term overall survival (OS). PMID 25750313

A vaccine strategy with multiple prostatic acid phosphatase-fused cytokines for prostate cancer treatment.
Feb 2015 | Fujio, Kei; Watanabe, Masami; Ueki, Hideo; Li, Shun-Ai; Kinoshita, Rie; Ochiai, Kazuhiko; Futami, Junichiro; Watanabe, Toyohiko; Nasu, Yasutomo; Kumon, Hiromi
Immunotherapy is one of the attractive treatment strategies for advanced prostate cancer. The US Food and Drug Administration (FDA) previously approved the therapeutic vaccine, sipuleucel-T, which is composed of autologous antigen-presenting cells cultured with a fusion protein [prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GMCSF)]. Although sipuleucel-T has been shown to prolong the median survival of patients for 4.1 months, more robust therapeutic effects may be expected by modifying the vaccination protocol. In the present study, we aimed to develop and validate a novel vaccination strategy using multiple PAP-fused cytokines for prostate cancer treatment. Using a super gene expression (SGE) system that we previously established to amplify the production of a recombinant protein, significant amounts of PAP-fused cytokines [human GMCSF, interleukin-2 (IL2), IL4, IL7 and mouse GMCSF and IL4] were obtained. We examined the activity of the fusion proteins in vitro to validate their cytokine functions. A significant upregulation of dendritic cell differentiation from monocytes was achieved by PAP-GMCSF when used with the other PAP-fused cytokines. The PAP-fused human IL2 significantly increased the proliferation of lymphocytes, as determined by flow cytometry. We also investigated the in vivo therapeutic effects of multiple PAP-fused cytokines in a mouse prostate cancer model bearing prostate-specific antigen (PSA)- and PAP-expressing tumors. The simultaneous intraperitoneal administration of PAP-GMCSF, -IL2, -IL4 and -IL7 significantly prevented tumor induction and inhibited the tumor growth in the PAP-expressing tumors, yet not in the PSA-expressing tumors. The in vivo therapeutic effects with the multiple PAP-fused cytokines were superior to the effects of PAP-GMCSF alone. We thus demonstrated the advantages of the combined use of multiple PAP-fused cytokines including PAP-GMCSF, and propose a promising prostatic antigen-vaccination strategy to enhance the therapeutic effects. PMID 25632844

Immune responses in patients with esophageal cancer treated with SART1 peptide-pulsed dendritic cell vaccine.
Feb 2015 | Narita, Miwako; Kanda, Tatsuo; Abe, Takashi; Uchiyama, Takayoshi; Iwafuchi, Minami; Zheng, Zhiyin; Liu, Aichun; Kaifu, Tsutomu; Kosugi, Shinichi; Minagawa, Masahiro; Itoh, Kyogo; Takahashi, Masuhiro
Patients with advanced stage of squamous cell carcinoma of esophagus have a poor prognosis with a lethal outcome. In order to explore the feasibility and effectiveness of dendritic cell (DC)-based immunotherapy for squamous cell carcinoma of esophagus, we performed a phase I/II clinical trial of monocyte-derived dendritic cells (moDCs) pulsed with SART1 peptide in seven patients with advanced stage of this disease. Although the feasibility of this therapy was definite, the effectiveness was not clearly confirmed in advanced stage of squamous cell carcinoma of esophagus. However, in vitro study revealed that moDCs generated for this therapy possessed a potent ability of inducing SART1 peptide-specific cytotoxic T lymphocytes (CTLs). In addition, these moDCs were demonstrated to be able to produce exosomes with an antigen presenting ability for inducing SART1 peptide-specific CTLs. ELISPOT assay using cryopreserved patient's lymphocytes demonstrated that IFN-γ ELISPOTs were increased after four times of SART1 peptide-pulsed moDC vaccinations compared with before the vaccination in a patient. The present study demonstrated that moDCs prepared from advanced stage of squamous cell carcinoma of esophagus possess a good immune function and in vivo immune responses (detected by ELISPOT assay) were evoked by the infusion of these moDCs. These findings suggest that DC-based immunotherapy could be one of the modalities applicable for squamous cell carcinoma of esophagus. PMID 25625346

Adoptive cellular immunotherapy for the treatment of patients with breast cancer: a meta-analysis.
Feb 2015 | Wang, Zheng-Xu; Cao, Jun-Xia; Wang, Min; Li, Duo; Cui, Yu-Xin; Zhang, Xiao-Yan; Liu, Jin-Long; Li, Jun-Li
To evaluate the therapeutic efficacy of dendritic cells (DC) alone, cytokine-induced killer (CIK) cells alone and the combination of DC and CIK cells in the treatment of breast cancer, we performed a systemic review of the relevant published clinical studies, collectively referred to as DC-CIK cell therapy. PMID 24794183

Novel dendritic cell-based vaccination in late stage melanoma.
Jan 2015 | Schneble, Erika J; Yu, Xianzhong; Wagner, T E; Peoples, George E
Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that play an important role in stimulating an immune response of both CD4(+) T helper cells and CD8(+) cytotoxic T lymphocytes (CTLs). As such, DCs have been studied extensively in cancer immunotherapy for their capability to induce a specific anti-tumor response when loaded with tumor antigens. However, when the most relevant antigens of a tumor remain to be identified, alternative approaches are required. Formation of a dentritoma, a fused DC and tumor cells hybrid, is one strategy. Although initial studies of these hybrid cells are promising, several limitations interfere with its clinical and commercial application. Here we present early experience in clinical trials and an alternative approach to manufacturing this DC/tumor cell hybrid for use in the treatment of late stage and metastatic melanoma. PMID 25483650

Tumor cell lysates as immunogenic sources for cancer vaccine design.
Jan 2015 | González, Fermín E; Gleisner, Alejandra; Falcón-Beas, Felipe; Osorio, Fabiola; López, Mercedes N; Salazar-Onfray, Flavio
Autologous dendritic cells (DCs) loaded with tumor-associated antigens (TAAs) are a promising immunological tool for cancer therapy. These stimulate the antitumor response and immunological memory generation. Nevertheless, many patients remain refractory to DC approaches. Antigen (Ag) delivery to DCs is relevant to vaccine success, and antigen peptides, tumor-associated proteins, tumor cells, autologous tumor lysates, and tumor-derived mRNA have been tested as Ag sources. Recently, DCs loaded with allogeneic tumor cell lysates were used to induce a potent immunological response. This strategy provides a reproducible pool of almost all potential Ags suitable for patient use, independent of MHC haplotypes or autologous tumor tissue availability. However, optimizing autologous tumor cell lysate preparation is crucial to enhancing efficacy. This review considers the role of cancer cell-derived lysates as a relevant source of antigens and as an activating factor for ex vivo therapeutic DCs capable of responding to neoplastic cells. These promising therapies are associated with the prolonged survival of advanced cancer patients. PMID 25625929

Clinical trials of dendritic cell-based cancer vaccines in hematologic malignancies.
Jan 2015 | Pyzer, Athalia R; Avigan, David E; Rosenblatt, Jacalyn
The potential for the immune system to target hematological malignancies is demonstrated in the allogeneic transplant setting, where durable responses can be achieved. However, allogeneic transplantation is associated with significant morbidity and mortality related to graft versus host disease. Cancer immunotherapy has the capacity to direct a specific cytotoxic immune response against cancer cells, particularly residual cancer cells, in order to reduce the likelihood of disease relapse in a more targeted and tolerated manner. Ex vivo dendritic cells can be primed in various ways to present tumor associated antigen to the immune system, in the context of co-stimulatory molecules, eliciting a tumor specific cytotoxic response in patients. Several approaches to prime dendritic cells and overcome the immunosuppressive microenvironment have been evaluated in pre-clinical and early clinical trials with promising results. In this review, we summarize the clinical data evaluating dendritic cell based vaccines for the treatment of hematological malignancies. PMID 25625926

Dendritic cell-based vaccine research against cancer.
Jan 2015 | Mody, Nishi; Dubey, Surbhi; Sharma, Rajeev; Agrawal, Udita; Vyas, Suresh P
Therapeutic vaccines that treat cancers with the help of the patient's own immune system signify a feasible option for active immunotherapy against the disease. Dendritic cells (DCs) play a central role in modulating the immune response and thus can be wisely utilized as an immunotherapeutic strategy for cancer regimens. Advances in the knowledge of DC biology and function have led to the development of DC-based vaccines for cancer therapy. In the present review, we discuss the biology and function of DCs, their subsets and receptors, antigen loading and route of administration of DC vaccines, as well as active and passive targeting strategies for treating the cancer. We also discuss the preclinical and clinical status of these newly developed vaccines. Special attention should be given by the scientific community to the challenges that need to be solved for the successful implication of these vaccines in cancer therapy. PMID 25467734

Therapeutic DC vaccination with IL-2 as a consolidation therapy for ovarian cancer patients: a phase I/II trial.
Jan 2015 | Baek, Soyoung; Kim, Yong-Man; Kim, Sung-Bae; Kim, Choung-Soo; Kwon, Seog-Woon; Kim, YongMan; Kim, HyunSoo; Lee, Hyunah
While ovarian cancer (OvCa) responds well to surgery and conventional chemotherapy, a high recurrence rate of advanced OvCa is observed. In this phase I/II study, 10 OvCa patients with minimal residual disease were treated with autologous dendritic cells (DCs) and IL-2 to evaluate the safety and feasibility of this therapeutic strategy and to characterize the antigen-specific immune alterations induced through this treatment. Approximately 4 months after initial debulking and chemotherapy, patients received two subcutaneous doses of autologous monocyte-derived DCs pulsed with autologous tumor lysate and keyhole limpet hemocyanin (KLH) at 4-week intervals. After each DC inoculation, low-dose (200 mIU) IL-2 was introduced for 14 consecutive days as an immune adjuvant. The vaccination was well tolerated. In three out of 10 patients, the inclusion status after the initial therapy showed the maintenance of complete remission (CR) after DC vaccination for 83, 80.9 and 38.2 months without disease relapse. One patient with stable disease (SD) experienced the complete disappearance of tumor after DC vaccination, and this status was maintained for 50.8 months until tumor recurrence. In two patients with partial response (PR) was not responding to DC vaccination and their disease recurred. In the three patients with disease free long-term survival, significant immune alterations were observed, including increased natural killer (NK) activity, IFN-γ-secreting T cells, immune-stimulatory cytokine secretion and reduced immune-suppressive factor secretion after DC vaccination. Thus, in patients with NED status and increased overall survival, DC vaccination induced tumor-related immunity, potentially associated with long-term clinical responses against OvCa. PMID 24976269

Randomized controlled phase III trial of adjuvant chemo-immunotherapy with activated killer T cells and dendritic cells in patients with resected primary lung cancer.
Jan 2015 | Kimura, Hideki; Matsui, Yukiko; Ishikawa, Aki; Nakajima, Takahiro; Yoshino, Mitsuru; Sakairi, Yuichi
We conducted a phase III randomized controlled trial (RCT) to investigate the efficacy of postsurgical adjuvant immunotherapy combined with chemotherapy. The immunotherapy targets were residual micrometastases and clones resistant to chemotherapy. PMID 25262164

Prognostic markers for patient outcome following vaccination with multiple MHC Class I/II-restricted WT1 peptide-pulsed dendritic cells plus chemotherapy for pancreatic cancer.
Dec 2014 | Takakura, Kazuki; Koido, Shigeo; Kan, Shin; Yoshida, Kosaku; Mori, Masako; Hirano, Yuta; Ito, Zensho; Kobayashi, Hiroko; Takami, Shinichiro; Matsumoto, Yoshihiro; Kajihara, Mikio; Misawa, Takeyuki; Okamoto, Masato; Sugiyama, Haruo; Homma, Sadamu; Ohkusa, Toshifumi; Tajiri, Hisao
Treatment combining dendritic cells (DCs) pulsed with three types of major histocompatibility complex (MHC) class I and II (DC/WT1-I/II)-restricted Wilms' tumor 1 (WT1) peptides with chemotherapy may stabilize disease in pancreatic cancer patients. PMID 25550602

Antigen-loaded dendritic cell migration: MR imaging in a pancreatic carcinoma model.
Dec 2014 | Zhang, Zhuoli; Li, Weiguo; Procissi, Daniele; Li, Kangan; Sheu, Alexander Y; Gordon, Andrew C; Guo, Yang; Khazaie, Khashayarsha; Huan, Yi; Han, Guohong; Larson, Andrew C
To test the following hypotheses in a murine model of pancreatic cancer: (a) Vaccination with antigen-loaded iron-labeled dendritic cells reduces T2-weighted signal intensity at magnetic resonance (MR) imaging within peripheral draining lymph nodes ( LN lymph node s) and (b) such signal intensity reductions are associated with tumor size changes after dendritic cell vaccination. PMID 25222066

Immunotherapy and lung cancer: current developments and novel targeted therapies.
Dec 2014 | Domingues, Duarte; Turner, Alice; Silva, Maria Dília; Marques, Dânia Sofia; Mellidez, Juan Carlos; Wannesson, Luciano; Mountzios, Giannis; de Mello, Ramon Andrade
Non-small-cell lung cancer (NSCLC) is a highly prevalent and aggressive disease. In the metastatic setting, major advances include the incorporation of immunotherapy and targeted therapies into the clinician's therapeutic armamentarium. Standard chemotherapeutic regimens have long been reported to interfere with the immune response to the tumor; conversely, antitumor immunity may add to the effects of those therapies. The aim of immunotherapy is to specifically enhance the immune response directed to the tumor. Recently, many trials addressed the role of such therapies for metastatic NSCLC treatment: ipilimumab, tremelimumab, nivolumab and lambrolizumab are immunotherapeutic agents of main interest in this field. In addition, anti-tumor vaccines, such as MAGE-A3, Tecetomide, TG4010, CIMAvax, ganglioside vaccines, tumor cell vaccines and dendritic cell vaccines, emerged as potent inducers of immune response against the tumor. The current work aims to address the most recent developments regarding these innovative immunotherapies and their implementation in the treatment of metastatic NSCLC. PMID 25496336

CD40-targeted dendritic cell delivery of PLGA-nanoparticle vaccines induce potent anti-tumor responses.
Dec 2014 | Rosalia, Rodney A; Cruz, Luis J; van Duikeren, Suzanne; Tromp, Angelino T; Silva, Ana L; Jiskoot, Wim; de Gruijl, Tanja; Löwik, Clemens; Oostendorp, Jaap; van der Burg, Sjoerd H; Ossendorp, Ferry
Dendritic cells (DC) play a prominent role in the priming of CD8(+) T cells. Vaccination is a promising treatment to boost tumor-specific CD8(+) T cells which is crucially dependent on adequate delivery of the vaccine to DC. Upon subcutaneous (s.c.) injection, only a small fraction of the vaccine is delivered to DC whereas the majority is cleared by the body or engulfed by other immune cells. To overcome this, we studied vaccine delivery to DC via CD40-targeting using a multi-compound particulate vaccine with the aim to induce potent CD8(+) T cell responses. To this end, biodegradable poly(lactic-co-glycolic acid) nanoparticles (NP) were formulated encapsulating a protein Ag, Pam3CSK4 and Poly(I:C) and coated with an agonistic αCD40-mAb (NP-CD40). Targeting NP to CD40 led to very efficient and selective delivery to DC in vivo upon s.c. injection and improved priming of CD8(+) T cells against two independent tumor associated Ag. Therapeutic application of NP-CD40 enhanced tumor control and prolonged survival of tumor-bearing mice. We conclude that CD40-mediated delivery to DC of NP-vaccines, co-encapsulating Ag and adjuvants, efficiently drives specific T cell responses, and therefore, is an attractive method to improve the efficacy of protein based cancer vaccines undergoing clinical testing in the clinic. PMID 25465442

Restoring immunosurveillance by dendritic cell vaccines and manipulation of the tumor microenvironment.
Dec 2014 | Vasaturo, Angela; Verdoes, Martijn; de Vries, Jolanda; Torensma, Ruurd; Figdor, Carl G
Cancer cells evolve from normal cells throughout life and are usually recognized by our immune system and destroyed, a process called immunosurveillance. Unfortunately, in some instances cancer cells paralyze our immune system, resulting in outgrowth and spreading of the tumor. Understanding the complexity of immunomodulation by tumors is important for the development of therapeutical strategies. Nowadays, various approaches have been developed to enhance anti-tumor immune responses and abrogate the immune dampening effect of the tumor and its surrounding environment, including dendritic cell-based vaccines, therapies to counteract myeloid derived suppressor cell function within the tumor and antagonists of inhibitory signaling pathways to overcome 'immune checkpoints'. The challenge is now to find the right combination of immune based therapies to fully restore immune function and provide a more efficacious and enduring anti-tumor response. PMID 25466585

Improved vaccine efficacy of tumor exosome compared to tumor lysate loaded dendritic cells in mice.
Dec 2014 | Gu, Xiaoyu; Erb, Ulrike; Büchler, Markus W; Zöller, Margot
Leukemia immunotherapy frequently does not meet expectation, one of the handicaps being tumor exosome (TEX)-promoted immunosuppression. We here asked, using the mouse myeloid leukemia WEHI3B and the renal cell carcinoma line RENCA, whether dendritic cell (DC) vaccination suffices to counterregulate TEX-induced immunosuppression and whether TEX could serve as tumor antigen for DC-loading. DC-vaccination significantly prolonged the survival time of WEHI3B-bearing mice, TEX-loaded DC (DC-TEX) being superior to lysate-loaded DC (DC-lys), even an excess of TEX not interfering with immune response induction. The superior response to DC-TEX was accompanied by an increase in WEHI3B-specific CD4+ T cells, evaluated by trogocytosis and proliferation. Similar findings accounted for DC loaded with RENCA TEX. TEX was efficiently taken-up by DC and TEX uptake supported CD11c, MHCII and IL12 upregulation in DC. Importantly, TEX was partly recruited into the MHCII-loading compartment such that "TEX" presentation time and recovery in T cells significantly exceeded that of tumor-lysate. Thus, TEX did not drive DC into a suppressive phenotype and were a superior antigen due to higher efficacy of TEX-presentation that is supported by prolonged persistence, preferential processing in the MHCII-loading compartment and pronounced trogocytosis by T helper cells. TEX is present in tumor patients' sera. TEX, recovered and enriched from patients' sera, might well provide an optimized, individual-specific antigen source for DC-loading and vaccination. PMID 25066479

Enhancing dendritic cell-based vaccination for highly aggressive glioblastoma.
Dec 2014 | Batich, Kristen A; Swartz, Adam M; Sampson, John H
Patients with primary glioblastoma (GBM) have a dismal prognosis despite standard therapy, which can induce potentially deleterious side effects. Arming the immune system is an alternative therapeutic approach, as its cellular effectors and inherent capacity for memory can be utilized to specifically target invasive tumor cells, while sparing collateral damage to otherwise healthy brain parenchyma. PMID 25327832

Natural killer and dendritic cells collaborate in the immune response induced by the vaccine against uterine cervical cancer.
Dec 2014 | Langers, Inge; Renoux, Virginie; Reschner, Anca; Touzé, Antoine; Coursaget, Pierre; Boniver, Jacques; Koch, Joachim; Delvenne, Philippe; Jacobs, Nathalie
Virus-like particles (VLPs) of human papillomavirus (HPV) are used as a vaccine against HPV-induced cancer, and recently we have shown that these VLPs are able to activate natural killer (NK) cells. Since NK cells collaborate with dendritic cells (DCs) to induce an immune response against viral infections and tumors, we studied the impact of this crosstalk in the context of HPV vaccination. NK cells in the presence of HPV-VLPs enhanced DC-maturation as shown by an upregulation of CD86 and HLA-DR and an increased production of IL-12p70, but not of the immunosuppressive cytokine IL-10. This activation was bidirectional. Indeed, in the presence of HPV-VLPs, DCs further activated NK cells by inducing the upregulation of cell surface activation markers (CD69 and HLA-DR). The function of NK cells was also improved as shown by an increase in IFN-γ secretion and cytotoxic activity against an HPV(+) cell line. This crosstalk between NK cells and DCs needed CD40 interaction and IL-12p70 secretion, whereas NKG2D was not implicated. Our results provide insight into how VLPs interact with innate immune cells and how NK cells and DCs play a role in the immune response induced by this vaccine agent. PMID 25229656

Immunotherapy for malignant gliomas.
Dec 2014 | Bloch, Orin
Cancer immunotherapy aims to harness the innate ability of the immune system to recognize and destroy malignant cells. Immunotherapy for malignant gliomas is an emerging field that promises the possibility of highly specific and less toxic treatment compared to conventional chemotherapy. In addition, immunotherapy has the added benefit of sustained efficacy once immunologic memory is induced. Although there are numerous therapeutic agents that boost general immune function and facilitate improved antitumor immunity, to date, immunotherapy for gliomas has focused primarily on active vaccination against tumor-specific antigens. The results of numerous early phase clinical trials demonstrate promising results for vaccine therapy, but no therapy has yet proven to improve survival in a randomized, controlled trial. The major barrier to immunotherapy in malignant gliomas is tumor-induced immunosuppression. The mechanisms of immunosuppression are only now being elucidated, but clearly involve a combination of factors including regulatory T cells, tumor-associated PD-L1 expression, and CTLA-4 signaling. Immunomodulatory agents have been developed to combat these immunosuppressive factors and have demonstrated efficacy in other cancers. The future of glioma immunotherapy likely lies in a combination of active vaccination and immune checkpoint inhibition. PMID 25468230

Dendritic cell immunotherapy in uterine cancer.
Nov 2014 | Coosemans, An; Tuyaerts, Sandra; Vanderstraeten, Anke; Vergote, Ignace; Amant, Frédéric; Van Gool, Stefaan W
Uterine cancer is the most common pelvic gynecological malignancy. Uterine sarcomas and relapsed uterine carcinomas have limited treatment options. The search for new therapies is urgent. Dendritic cell (DC) immunotherapy holds much promise, though has been poorly explored in uterine cancer. This commentary gives an insight in existing DC immunotherapy studies in uterine cancer and summarizes the possibilities and the importance of the loading of tumor antigens onto DC and their subsequent maturation. However, the sole application of DC immunotherapy to target uterine cancer will be insufficient because of tumor-induced immunosuppression, which will hamper the establishment of an effective anti-tumor immune response. The authors give an overview on the limited existing immunosuppressive data and propose a novel approach on DC immunotherapy in uterine cancer. PMID 25424788

Dendritic cell cancer vaccines: from the bench to the bedside.
Nov 2014 | Katz, Tamar; Avivi, Irit; Benyamini, Noam; Rosenblatt, Jacalyn; Avigan, David
The recognition that the development of cancer is associated with acquired immunodeficiency, mostly against cancer cells themselves, and understanding pathways inducing this immunosuppression, has led to a tremendous development of new immunological approaches, both vaccines and drugs, which overcome this inhibition. Both "passive" (e.g. strategies relying on the administration of specific T cells) and "active" vaccines (e.g. peptide-directed or whole-cell vaccines) have become attractive immunological approaches, inducing cell death by targeting tumor-associated antigens. Whereas peptide-targeted vaccines are usually directed against a single antigen, whole-cell vaccines (e.g. dendritic cell vaccines) are aimed to induce robust responsiveness by targeting several tumor-related antigens simultaneously. The combination of vaccines with new immuno-stimulating agents which target "immunosuppressive checkpoints" (anti-CTLA-4, PD-1, etc.) is likely to improve and maintain immune response induced by vaccination. PMID 25386340

Emerging treatment strategies for glioblastoma multiforme.
Nov 2014 | Carlsson, Steven K; Brothers, Shaun P; Wahlestedt, Claes
Glioblastoma multiforme (GBM) is the deadliest form of brain tumor with a more than 90% 5-year mortality. GBM has a paltry median survival of 12.6 months attributed to the unique treatment limitations such as the high average age of onset, tumor location, and poor current understandings of the tumor pathophysiology. The resection techniques, chemotherapic strategies, and radiation therapy currently used to treat GBM have slowly evolved, but the improvements have not translated to marked increases in patient survival. Here, we will discuss the recent progress in our understanding of GBM pathophysiology, and the diagnostic techniques and treatment options. The discussion will include biomarkers, tumor imaging, novel therapies such as monoclonal antibodies and small-molecule inhibitors, and the heterogeneity resulting from the GBM cancer stem cell population. PMID 25312641

Long-term remission of prostate cancer with extensive bone metastases upon immuno- and virotherapy: A case report.
Nov 2014 | Schirrmacher, Volker; Bihari, Akos-Sigmund; Stücker, Wilfried; Sprenger, Tobias
The present study reports the case of a patient with hormone-refractory metastatic prostate cancer who had failed standard therapy, but then achieved complete remission following combined treatment with local hyperthermia (LHT), Newcastle disease virus and dendritic cell (DC) vaccination, which was an unusual combination. In August 2005, the patient underwent a radical prostatectomy. Despite standard treatment, the patient developed progressive bone metastases and stopped conventional therapy in June 2007. Starting in October 2007, the patient was treated with LHT, oncolytic virotherapy and DC vaccination. Prostate-specific antigen (PSA)-levels, with the highest level of 233.8 ng/ml in January 2008, decreased to 0.8 ng/ml in late February 2008. In March 2008, a reduction in bone metastases could be detected by positron emission tomography/computed tomography. Since then, the PSA levels have remained low and the patient is doing well. The treatment induced a long-lasting antitumor memory T-cell response. This possibly explains the long-term effectiveness of this novel experimental combined treatment approach. PMID 25364402

Modulated electro-hyperthermia enhances dendritic cell therapy through an abscopal effect in mice.
Oct 2014 | Qin, Wei; Akutsu, Yasunori; Andocs, Gabor; Suganami, Akiko; Hu, Xin; Yusup, Gulbostan; Komatsu-Akimoto, Aki; Hoshino, Isamu; Hanari, Naoyuki; Mori, Mikito; Isozaki, Yuka; Akanuma, Naoki; Tamura, Yutaka; Matsubara, Hisahiro
The aim of this study was to assess whether modulated electro-hyperthermia (mEHT) can induce an abscopal effect and thereby enhance the antitumor effects of immunotherapy. We used an intratumoral dendritic cell (DC) injection and mEHT to treat C3H/He mice inoculated with squamous cell carcinoma SCCVII cells in the left leg, and we assessed the whole body antitumor effects. Tumors were examined every two or three days in order to assess growth inhibition. The tumor-draining lymph nodes were removed to enable flow cytometric analysis of CD3+ and CD8+ cells, whereas immunohistochemistry was used to assess CD8, S100 and Foxp3 expression in the tumors. Additionally, GP96 expression in the tumors from the different treatment groups was measured. In the control group, the mean tumor volume was larger than that in other groups. These results indicated that the combination therapy of an intratumoral DC injection and mEHT evoked systemic antitumor activity. A larger number of CD3+ and CD8+ cells were detected by flow cytometric analysis in the DC plus mEHT treatment group. Tumor tissue immunostaining showed that CD8 and S100 were more strongly expressed in the DC plus mEHT treatment group, although Foxp3 expression was much higher in the control group. The GP96 gene expression level in the mEHT group was significantly different from the expression level in the control group. An abscopal effect may be induced by mEHT, and the effect of immunotherapy with DCs was strongly enhanced by the overexpression of GP96. GP96 is thought to be one of the molecules explaining the abscopal effect. Direct intratumoral administration of DCs and mEHT may be a feasible future treatment strategy. PMID 25242303

Multimodal cancer therapy involving oncolytic newcastle disease virus, autologous immune cells, and bi-specific antibodies.
Oct 2014 | Schirrmacher, Volker; Fournier, Philippe
This paper focuses on oncolytic Newcastle disease virus (NDV). This paper summarizes (i) the peculiarities of this virus as an anti-cancer and immune stimulatory agent and (ii) the approaches to further harness this virus as a vector to combat cancer. Special emphasis is given on combining virus therapy with cell therapy and on improving tumor targeting. The review will include some of the authors work on NDV, bi-specific antibodies, and cell therapy as building blocks for a new perspective of multimodal cancer therapy. The broad anti-tumor immune reactivation includes innate and adaptive, tumor antigen (TA) specific and TA independent activities. PMID 25309868

The feasibility and clinical effects of dendritic cell-based immunotherapy targeting synthesized peptides for recurrent ovarian cancer.
Oct 2014 | Kobayashi, Masanori; Chiba, Asako; Izawa, Hiromi; Yanagida, Eri; Okamoto, Masato; Shimodaira, Shigetaka; Yonemitsu, Yoshikazu; Shibamoto, Yuta; Suzuki, Noboru; Nagaya, Masaki; ,
Despite the increased rate of complete response to initial chemotherapy, most patients with advanced ovarian cancer relapse and succumb to progressive disease. Dendritic cell (DC)-based immunotherapy has been developed as a novel strategy for generating antitumor immunity as part of cancer treatments. The present study aimed to assess the feasibility and clinical effects of DC therapy for recurrent ovarian cancer (ROC). PMID 25298213

Dendritic cell-based vaccine for the treatment of malignant glioma: a systematic review.
Oct 2014 | Wang, Xuan; Zhao, Hong-Yang; Zhang, Fang-Cheng; Sun, Yun; Xiong, Zhi-Yong; Jiang, Xiao-Bing
Glioblastoma multiforme (GBM) has a poor prognosis. The purpose of this systematic review and meta-analysis was to analyze the outcomes of clinical trials which compared immunotherapy with conventional therapy for the treatment of malignant gliomas. PMID 25259676

Radiotherapy as an immunological booster in patients with metastatic melanoma or renal cell carcinoma treated with high-dose Interleukin-2: evaluation of biomarkers of immunologic and therapeutic response.
Oct 2014 | Ridolfi, Laura; de Rosa, Francesco; Ridolfi, Ruggero; Gentili, Giorgia; Valmorri, Linda; Scarpi, Emanuela; Parisi, Elisabetta; Romeo, Antonino; Guidoboni, Massimo
Tumor cells killed by radiation therapy (RT) are a potentially good source of antigens for dendritic cell (DC) uptake and presentation to T-cells. RT upregulates cell death receptors such as Fas/CD95 and MHC-I, induces the expression of co-stimulatory molecules on tumor cells, and promotes production of pro-inflammatory cytokines. High-dose interleukin-2 (HD-IL-2) bolus has been shown to obtain objective response rates ranging from 15% to 17% in patients with metastatic melanoma or renal cell carcinoma (RCC), with 6% to 8% of cases experiencing a durable complete response. However, HD-IL-2 is also associated with severe side-effects; if it is to remain a component of the curative treatment strategy in patients with metastatic melanoma or RCC, its therapeutic efficacy must be improved and patients who are most likely to benefit from treatment must be identified a priori. We designed a clinical study combining immunomodulating RT and HD-IL-2 to evaluate their clinical and immunological efficacy and to explore the predictive and prognostic value of 1) tumor-specific immune response and 2) serum levels of proangiogenic cytokines. PMID 25245327

Ovarian cancer biology and immunotherapy.
Oct 2014 | Latha, T Sree; Panati, Kalpana; Gowd, D Sravan Kumar; Reddy, Madhava C; Lomada, Dakshayani
Ovarian cancer is the most lethal malignancy of the female reproductive system and the fifth leading cause of cancer death in women. In the year 2012 alone, United States had 22,280 new ovarian cancer cases and 15,500 deaths were reported. About 7%-10% of ovarian cancers result from an inherited tendency to develop the disease. Ovarian cancer has the ability to escape the immune system because of its pathological interactions between cancer cells and host immune cells in the tumor microenvironment create an immunosuppressive network that promotes tumor growth, protects the tumor from immune system. The levels of immune suppressive elements like regulatory T cells, plasmacytoid dendritic cells and cytokines such as IL-10, IL-6, TNF-α, and TGF-β are elevated in the tumor microenvironment. Vascular endothelial growth factor is known to have an immune suppressing role besides its angiogenic role in the tumor microenvironment. Ovarian cancer is associated with high mortality partly due to difficulties in early diagnosis and development of metastases. These problems may overcome by developing accurate mouse models that should mimic the complexity of human ovarian cancer. Such animal models are better suited to understand pathophysiology, metastases, and also for preclinical testing of targeted molecular therapeutics. Immunotherapy is an area of active investigation and off late many clinical trials is ongoing to prevent disease progression. The main aim of dendritic cells vaccination is to stimulate tumor specific effector T cells that can reduce tumor size and induce immunological memory to prevent tumor relapse. PMID 24911597

Perspectives for immunotherapy in glioblastoma treatment.
Oct 2014 | Finocchiaro, Gaetano; Pellegatta, Serena
Avoiding immune destruction is one emerging hallmark of cancer, including glioblastoma. The number of immunotherapy approaches to fight glioblastoma is growing. Here, we review the recent progress in four main areas: dendritic cell immunotherapy, peptide vaccination, chimeric antigen receptors and immune checkpoints. PMID 25210870

Melanoma cell lysate induces CCR7 expression and in vivo migration to draining lymph nodes of therapeutic human dendritic cells.
Sep 2014 | González, Fermín E; Ortiz, Carolina; Reyes, Montserrat; Dutzan, Nicolás; Patel, Vyomesh; Pereda, Cristián; Gleisner, Maria A; López, Mercedes N; Gutkind, J Silvio; Salazar-Onfray, Flavio
We have previously reported a novel method for the production of tumour-antigen-presenting cells (referred to as TAPCells) that are currently being used in cancer therapy, using an allogeneic melanoma-derived cell lysate (referred to as TRIMEL) as an antigen provider and activation factor. It was recently demonstrated that TAPCell-based immunotherapy induces T-cell-mediated immune responses resulting in improved long-term survival of stage IV melanoma patients. Clinically, dendritic cell (DC) migration from injected sites to lymph nodes is an important requirement for an effective anti-tumour immunization. This mobilization of DCs is mainly driven by the C-C chemokine receptor type 7 (CCR7), which is up-regulated on mature DCs. Using flow cytometry and immunohistochemistry, we investigated if TRIMEL was capable of inducing the expression of the CCR7 on TAPCells and enhancing their migration in vitro, as well as their in vivo relocation to lymph nodes in an ectopic xenograft animal model. Our results confirmed that TRIMEL induces a phenotypic maturation and increases the expression of surface CCR7 on melanoma patient-derived DCs, and also on the monocytic/macrophage cell line THP-1. Moreover, in vitro assays showed that TRIMEL-stimulated DCs and THP-1 cells were capable of migrating specifically in the presence of the CCR7 ligand CCL19. Finally, we demonstrated that TAPCells could migrate in vivo from the injection site into the draining lymph nodes. This work contributes to an increased understanding of the biology of DCs produced ex vivo allowing the design of new strategies for effective DC-based vaccines for treating aggressive melanomas. PMID 24673602

Retrospective comparative study of the effects of dendritic cell vaccine and cytokine-induced killer cell immunotherapy with that of chemotherapy alone and in combination for colorectal cancer.
Sep 2014 | Niu, Jingxiu; Ren, Yanjie; Zhang, Tianyu; Yang, Xuejing; Zhu, Wei; Zhu, Hui; Li, Jing; Li, Jiali; Pang, Yan
This retrospective study determined the delayed-type hypersensitivity (DTH) skin test and safety of dendritic cell (DC) vaccine and cytokine-induced killer (CIK) cell immunotherapy and the survival compared to chemotherapy in 239 colorectal cancer (CRC) patients. PMID 25210706

Vaccination with autologous dendritic cells loaded with autologous tumor lysate or homogenate combined with immunomodulating radiotherapy and/or preleukapheresis IFN-α in patients with metastatic melanoma: a randomised "proof-of-principle" phase II study.
Aug 2014 | de Rosa, Francesco; Ridolfi, Laura; Ridolfi, Ruggero; Gentili, Giorgia; Valmorri, Linda; Nanni, Oriana; Petrini, Massimiliano; Fiammenghi, Laura; Granato, Anna Maria; Ancarani, Valentina; Pancisi, Elena; Soldati, Valentina; Cassan, Serena; Riccobon, Angela; Parisi, Elisabetta; Romeo, Antonino; Turci, Livia; Guidoboni, Massimo
Vaccination with dendritic cells (DC) loaded with tumor antigens elicits tumor-specific immune responses capable of killing cancer cells without inducing meaningful side-effects. Patients with advanced melanoma enrolled onto our phase II clinical studies have been treated with autologous DC loaded with autologous tumor lysate/homogenate matured with a cytokine cocktail, showing a clinical benefit (PR + SD) in 55.5% of evaluable cases to date. The beneficial effects of the vaccine were mainly restricted to patients who developed vaccine-specific immune response after treatment. However, immunological responses were only induced in about two-thirds of patients, and treatments aimed at improving immunological responsiveness to the vaccine are needed. PMID 25053129

Efficiency of dendritic cell vaccination against B16 melanoma depends on the immunization route.
Aug 2014 | Edele, Fanny; Dudda, Jan C; Bachtanian, Eva; Jakob, Thilo; Pircher, Hanspeter; Martin, Stefan F
Dendritic cells (DC) presenting tumor antigens are crucial to induce potent T cell-mediated anti-tumor immune responses. Therefore DC-based cancer vaccines have been established for therapy, however clinical outcomes are often poor and need improvement. Using a mouse model of B16 melanoma, we found that the route of preventive DC vaccination critically determined tumor control. While repeated DC vaccination did not show an impact of the route of DC application on the prevention of tumor growth, a single DC vaccination revealed that both the imprinting of skin homing receptors and an enhanced proliferation state of effector T cells was seen only upon intracutaneous but not intravenous or intraperitoneal immunization. Tumor growth was prevented only by intracutaneous DC vaccination. Our results indicate that under suboptimal conditions the route of DC vaccination crucially determines the efficiency of tumor defense. DC-based strategies for immunotherapy of cancer should take into account the immunization route in order to optimize tissue targeting of tumor antigen specific T cells. PMID 25121970

Immunotherapy of cancer stem cells in solid tumors: initial findings and future prospective.
Aug 2014 | Gammaitoni, Loretta; Leuci, Valeria; Mesiano, Giulia; Giraudo, Lidia; Todorovic, Maja; Carnevale-Schianca, Fabrizio; Aglietta, Massimo; Sangiolo, Dario
Conventional chemotherapies seemed to have reached a therapeutic plateau in the treatment of solid tumors and many metastatic diseases are still incurable. Events of chemo-resistance and relapses appear to be sustained by a subset of putative cancer stem cells (CSCs). New anticancer strategies need to face this new challenge exploring their efficacy against CSCs. Immunotherapy has raised enthusiasms in cancer therapy and its potential against CSCs is an intriguing field of research. PMID 24835841

Prognostic factors related to add-on dendritic cell vaccines on patients with inoperable pancreatic cancer receiving chemotherapy: a multicenter analysis.
Jul 2014 | Kobayashi, Masanori; Shimodaira, Shigetaka; Nagai, Kazuhiro; Ogasawara, Masahiro; Takahashi, Hidenori; Abe, Hirofumi; Tanii, Mitsugu; Okamoto, Masato; Tsujitani, Sun-Ichi; Yusa, Seiichi; Ishidao, Takefumi; Kishimoto, Junji; Shibamoto, Yuta; Nagaya, Masaki; Yonemitsu, Yoshikazu; ,
Dendritic cell (DC)-based cancer vaccines may have a significant benefit to patients with advanced pancreatic cancer. However, variations among clinical studies make it difficult to compare clinical outcomes. Here, we identified factors that determined the clinical benefits by analyzing data obtained at seven Japanese institutions that employed the same DC preparation and treatment regimens. PMID 24777613

Dendritic cell immunotherapy for glioblastoma.
Jun 2014 | Polyzoidis, Stavros; Ashkan, Keyoumars
Dendritic cell immunotherapy is emerging as a promising addition to the multimodal treatment of patients with glioblastoma multiform. Initial Phase I and II trials have demonstrated favorable outcomes with minimal toxicity. In this editorial, the current status and the future challenges of this therapy are discussed. PMID 24850137

Identification of pancreatic cancer-associated tumor antigen from HSP-enriched tumor lysate-pulsed human dendritic cells.
Jun 2014 | Kim, Han-Soo; Kang, Dukjin; Moon, Myeong Hee; Kim, Hyung Jik
Vaccine strategies utilizing dendritic cells (DCs) to elicit anti-tumor immunity are the subject of intense research. Although we have shown that DCs pulsed with heat-treated tumor lysate (HTL) induced more potent anti-tumor immunity than DCs pulsed with conventional tumor lysate (TL), the underlying molecular mechanism is unclear. In order to explore the molecular basis of this approach and to identify potential antigenic peptides from pancreatic cancer, we analyzed and compared the major histocompatibility complex (MHC) ligands derived from TL- and HTL-pulsed dendritic cells by mass spectrophotometry. PMID 24954332

Immunotherapy for high-grade glioma.
Jun 2014 | Dixit, Sanjay
4th Quadrennial Meeting of the World Federation of Neuro-Oncology in conjunction with the 18th Annual Meeting of the Society for Neuro-Oncology, San Francisco, CA, USA, 21-24 November 2013. Aside from temozolomide, there has been no major breakthrough for decades to improve outcome for high-grade glioma. Bevacizumab failed to show a survival advantage in two large studies - AVaglio and RTOG-0825 - and no other novel chemotherapy agents seem to be appearing on the horizon for this universally fatal disease. Consequently, the neuro-oncology fraternity is turning to immunotherapy. This became apparent in this meeting, considering a number of delegates focused their attention to presentations on immunotherapy. The ReACT study demonstrated the safety and efficacy of the combination of a promising peptide vaccine, rindopepimut, and bevacizumab with longer survival seen in patients with a higher antibody titer. Several presentations reassured that dendritic cell-based immunotherapy is safe and can generate a lasting immune response. Employing gene therapy, increased intratumor 5-fluorouracil chemotherapy concentration can be achieved using TOCA 511, and temozolomide-resistant transgenic lymphocytes could be produced through retroviral coding. Blocking immune checkpoints PDL-01, CTLA-4 and indoleamine 2,3-dioxygenase through monoclonal antibodies appears promising. PMID 24941977

Development and validation of a fully GMP-compliant production process of autologous, tumor-lysate-pulsed dendritic cells.
Jun 2014 | Eyrich, Matthias; Schreiber, Susanne C; Rachor, Johannes; Krauss, Jürgen; Pauwels, Femke; Hain, Johannes; Wölfl, Matthias; Lutz, Manfred B; de Vleeschouwer, Steven; Schlegel, Paul G; Van Gool, Stefaan W
One of the major challenges of dendritic cell (DC) vaccination is the establishment of harmonized DC production protocols. Here, we report the transfer and validation of a successfully used open DC manufacturing method into a closed system, good manufacturing practice (GMP)-compatible protocol. PMID 24831836

Cytokine responsiveness of CD8(+) T cells is a reproducible biomarker for the clinical efficacy of dendritic cell vaccination in glioblastoma patients.
Jun 2014 | Everson, Richard G; Jin, Richard M; Wang, Xiaoyan; Safaee, Michael; Scharnweber, Rudi; Lisiero, Dominique N; Soto, Horacio; Liau, Linda M; Prins, Robert M
Immunotherapeutic approaches, such as dendritic cell (DC) vaccination, have emerged as promising strategies in the treatment of glioblastoma. Despite their promise, however, the absence of objective biomarkers and/or immunological monitoring techniques to assess the clinical efficacy of immunotherapy still remains a primary limitation. To address this, we sought to identify a functional biomarker for anti-tumor immune responsiveness associated with extended survival in glioblastoma patients undergoing DC vaccination. PMID 24883189

Clinical use of dendritic cells for cancer therapy.
May 2014 | Anguille, Sébastien; Smits, Evelien L; Lion, Eva; van Tendeloo, Viggo F; Berneman, Zwi N
Since the mid-1990s, dendritic cells have been used in clinical trials as cellular mediators for therapeutic vaccination of patients with cancer. Dendritic cell-based immunotherapy is safe and can induce antitumour immunity, even in patients with advanced disease. However, clinical responses have been disappointing, with classic objective tumour response rates rarely exceeding 15%. Paradoxically, findings from emerging research indicate that dendritic cell-based vaccination might improve survival, advocating implementation of alternative endpoints to assess the true clinical potency of dendritic cell-based vaccination. We review the clinical effectiveness of dendritic cell-based vaccine therapy in melanoma, prostate cancer, malignant glioma, and renal cell carcinoma, and summarise the most important lessons from almost two decades of clinical studies of dendritic cell-based immunotherapy in these malignant disorders. We also address how the specialty is evolving, and which new therapeutic concepts are being translated into clinical trials to leverage the clinical effectiveness of dendritic cell-based cancer immunotherapy. Specifically, we discuss two main trends: the implementation of the next-generation dendritic cell vaccines that have improved immunogenicity, and the emerging paradigm of combination of dendritic cell vaccination with other cancer therapies. PMID 24872109

Wilms' tumor gene 1 immunotherapy in pelvic gynecological malignancies.
May 2014 | Coosemans, A; Vergote, I; Van Gool, S W
Pelvic gynecological malignancies account for 6% of all cancers. In the relapsed state, classical treatments are limited. There is an urgent need for new and personalized treatment. Wilms' tumor gene 1 (WT1) is the most important tumor-associated antigen. Although highly present in gynecological tumors, active immunotherapy against it is still underexplored. This review gives an insight into the importance of WT1 in pelvic gynecological malignancies and the first taken steps into the world of WT1 immunotherapy. PMID 24784346

Oncolytic Newcastle Disease Virus as Cutting Edge between Tumor and Host.
May 2014 | Fournier, Philippe; Schirrmacher, Volker
Oncolytic viruses (OVs) replicate selectively in tumor cells and exert anti-tumor cytotoxic activity. Among them, Newcastle Disease Virus (NDV), a bird RNA virus of the paramyxovirus family, appears outstanding. Its anti-tumor effect is based on: (i) oncolytic activity and (ii) immunostimulation. Together these activities facilitate the induction of post-oncolytic adaptive immunity. We will present milestones during the last 60 years of clinical evaluation of this virus. Two main strategies of clinical application were followed using the virus (i) as a virotherapeutic agent, which is applied systemically or (ii) as an immunostimulatory agent combined with tumor cells for vaccination of cancer patients. More recently, a third strategy evolved. It combines the strategies (i) and (ii) and includes also dendritic cells (DCs). The first step involves systemic application of NDV to condition the patient. The second step involves intradermal application of a special DC vaccine pulsed with viral oncolysate. This strategy, called NDV/DC, combines anti-cancer activity (oncolytic virotherapy) and immune-stimulatory properties (oncolytic immunotherapy) with the high potential of DCs (DC therapy) to prime naive T cells. The aim of such treatment is to first prepare the cancer-bearing host for immunocompetence and then to instruct the patient's immune system with information about tumor-associated antigens (TAAs) of its own tumor together with danger signals derived from virus infection. This multimodal concept should optimize the generation of strong polyclonal T cell reactivity targeted against the patient's TAAs and lead to the establishment of a long-lasting memory T cell repertoire. PMID 24833054

Colorectal cancer and immunity: what we know and perspectives.
May 2014 | Pernot, Simon; Terme, Magali; Voron, Thibault; Colussi, Orianne; Marcheteau, Elie; Tartour, Eric; Taieb, Julien
Strong evidence supports the concept of immunosurveillance and immunoediting in colorectal cancer. In particular, the density of T CD8⁺ and CD45⁺ lymphocyte infiltration was recently shown to have a better prognostic value than the classic tumor node metastasis classification factor. Other immune subsets, as macrophages, natural killer cells or unconventionnal lymphocytes, seem to play an important role. Induction of regulatory T cells (Tregs) or immunosuppressive molecules such as PD-1 or CTLA-4 and downregulation of antigen-presenting molecules are major escape mechanisms to antitumor immune response. The development of these mechanisms is a major obstacle to the establishment of an effective immune response, but also to the use of immunotherapy. Although immunotherapy is not yet routinely used in colorectal cancer, we now know that most treatments used (chemotherapy and biotherapy) have immunomodulatory effects, such as induction of immunogenic cell death by chemotherapy, inhibition of immunosuppression by antiangiogenic agents, and antibody-dependent cytotoxicity induced by cetuximab. Finally, many immunotherapy strategies are being developed and tested in phase I to III clinical trials. The most promising strategies are boosting the immune system with cytokines, inhibition of immunoregulatory checkpoints, vaccination with vectorized antigens, and adoptive cell therapy. Comprehension of antitumor immune response and combination of the different approaches of immunotherapy may allow the use of effective immunotherapy for treatment of colorectal cancer in the near future. PMID 24833840

Vaccination with dendritic cells loaded with allogeneic brain tumor cells for recurrent malignant brain tumors induces a CD4(+)IL17(+) response.
May 2014 | Olin, Michael R; Low, Walter; McKenna, David H; Haines, Stephen J; Dahlheimer, Tambra; Nascene, David; Gustafson, Michael P; Dietz, Allan B; Clark, H Brent; Chen, Wei; Blazar, Bruce; Ohlfest, John R; Moertel, Christopher
We tested the hypothesis that a novel vaccine developed from autologous dendritic cells (DC) loaded with cells from a unique allogeneic brain tumor cell line (GBM6-AD) would be well-tolerated and would generate an immune response. PMID 24829761

Current vaccine trials in glioblastoma: a review.
May 2014 | Xu, Linda W; Chow, Kevin K H; Lim, Michael; Li, Gordon
Glioblastoma (GBM) is the most common primary brain tumor, and despite aggressive therapy with surgery, radiation, and chemotherapy, average survival remains at about 1.5 years. The highly infiltrative and invasive nature of GBM requires that alternative treatments for this disease be widespread and targeted to tumor cells. Immunotherapy in the form of tumor vaccines has the potential to meet this need. Vaccines against GBM hold the promise of triggering specific and systemic antitumor immune responses that may be the key to eradicating this unrelenting cancer. In this review, we will discuss past and present clinical trials of various GBM vaccines and their potential impact on the future care of GBM patients. There have been many promising phase I and phase II GBM vaccine studies that have led to ongoing and upcoming phase III trials. If the results of these randomized trials show a survival benefit, immunotherapy will become a standard part of the treatment of this devastating disease. PMID 24804271

Phase I dendritic cell p53 peptide vaccine for head and neck cancer.
May 2014 | Schuler, Patrick J; Harasymczuk, Malgorzata; Visus, Carmen; Deleo, Albert; Trivedi, Sumita; Lei, Yu; Argiris, Athanassios; Gooding, William; Butterfield, Lisa H; Whiteside, Theresa L; Ferris, Robert L
p53 accumulation in head and neck squamous cell carcinoma (HNSCC) cells creates a targetable tumor antigen. Adjuvant dendritic cell (DC)-based vaccination against p53 was tested in a phase I clinical trial. PMID 24583792

Long-term complete remission following radiosurgery and immunotherapy in a melanoma patient with brain metastasis: immunologic correlates.
May 2014 | Karbach, Julia; Gnjatic, Sacha; Biskamp, Melina; Atmaca, Akin; Weidmann, Eckhart; Brandt, Kathrin; Wahle, Claudia; Bernhard, Helga; Knuth, Alexander; Jäger, Elke
A melanoma patient with brain metastases was treated by gamma-knife radiosurgery and immunotherapy with autologous tumor-lysate-loaded dendritic cells (DC). Ten years after the combined treatment, the patient remains in complete remission. Remarkable immunologic correlates to the clinical development were the transient induction of NY-ESO-1 antibody and the durable expansion of MAGE-A1p161-169 EADPTGHSY-specific CD8+ T cells. Although the induction of NY-ESO-1 antibody most likely resulted from gamma-knife-mediated "auto-vaccination," the persistence of circulating MAGE-A1-specific T cells, which are still detectable ex vivo in the absence of any tumor manifestation, coincides with DC-based vaccination administered monthly until today. PMID 24795353

Dendritic cell-based vaccines: clinical applications in breast cancer.
Apr 2014 | Gelao, Lucia; Criscitiello, Carmen; Esposito, Angela; De Laurentiis, Michele; Fumagalli, Luca; Locatelli, Marzia Adelia; Minchella, Ida; Santangelo, Michele; De Placido, Sabino; Goldhirsch, Aron; Curigliano, Giuseppe
Recent evidence suggests that the immune system is involved in the carcinogenesis process and the antitumor immune responses impact the clinical outcome, thus emphasizing the concept of cancer immune surveillance. In this context, dendritic cells (DCs) seem to play a crucial role, as they are the most potent antigen-presenting cells (APCs) and are able to stimulate naive T lymphocytes and to generate memory T lymphocytes. Immunotherapy with DC-based vaccines is a very attractive approach to treat cancer, offering the potential for high tumor-specific cytotoxicity. Although breast cancer (BC) is traditionally considered a poorly immunogenic tumor, increasing numbers of both preclinical and clinical studies demonstrate that vaccination with DCs is capable of inducing an antitumor-specific response, while being well tolerated and safe. However, clinical objective responses are still disappointing and many reasons may explain the difficulty of developing effective DC-based therapies for BC. In this review, we discuss the characteristics of DCs, and the major clinical indications for DC-based immunotherapy in BC with related drawbacks. PMID 24762078

Dasatinib promotes the expansion of a therapeutically superior T-cell repertoire in response to dendritic cell vaccination against melanoma.
Apr 2014 | Lowe, Devin B; Bose, Anamika; Taylor, Jennifer L; Tawbi, Hussein; Lin, Yan; Kirkwood, John M; Storkus, Walter J
Dasatinib (DAS) is a potent inhibitor of the BCR-ABL, SRC, c-KIT, PDGFR, and ephrin tyrosine kinases that has demonstrated only modest clinical efficacy in melanoma patients. Given reports suggesting that DAS enhances T cell infiltration into the tumor microenvironment, we analyzed whether therapy employing the combination of DAS plus dendritic cell (DC) vaccination would promote superior immunotherapeutic benefit against melanoma. Using a M05 (B16.OVA) melanoma mouse model, we observed that a 7-day course of orally-administered DAS (0.1 mg/day) combined with a DC-based vaccine (VAC) against the OVA257-264 peptide epitope more potently inhibited tumor growth and extended overall survival as compared with treatment with either single modality. The superior efficacy of the combinatorial treatment regimen included a reduction in hypoxic-signaling associated with reduced levels of immunosuppressive CD11b(+)Gr1(+) myeloid-derived suppressor cells (MDSC) and CD4(+)Foxp3(+) regulatory T (Treg) populations in the melanoma microenvironment. Furthermore, DAS + VAC combined therapy upregulated expression of Type-1 T cell recruiting CXCR3 ligand chemokines in the tumor stroma correlating with activation and recruitment of Type-1, vaccine-induced CXCR3(+)CD8(+) tumor-infiltrating lymphocytes (TILs) and CD11c(+) DC into the tumor microenvironment. The culmination of this bimodal approach was a profound "spreading" in the repertoire of tumor-associated antigens recognized by CD8(+) TILs, in support of the therapeutic superiority of combined DAS + VAC immunotherapy in the melanoma setting. PMID 24734217

SnapShot: cancer vaccines.
Apr 2014 | Palucka, Karolina; Banchereau, Jacques
This SnapShot illustrates the main concepts and underlying biology of therapeutic vaccination in cancer. Dendritic cells (DCs) are an essential component of vaccination through their capacity to capture, process, and present antigens to T cells. We have come a long way in our understanding of what is needed to elicit therapeutic immunity when cancer escapes the natural barrier of protective immunity. This progress enables the development of novel vaccines. PMID 24725415

Autologous tumor lysate-pulsed dendritic cell immunotherapy with cytokine-induced killer cells improves survival in gastric and colorectal cancer patients.
Apr 2014 | Gao, Daiqing; Li, Changyou; Xie, Xihe; Zhao, Peng; Wei, Xiaofang; Sun, Weihong; Liu, Hsin-Chen; Alexandrou, Aris T; Jones, Jennifer; Zhao, Ronghua; Li, Jian Jian
Gastric and colorectal cancers (GC and CRC) have poor prognosis and are resistant to chemo- and/or radiotherapy. In the present study, the prophylactic effects of dendritic cell (DC) vaccination are evaluated on disease progression and clinical benefits in a group of 54 GC and CRC patients treated with DC immunotherapy combined with cytokine-induced killer (CIK) cells after surgery with or without chemo-radiotherapy. DCs were prepared from the mononuclear cells isolated from patients using IL-2/GM-CSF and loaded with tumor antigens; CIK cells were prepared by incubating peripheral blood lymphocytes with IL-2, IFN-γ, and CD3 antibodies. The DC/CIK therapy started 3 days after low-dose chemotherapy and was repeated 3-5 times in 2 weeks as one cycle with a total of 188.3 ± 79.8 × 10(6) DCs and 58.8 ± 22.3 × 10(8) CIK cells. Cytokine levels in patients' sera before and after treatments were measured and the follow-up was conducted for 98 months to determine disease-free survival (DFS) and overall survival (OS). The results demonstrate that all cytokines tested were elevated with significantly higher levels of IFN-γ and IL-12 in both GC and CRC cohorts of DC/CIK treated patients. By Cox regression analysis, DC/CIK therapy reduced the risk of post-operative disease progression (p<0.01) with an increased OS (<0.01). These results demonstrate that in addition to chemo- and/or radiotherapy, DC/CIK immunotherapy is a potential effective approach in the control of tumor growth for post-operative GC and CRC patients. PMID 24699863

Novel approaches and mechanisms of immunotherapy for glioblastoma.
Mar 2014 | Hegde, Meenakshi; Bielamowicz, Kevin J; Ahmed, Nabil
Glioblastoma (GBM) is the most aggressive primary brain tumor. Combination therapy with surgery, radiation, and chemotherapy is not curative at present and carries a significant risk of toxicity. Advancements in the knowledge of tumor biology and tumor microenvironment have led to the development of novel targeted therapies for glioblastoma. In the past 15 years, a vast amount of pre-clinical data has been generated for glioblastoma immunotherapy. Translating these promising results into the clinic is, however, still an evolving process. Early clinical trials have demonstrated the feasibility and safety of several such approaches in patients with recurrent as well as newly diagnosed glioblastoma. Both passive as well as active immunotherapeutic modalities have also shown potential clinical benefit in at least a subset of these patients. This brief review discusses 'why' and 'how' various types of immunotherapies are being employed to treat glioblastoma. PMID 24641957

Concomitant gemcitabine therapy negatively affects DC vaccine-induced CD8(+) T-cell and B-cell responses but improves clinical efficacy in a murine pancreatic carcinoma model.
Mar 2014 | Bauer, Christian; Sterzik, Alexander; Bauernfeind, Franz; Duewell, Peter; Conrad, Claudius; Kiefl, Rosemarie; Endres, Stefan; Eigler, Andreas; Schnurr, Max; Dauer, Marc
Multiple studies have shown that dendritic cell (DC)-based vaccines can induce antitumor immunity. Previously, we reported that gemcitabine enhances the efficacy of DC vaccination in a mouse model of pancreatic carcinoma. The present study aimed at investigating the influence of gemcitabine on vaccine-induced anti-tumoral immune responses in a syngeneic pancreatic cancer model. PMID 24384835

Antigen trapping by dendritic cells for antitumor therapy.
Mar 2014 | Pal, Chiranjib
Dendritic cells (DC) are potent antigen-presenting cells (APC) that are capable of stimulating both naive CD4(+) T helper cells and CD8(+) cytotoxic T cells. Therefore, DC are being extensively evaluated as vehicles for antigen delivery in immunotherapies for the treatment of patients with cancer. Many techniques have been used to load DC with tumor-associated antigens (TAA), including pulsing with synthetic peptides that represent T cell epitopes. This strategy has been used in several human clinical vaccination trials; however, it is limited to patients who express the particular peptide MHC-restricting molecule. Alternatively, DC have been pulsed with recombinant proteins or transduced with recombinant viruses. These approaches circumvent the MHC restrictions associated with peptides but are generally limited to individual proteins. Because many tumors display heterogenous expression of target antigens, strategies that induce T cell responses against multiple proteins may be more efficacious. Another concern is that some of these antigen-loading techniques facilitate the presentation of immunogenic viral or bacterial epitopes in addition to those from the tumor-associated protein. PMID 24619668

Generation of multiple peptide cocktail-pulsed dendritic cells as a cancer vaccine.
Mar 2014 | Lee, Hyun-Ju; Choi, Nu-Ri; Vo, Manh-Cuong; Hoang, My-Dung; Lee, Youn-Kyung; Lee, Je-Jung
Cancer immunotherapy based on dendritic cell (DC) vaccination has promising alternatives for the treatment of cancer. A central tenet of DC-based cancer immunotherapy is the generation of antigen-specific cytotoxic T lymphocyte (CTL) response. Tumor-associated antigens (TAA) and DC play pivotal roles in this process. DCs are well known to be the most potent antigen-presenting cells and have the most powerful antigen-presenting capacity. DCs pulsed with various TAA have been shown to be effective in producing specific antitumor effects both in vitro and in vivo. Several types of tumor antigens have been applied in cancer treatment including tumor RNA, lysates, apoptotic bodies, heat shock protein, peptides from TAA, and allogeneic tumor cells. Among them, the use of immunogenic HLA-A*0201-specific epitopes from multiple TAA enhances induction of antigen-specific CTL and associated therapeutic efficacy in HLA-A*0201(+) cancer patients. The current chapter provides a detailed protocol of generating multiple peptide cocktail-pulsed DC to elicit CTL with a broad spectrum of immune responses against the related tumor antigens. PMID 24619666

Natural killer cells: the secret weapon in dendritic cell vaccination strategies.
Mar 2014 | Van Elssen, Catharina H M J; Oth, Tammy; Germeraad, Wilfred T V; Bos, Gerard M J; Vanderlocht, Joris
In cancer therapy, dendritic cell (DC) vaccination is still being explored. Clinical responses, however, are diverse and there is a lack of immunologic readout systems that correspond with clinical outcome. Only in the minority of patients, T-cell responses correlate with clinical outcome, indicating that other immune cells also gain anticancer activity. We still have limited knowledge of the effect of DC vaccination on different immune effector cells. However, it has been shown that bidirectional cross-talk between natural killer (NK) cells and DCs is responsible for enhanced activation of both cell types and increases their antitumor activity. In this review, we postulate the possibility that NK cells are the secret weapons in DC vaccination and studying their behavior together with T-cell activation in vaccinated individuals might predict clinical outcome. PMID 24590885

Dendritic cell-based immunotherapy in ovarian cancer.
Feb 2014 | Coosemans, An; Vergote, Ignace; Van Gool, Stefaan W
Worldwide, 80% of patients with ovarian cancer die of the disease. New treatments for this aggressive disease are therefore being intensively searched. Although dendritic cell-based vaccines against gynecological malignancies are in their infancy, this immunotherapeutic approach holds much promise. Here, we present our view on an optimal dendritic cell-based immunotherapeutic strategy against ovarian cancer. PMID 24501688

Autologous tumor cell vaccines for post-operative active-specific immunotherapy of colorectal carcinoma: long-term patient survival and mechanism of function.
Jan 2014 | Schirrmacher, Volker; Fournier, Philippe; Schlag, Peter
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Surgery remains the primary curative treatment but nearly 50% of patients relapse as consequence of micrometastatic or minimal residual disease (MRD) at the time of surgery. Spontaneous T-cell-mediated immune responses to CRC tumor-associated antigens (TAAs) in tumor-draining lymph nodes and in the bone marrow (BM) lead to infiltration of the tumors by lymphocytes. Certain types of such tumor-infiltrating lymphocytes (TILs) have a positive and others a negative impact on the patients' prognosis. This review focuses on advances in CRC active-specific immunotherapy (ASI), in particular on results from randomized controlled clinical studies employing therapeutic autologous tumor cell vaccines. The observed improvement of long-term survival is explained by activation and mobilization of a pre-existing repertoire of tumor-reactive memory T cells which, according to recent discoveries, reside in distinct niches of patients' bone marrow in neighborhood with hematopoietic (HSC) and mesenchymal (MSC) stem cells. Interestingly, memory T cells also contain a subset of stem memory T cells (SMTs) in addition to effector (EMTs) and central memory T cells (CMTs). The mechanism of function of a therapeutic vaccine in a chronic disease is distinct from that of prophylactic vaccines which have to generate de novo protective immune responses. The advantage of autologous vaccines for mobilization of a broad and highly individual repertoire of memory T cells will be discussed. PMID 24219122

Superior anti-tumor protection and therapeutic efficacy of vaccination with dendritic cell/tumor cell fusion hybrids for murine Lewis lung carcinoma.
Jan 2014 | Chen, Xiaodan; Liu, Zhimin; Huang, Yunchao; Li, Ruilei; Zhang, Hongqing; Dong, Suwei; Ge, Chunlei; Zhang, Zhiwei; Wang, Ying; Wang, Ying; Xue, Yuanbo; Li, Zhen; Song, Xin
The development of protocols for the ex vivo generation of dendritic cells (DCs) has led to intensive research into their potential use in immunotherapy in the treatment of cancer. In this study, we examined the efficacy of dendritic cell-tumor cell fusion hybrid vaccines in eliciting an immune response against Lewis lung carcinoma (LLC) cells, as compared to other types of tumor vaccines. In addition, we also tested whether the efficacy of the vaccines was affected by the route of administration. Four different tumor vaccines were compared: (1) HC (hybrid cell), consisting of DC/LLC hybrids; (2) DC+LLC (DCs pulsed with apoptotic LLCs); (3) DC without antigen loading/pulsing; (4) LLC (apoptotic/irradiated tumor cells). We also compared four different routes of administration for each vaccine: (1) Preimmunization; (2) Vaccination therapy; (3) Adoptive immunotherapy; (4) Vaccination therapy combined with adoptive immunotherapy. Anti-tumor immunity was assessed in vivo and the CTL (cytotoxic T lymphocyte) response as well as the expression of key cytokines, IFN-γ and IL-10 were further evaluated using in vitro assays. PMID 24191684

In vitro and in vivo evaluations of human papillomavirus type 16 (HPV16)-derived peptide-loaded dendritic cells (DCs) with a CpG oligodeoxynucleotide (CpG-ODN) adjuvant as tumor vaccines for immunotherapy of cervical cancer.
Jan 2014 | Wang, Hua Li; Xu, Hui; Lu, Wei Hua; Zhu, Lin; Yu, Yun Hai; Hong, Fan Zhen
To evaluate the immunotherapeutic potentials for human dendritic cells (DCs) loaded with different HPV16-associated antigens, including HPV16E7 (E) protein, HPV16E7 polypeptide (P), as well as CpG-oligodeoxynucleotide (ODN) 2006 as a promising immune adjuvant for vaccination against cervical carcinoma. PMID 23912529

Dendritic cells in cancer immunotherapy clinical trials: are we making progress?
Dec 2013 | Butterfield, Lisa H
Dendritic cells (DC) have been tested in cancer immunotherapy clinical trials for two decades. Over this time, the methods of DC culture (or manufacture) have evolved, the approaches for antigen loading have broadened, the maturation signals have varied and different sites of administration have been tested. The post-vaccination immunologic questions asked have also varied between trials and over time. In this review, I will consider multiple aspects of DC-based vaccines tested in cancer patients, including the cell culture, antigen loading, maturation, and delivery, as well as what we have learned from testing immune responses in vaccinated patients who have benefited clinically, and those who have not measurably benefited. PMID 24379816

Clinical Implications of Co-Inhibitory Molecule Expression in the Tumor Microenvironment for DC Vaccination: A Game of Stop and Go.
Dec 2013 | Vasaturo, Angela; Di Blasio, Stefania; Peeters, Deborah G A; de Koning, Coco C H; de Vries, Jolanda M; Figdor, Carl G; Hato, Stanleyson V
The aim of therapeutic dendritic cell (DC) vaccines in cancer immunotherapy is to activate cytotoxic T cells to recognize and attack the tumor. T cell activation requires the interaction of the T cell receptor with a cognate major-histocompatibility complex-peptide complex. Although initiated by antigen engagement, it is the complex balance between co-stimulatory and co-inhibitory signals on DCs that results in T cell activation or tolerance. Even when already activated, tumor-specific T cells can be neutralized by the expression of co-inhibitory molecules on tumor cells. These and other immunosuppressive cues in the tumor microenvironment are major factors currently hampering the application of DC vaccination. In this review, we discuss recent data regarding the essential and complex role of co-inhibitory molecules in regulating the immune response within the tumor microenvironment. In particular, possible therapeutic intervention strategies aimed at reversing or neutralizing suppressive networks within the tumor microenvironment will be emphasized. Importantly, blocking co-inhibitory molecule signaling, often referred to as immune checkpoint blockade, does not necessarily lead to an effective activation of tumor-specific T cells. Therefore, combination of checkpoint blockade with other immune potentiating therapeutic strategies, such as DC vaccination, might serve as a synergistic combination, capable of reversing effector T cells immunosuppression while at the same time increasing the efficacy of T cell-mediated immunotherapies. This will ultimately result in long-term anti-tumor immunity. PMID 24348481

Wilms' Tumor Gene 1 (WT1)--loaded dendritic cell immunotherapy in patients with uterine tumors: a phase I/II clinical trial.
Dec 2013 | Coosemans, An; Vanderstraeten, Anke; Tuyaerts, Sandra; Verschuere, Tina; Moerman, Philippe; Berneman, Zwi N; Vergote, Ignace; Amant, Frédéric; VAN Gool, Stefaan W
Treatment options are limited in uterine cancer, leading to a poor prognosis. Overexpression of Wilms' tumor gene 1 (WT1), the highest ranked tumor antigen, is attractive for immunotherapy. PMID 24324087

Dendritic cell vaccination, immune regulation, and clinical outcomes in ovarian cancer.
Dec 2013 | Goyne, Hannah E; Cannon, Martin J
Clinical optimism for dendritic cell vaccination against ovarian cancer has been tempered by the knowledge that tumors avail themselves of multiple mechanisms of immune evasion, thus blunting the efficacy of therapeutic vaccination. Mechanisms of immune suppression include infiltration by regulatory T cells (Treg) and myeloid suppressor cell populations, expression of co-inhibitory receptors, and expression of indoleamine 2,3-dioxygenase (IDO). Expression of both B7-H1 and IDO are associated with differentiation and recruitment of Treg, and clinical studies have shown that each of these mechanisms correlates independently with increased morbidity and mortality in ovarian cancer patients. In sharp contrast, recent studies have indicated that Th17 cell infiltration in ovarian cancer correlates with improved patient outcomes and prolonged overall survival. Given that IDO plays a pivotal role in the balance between Treg and Th17 immunity, elucidation of the mechanisms that regulate IDO activity and immune suppression may lead to novel adjuvants to boost the clinical efficacy of dendritic cell vaccination against ovarian cancer and other malignancies. PMID 24302925

Dendritic cell-based immunotherapy for glioma: multiple regimens and implications in clinical trials.
Nov 2013 | Mineharu, Yohei; Castro, Maria G; Lowenstein, Pedro R; Sakai, Nobuyuki; Miyamoto, Susumu
High grade glioma is a highly invasive brain tumor and recurrence is almost inevitable, even after radical resection of the tumor mass. Cytotoxic immune responses and immunological memory induced by immunotherapy might prevent tumor recurrence. Dendritic cells (DCs) are professional antigen-presenting cells of the innate immune system with the potential to generate robust antigen-specific T cell immune responses. DC-based immunotherapeutic strategies have been intensively studied in both preclinical and clinical settings. Although advances have been made in the experimental use of DCs, there are still considerable challenges that need to be addressed for clinical translation. In this review, we describe the variability of regimens currently available for DC-based immunotherapy and then review strategies to optimize DC therapeutic efficacy against glioma. PMID 24140772

Tumour-derived exosomes as antigen delivery carriers in dendritic cell-based immunotherapy for malignant mesothelioma.
Nov 2013 | Mahaweni, Niken M; Kaijen-Lambers, Margaretha E H; Dekkers, Jacqueline; Aerts, Joachim G J V; Hegmans, Joost P J J
In 2001, it was postulated that tumour-derived exosomes could be a potent source of tumour-associated antigens (TAA). Since then, much knowledge is gained on their role in tumorigenesis but only very recently tumour-derived exosomes were used in dendritic cell (DC)-based immunotherapy. For this, DCs were cultured ex-vivo and loaded with exosomes derived from immunogenic tumours such as melanoma or glioma and re-administrated to induce anti-tumour responses in primary and metastatic tumour mouse models. In contrast, malignant mesothelioma (MM) is a non-immunogenic tumour and because only a few mesothelioma-specific TAA are known to date, we investigated whether mesothelioma-derived exosomes could be used as antigen source in DC-based immunotherapy. PMID 24223258

Dendritic cell vaccine for recurrent high-grade gliomas in pediatric and adult subjects: clinical trial protocol.
Oct 2013 | Shah, Ashish H; Bregy, Amade; Heros, Deborah O; Komotar, Ricardo J; Goldberg, John
Although there have been significant advances in understanding the basic pathogenesis of glioblastoma multiforme, the median survival of patients has changed little in the past 25 years. Recent studies have suggested that immune modulation through dendritic cell (DC) vaccines may stimulate the immune system against tumor antigens and potentially increase survival. PMID 23867302

Immune response, clinical outcome and safety of dendritic cell vaccine in combination with cytokine-induced killer cell therapy in cancer patients.
Oct 2013 | Cui, Yu; Yang, Xuejing; Zhu, Wei; Li, Jiali; Wu, Xiaojing; Pang, Yan
The aim of the present study was to determine the clinical value of autologous immunocyte therapy as a standard treatment regimen for patients with cancer. A total of 121 patients with cancer were included in this study. Subsequent to performing leukapheresis using the Fresenius Kabi System, 1×10(7) dendritic cells (DCs) for the vaccine and 1×10(9) cytokine-induced killer (CIK) cells for injection were prepared. An analysis of the immune phenotypes of HLA2DR, CD80 and CD83 for the DCs and of CD3, CD8 and CD56 for the CIK cells, as well as negative detection of bacteria and endotoxin, were used as the quality standards. The delayed-type hyper-sensitivity (DTH) skin test was used to measure the immune response, while physical strength, appetite and sleeping status were analyzed for the clinical outcome. Fever, insomnia, anorexia, joint soreness and skin rashes were recorded as side-effects. Patients received the DC vaccination once a week for six weeks and a CIK cell injection six times within four days. In total, 121 cancer patients with primary tumors located in the colorectum (43.0%), lung (15.7%), breast (11.6%), kidney (5.8%), stomach (4.1%) and other regions (19.8%) were included in the study. A positive cell-mediated cytotoxicity response rate of 76.9% was detected by the DTH skin tests. Improvements in physical strength, appetite and sleeping status were observed in 94.1, 83.9 and 76.3% of cases, respectively. None of the serious adverse side-effects that commonly occur during chemotherapy and radiotherapy were observed. During therapy, 69 cases developed a fever that was resolved with antipyretics, dexamethasone or physical cooling, while 28 cases developed insomnia combined with excitement, 19 cases complained of anorexia, 11 cases complained of joint soreness, which was alleviated using analgesics, and 8 cases developed skin rashes. The combined use of CIK cells with a DC-based cancer vaccination strategy may be used to target innate and adaptive immune mechanisms and synergistically promote positive clinical outcomes. The therapy was safe and no serious adverse side-effects similar to those caused by chemotherapy and radiotherapy were observed. The regimen may have a beneficial effect in the future treatment of patients with cancer. PMID 24137363

Exploiting dendritic cells in the development of cancer vaccines.
Oct 2013 | Bracci, Laura; Capone, Imerio; Moschella, Federica; Proietti, Enrico; Belardelli, Filippo
Due to their central role in priming and modulating the immune response, dendritic cells (DCs) represent an ideal instrument for the design of effective immunotherapeutic strategies for cancer patients. Recent advancement on the knowledge of the numerous DC subtypes, their functions and T-cell polarizing abilities has led to the development of several protocols for the ex vivo differentiation of autologous DCs and their loading with tumor-associated antigens. Moreover, novel strategies for the in vivo targeting of tumor antigens and adjuvants to natural DC subsets have been developed. Despite the large number of clinical studies carried out in cancer patients, a consensus on the optimal treatment modalities has not been reached yet. In this review, we summarize our current knowledge on DC biology and on DC use in clinical trials. Special attention is given to the many open issues regarding DC-based vaccination to sensitize researchers in the field to the compelling need of conducting comparative studies systematically addressing the still unresolved problems. PMID 24090117

Allogeneic partially HLA-matched dendritic cells pulsed with autologous tumor cell lysate as a vaccine in metastatic renal cell cancer: a clinical phase I/II study.
Oct 2013 | Flörcken, Anne; Kopp, Joachim; van Lessen, Antje; Movassaghi, Kamran; Takvorian, Anna; Jöhrens, Korinna; Möbs, Markus; Schönemann, Constanze; Sawitzki, Birgit; Egerer, Karl; Dörken, Bernd; Pezzutto, Antonio; Westermann, Jörg
Multi-kinase inhibitors have been established for the treatment of advanced renal cell cancer, but long-term results are still disappointing and immunotherapeutic approaches remain an interesting experimental option particularly in patients with a low tumor burden. DC are crucial for antigen-specific MHC-restricted T cell immunity. Furthermore, allogeneic HLA-molecules pose a strong immunogenic signal and may help to induce tumor-specific T cell responses. In this phase I/II trial, 7 patients with histologically confirmed progressive metastatic RCC were immunized repetitively with 1 × 10 (7) allogeneic partially HLA-matched DC pulsed with autologous tumor lysate following a schedule of 8 vaccinations over 20 weeks. Patients also received 3 Mio IE IL-2 s.c. once daily starting in week 4. Primary endpoints of the study were feasibility and safety. Secondary endpoints were immunological and clinical responses. Vaccination was feasible and safe with no severe toxicity being observed. No objective response could be documented. However, while all patients had documented progress at study entry, 29% of the patients showed SD throughout the study with a mean TTP of 24.6 weeks (range 5 to 96 weeks). In 3/7 patients, TH1-polarized immune responses against RCC-associated antigens were observed. In one patient showing a minimal clinical response and a TTP of 96 weeks, clonally proliferated T cells against yet undefined antigens were induced by the vaccine. Vaccination with tumor antigen loaded DC remains an interesting experimental approach, but should rather be applied in the situation of minimal residual disease after systemic therapy. Additional depletion of regulatory cells might be a promising strategy. PMID 23458999

Current status of immunotherapy for the treatment of biliary tract cancer.
Oct 2013 | Takahashi, Ryuji; Yoshitomi, Munehiro; Yutani, Shigeru; Shirahama, Takahisa; Noguchi, Masanori; Yamada, Akira; Itoh, Kyogo; Sasada, Tetsuro
Biliary tract cancer (BTC) is one of the most aggressive malignancies. Although various promising regimens of chemotherapeutic and/or molecular targeted agents have been developed, further treatment modalities, including immunotherapies, still remain to be established for refractory patients who are unresponsive to or relapse after currently available therapeutic options for BTC. Recently, several clinical trials of immunotherapies, including peptide-based vaccines and dendritic cell (DC)-based vaccines, have been reported with promising results. Here we summarize the data from phase I or phase II clinical trials of immunotherapies for BTC. In particular, we introduce our novel immunotherapeutic approach called personalized peptide vaccine (PPV), in which HLA-matched peptides were selected and administered based on the pre-existing host immunity before vaccination, for the treatment of advanced BTC. Further clinical trials would be recommended to prove clinical benefits of these novel immunotherapeutic approaches. Recently concomitant treatments, such as chemotherapies and immune checkpoint blockade, have been reported to enhance the therapeutic effects of cancer immunotherapies through multiple coordinated immune mechanisms. Additional therapies in combination with immunotherapies could produce synergistic effects in the treatment of advanced BTC. PMID 23376808

Vaccination with dendritic cell-tumor fusion cells in multiple myeloma patients: a promising strategy?
Oct 2013 | Garcia-Marquez, Maria A; Shimabukuro-Vornhagen, Alexander; Theurich, Sebastian; von Bergwelt-Baildon, Michael
Evaluation of: Rosenblatt J, Avivi I, Vasir B et al. Vaccination with dendritic cell/tumor fusions following autologous stem cell transplant induces immunologic and clinical responses in multiple myeloma patients. Clin. Cancer Res. 19(13), 3640-3648 (2013). Recently, dendritic cell (DC)-tumor fusion vaccines have been explored as a promising therapeutic approach for the treatment of cancer. Fusion vaccines offer several advantages that distinguish them from other DC-based vaccines. In this Phase II clinical trial, Rosenblatt et al. demonstrate that repeated immunization with a DC-tumor fusion vaccine after autologous stem cell transplantation induces myeloma-specific immunity and improves clinical response. They showed that generation of an autologous fusion vaccine with dendritic and myeloma cells was feasible and that vaccination was well tolerated without grade 3-4 toxicities. The results of this study suggest that the time after autologous stem cell transplantation represents a unique setting for cancer vaccination and that combining autologous stem cell transplantation with post-transplant vaccination increases the immunogenicity. PMID 24088074

Developing an effective breast cancer vaccine: challenges to achieving sterile immunity versus resetting equilibrium.
Sep 2013 | Curigliano, Giuseppe; Criscitiello, Carmen; Esposito, Angela; Fumagalli, Luca; Gelao, Lucia; Locatelli, Marzia; Minchella, Ida; Goldhirsch, Aron
Evading immune destruction is an emerging hallmark of cancer. Immunotherapy of cancer is categorized as either specific stimulation of the immune system by active immunization, with cancer vaccines, or passive transfer of humor or cellular materials, such as, tumor specific antibodies (including immunomodulators) or adoptive cell therapy that inhibit the function of- or directly kill tumor cells. Modulation of immune response in cancer patients is the result of a balanced activity of T regulators and T effector cells. PMID 24074802

A review of dendritic cell therapy for cancer: progress and challenges.
Sep 2013 | Mantia-Smaldone, Gina M; Chu, Christina S
Dendritic cells are the professional antigen-presenting cells of the innate immune system with the potential to generate robust antigen-specific T cell immune responses. Immunotherapeutic strategies have attempted to monopolize on this ability of dendritic cells to deliver antigens as a means of therapeutic vaccination in individuals with advanced malignancies. Since the publication of the first clinical trial in melanoma patients in 1995, therapeutic dendritic cell cancer vaccines have been extensively studied in numerous phase I and II trials. While advances have been encountered (especially with prostate cancer), there are still considerable challenges that need to be addressed in future clinical trials. In this review, we describe the current methodology and highlight trials which have contributed to the development of dendritic cell vaccines. We then review strategies to optimize dendritic cell vaccines in order to improve antitumor responses in cancer patients. PMID 23592406

Therapeutic outcomes of combining cryotherapy, chemotherapy and DC-CIK immunotherapy in the treatment of metastatic non-small cell lung cancer.
Sep 2013 | Yuanying, Yuan; Lizhi, Niu; Feng, Mu; Xiaohua, Wang; Jianying, Zeng; Fei, Yao; Feng, Jiang; Lihua, He; Jibing, Chen; Jialiang, Li; Kecheng, Xu
Currently there are no effective therapies for the treatment of metastatic non-small cell lung cancer (NSCLC). Here, we conducted a retrospective study of 161 patients to evaluate the therapeutic effects of combining cryosurgery, chemotherapy and dendritic cell-activated cytokine-induced killer cells (DC-CIK) immunotherapy. The overall survival (OS) after diagnosis of metastatic NSCLC to patient death was assessed during a 5-years follow-up period. OS of patients who received comprehensive cryotherapy was (median OS, 20 months; n = 86) significantly longer than that of patients who did not received cryotherapy (median OS, 10 months; n = 75; P < 0.0001). Five treatment combinations were selected: chemotherapy (n = 44); chemo-immunotherapy (n = 31); cryo-chemotherapy (n = 32); cryo-immunotherapy (n = 21); and cryo-chemo-immunotherapy (n = 33). A combination of cryotherapy with either chemotherapy or immunotherapy lead to significantly longer OS (18 months and 17 months, respectively) compared to chemotherapy and chemo-immunotherapy (8.5 months and 12 months, respectively; P < 0.001); however, the median OS of patients who underwent cryo-chemo-immunotherapy was significantly longer (27 months) compared to the other treatment programs (P < 0.001). In conclusion, a combination of cryotherapy, chemotherapy and DC-CIK immunotherapy proved the best treatment option for metastatic NSCLC in this group of patients. PMID 23948179

Active immunotherapy using dendritic cells in the treatment of glioblastoma multiforme.
Sep 2013 | Bregy, Amade; Wong, Theresa M; Shah, Ashish H; Goldberg, John M; Komotar, Ricardo J
Glioblastoma multiforme, the most common malignant brain tumor still has a dismal prognosis with conventional treatment. Therefore, it is necessary to explore new and/or adjuvant treatment options to improve patient outcomes. Active immunotherapy is a new area of research that may be a successful treatment option. The focus is on vaccines that consist of antigen presenting cells (APCs) loaded with tumor antigen. We have conducted a systematic review of prospective studies, case reports and clinical trials. The goal of this study was to examine the efficacy and safety in terms of complications, median overall survival (OS), progression free survival (PFS) and quality of life. PMID 23790634

A dendritic cell vaccine pulsed with autologous hypochlorous acid-oxidized ovarian cancer lysate primes effective broad antitumor immunity: from bench to bedside.
Sep 2013 | Chiang, Cheryl Lai-Lai; Kandalaft, Lana E; Tanyi, Janos; Hagemann, Andrea R; Motz, Gregory T; Svoronos, Nikolaos; Montone, Kathleen; Mantia-Smaldone, Gina M; Smith, Lori; Nisenbaum, Harvey L; Levine, Bruce L; Kalos, Michael; Czerniecki, Brian J; Torigian, Drew A; Powell, Daniel J; Mick, Rosemarie; Coukos, George
Whole tumor lysates are promising antigen sources for dendritic cell (DC) therapy as they contain many relevant immunogenic epitopes to help prevent tumor escape. Two common methods of tumor lysate preparations are freeze-thaw processing and UVB irradiation to induce necrosis and apoptosis, respectively. Hypochlorous acid (HOCl) oxidation is a new method for inducing primary necrosis and enhancing the immunogenicity of tumor cells. PMID 23838316

Response to HER-2 pulsed DC1 vaccines is predicted by both HER-2 and estrogen receptor expression in DCIS.
Sep 2013 | Fracol, Megan; Xu, Shuwen; Mick, Rosemarie; Fitzpatrick, Elizabeth; Nisenbaum, Harvey; Roses, Robert; Fisher, Carla; Tchou, Julia; Fox, Kevin; Zhang, Paul; Czerniecki, Brian J
Patients with estrogen-independent (ER(neg)) human epidermal growth factor receptor-2 (HER-2)-positive ductal carcinoma in situ (DCIS) treated with lumpectomy alone or lumpectomy and radiation are at increased risk of developing subsequent breast cancer events. PMID 23851609

Therapeutic vaccination against autologous cancer stem cells with mRNA-transfected dendritic cells in patients with glioblastoma.
Aug 2013 | Vik-Mo, Einar Osland; Nyakas, Marta; Mikkelsen, Birthe Viftrup; Moe, Morten Carstens; Due-Tønnesen, Paulina; Suso, Else Marit Inderberg; Sæbøe-Larssen, Stein; Sandberg, Cecilie; Brinchmann, Jan E; Helseth, Eirik; Rasmussen, Anne-Marie; Lote, Knut; Aamdal, Steinar; Gaudernack, Gustav; Kvalheim, Gunnar; Langmoen, Iver A
The growth and recurrence of several cancers appear to be driven by a population of cancer stem cells (CSCs). Glioblastoma, the most common primary brain tumor, is invariably fatal, with a median survival of approximately 1 year. Although experimental data have suggested the importance of CSCs, few data exist regarding the potential relevance and importance of these cells in a clinical setting. PMID 23817721

Dendritic cell-based immunotherapy targeting synthesized peptides for advanced biliary tract cancer.
Aug 2013 | Kobayashi, Masanori; Sakabe, Tomoyo; Abe, Hirofumi; Tanii, Mitsugu; Takahashi, Hidenori; Chiba, Asako; Yanagida, Eri; Shibamoto, Yuta; Ogasawara, Masahiro; Tsujitani, Shun-ichi; Koido, Shigeo; Nagai, Kazuhiro; Shimodaira, Shigetaka; Okamoto, Masato; Yonemitsu, Yoshikazu; Suzuki, Noboru; Nagaya, Masaki; ,
The aim of this retrospective study was to clarify the safety and efficacy of dendritic cell (DC)-based immunotherapy targeting synthesized peptides, Wilms tumor 1 (WT1) and Mucin 1, cell surface associated (MUC1) for biliary tract cancers (BTCs). PMID 23877328

Melanoma immunotherapy using mature DCs expressing the constitutive proteasome.
Aug 2013 | Dannull, Jens; Haley, N Rebecca; Archer, Gary; Nair, Smita; Boczkowski, David; Harper, Mark; De Rosa, Nicole; Pickett, Nancy; Mosca, Paul J; Burchette, James; Selim, Maria A; Mitchell, Duane A; Sampson, John; Tyler, Douglas S; Pruitt, Scott K
Many cancers, including melanoma, exclusively express constitutive proteasomes (cPs) and are unable to express immunoproteasomes (iPs). In contrast, mature DCs used for immunotherapy exclusively express iPs. Since proteasomes generate peptides presented by HLA class I molecules, we hypothesized that mature melanoma antigen-loaded DCs engineered to process antigens through cPs would be superior inducers of antimelanoma immunity in vivo. PMID 23934126

Current status and future perspectives of dendritic cell-based cancer immunotherapy.
Jul 2013 | H Yi, D; Appel, S
Dendritic cells (DCs) are considered to be the most potent antigen-presenting cells. Ever since the development of protocols for the in vitro generation of DCs, their application in immunotherapy against various malignancies has been explored. Even though the approach of using tumour antigen-presenting DCs in therapeutic vaccination strategies has been shown to work effectively in mice and look promising in in vitro studies, the actual clinical benefit for patients with cancer has been marginal. There clearly is still room for improvement. In this review, we will summarize recent clinical trials and findings and try to shed some light on the current status and the future of DC-based cancer immunotherapy. PMID 23672402

Immunogenicity of dendritic cells pulsed with MAGE3, Survivin and B-cell maturation antigen mRNA for vaccination of multiple myeloma patients.
Jul 2013 | Hobo, Willemijn; Strobbe, Leonie; Maas, Frans; Fredrix, Hanny; Greupink-Draaisma, Annelies; Esendam, Ben; de Witte, Theo; Preijers, Frank; Levenga, Henriëtte; van Rees, Bas; Raymakers, Reinier; Schaap, Nicolaas; Dolstra, Harry
The introduction of autologous stem cell transplantation (SCT) and novel drugs has improved overall survival in multiple myeloma (MM) patients. However, minimal residual disease (MRD) remains and most patients eventually relapse. Myeloma plasma cells express tumor-associated antigens (TAA), which are interesting targets for immunotherapy. In this phase 1 study, we investigated the safety and immunological effects of TAA-mRNA-loaded dendritic cell (DC) vaccination for treatment for MRD in MM after SCT. Mature monocyte-derived DCs were pulsed with keyhole limpet hemocyanin (KLH) and electroporated with MAGE3, Survivin or B-cell maturation antigen (BCMA) mRNA. Twelve patients were vaccinated three times with intravenous (5-22 × 10(6) DCs) and intradermal vaccines (4-11 × 10(6) DCs), at biweekly intervals. Immunological responses were monitored in blood and delayed-type hypersensitivity (DTH) biopsies. All patients developed strong anti-KLH T-cell responses, but not KLH antibodies. In 2 patients, vaccine-specific T cells were detected in DTH biopsies. In one patient, we found MAGE3-specific CD4(+) and CD8(+) T cells, and CD3(+) T cells reactive against BCMA and Survivin. In the other patient, we detected low numbers of MAGE3 and BCMA-reactive CD8(+) T cells. Vaccination was well tolerated with limited toxicity. These findings illustrate that TAA-mRNA-electroporated mature DCs are capable of inducing TAA-T-cell responses in MM patients after SCT. PMID 23728352

Heat-shock proteins as dendritic cell-targeting vaccines--getting warmer.
Jul 2013 | McNulty, Shaun; Colaco, Camilo A; Blandford, Lucy E; Bailey, Christopher R; Baschieri, Selene; Todryk, Stephen
Heat-shock proteins (hsp) provide a natural link between innate and adaptive immune responses by combining the ideal properties of antigen carriage (chaperoning), targeting and activation of antigen-presenting cells (APC), including dendritic cells (DC). Targeting is achieved through binding of hsp to distinct cell surface receptors and is followed by antigen internalization, processing and presentation. An improved understanding of the interaction of hsp with DC has driven the development of numerous hsp-containing vaccines, designed to deliver antigens directly to DC. Studies in mice have shown that for cancers, such vaccines generate impressive immune responses and protection from tumour challenge. However, translation to human use, as for many experimental immunotherapies, has been slow partly because of the need to perform trials in patients with advanced cancers, where demonstration of efficacy is challenging. Recently, the properties of hsp have been used for development of prophylactic vaccines against infectious diseases including tuberculosis and meningitis. These hsp-based vaccines, in the form of pathogen-derived hsp-antigen complexes, or recombinant hsp combined with selected antigens in vitro, offer an innovative approach against challenging diseases where broad antigen coverage is critical. PMID 23551234

Blockade of PD-1/PD-L1 immune checkpoint during DC vaccination induces potent protective immunity against breast cancer in hu-SCID mice.
Jul 2013 | Ge, Yan; Xi, Hong; Ju, Songguang; Zhang, Xueguang
Immune checkpoints, such as the PD-1/PD-L1 pathway, negatively interfere in the efficiency of dendritic cell (DC) vaccination in cancer immunotherapy. In this study, we demonstrated that the blockade of PD-L1 signaling could promote DC maturation, proliferation, and IL-12 secretion, augment DC primed T cell response and reverse tumor cell dampened T cell impairment. Blockade of PD-L1 signaling during DC vaccination showed better therapeutic effects than classic DC vaccination by preventing tumor growth and prolonging survival times in a breast tumor-bearing hu-SCID model. Taken together, suppressing immune checkpoints during DC vaccination might be a more efficient strategy for cancer therapy. PMID 23523609

The natural killer cell response and tumor debulking are associated with prolonged survival in recurrent glioblastoma patients receiving dendritic cells loaded with autologous tumor lysates.
Jun 2013 | Pellegatta, Serena; Eoli, Marica; Frigerio, Simona; Antozzi, Carlo; Bruzzone, Maria Grazia; Cantini, Gabriele; Nava, Sara; Anghileri, Elena; Cuppini, Lucia; Cuccarini, Valeria; Ciusani, Emilio; Dossena, Marta; Pollo, Bianca; Mantegazza, Renato; Parati, Eugenio A; Finocchiaro, Gaetano
Recurrent glioblastomas (GBs) are highly aggressive tumors associated with a 6-8 mo survival rate. In this study, we evaluated the possible benefits of an immunotherapeutic strategy based on mature dendritic cells (DCs) loaded with autologous tumor-cell lysates in 15 patients affected by recurrent GB. The median progression-free survival (PFS) of this patient cohort was 4.4 mo, and the median overall survival (OS) was 8.0 mo. Patients with small tumors at the time of the first vaccination (< 20 cm; n = 8) had significantly longer PFS and OS than the other patients (6.0 vs. 3.0 mo, p = 0.01; and 16.5 vs. 7.0 mo, p = 0.003, respectively). CD8 T cells, CD56 natural killer (NK) cells and other immune parameters, such as the levels of transforming growth factor β, vascular endothelial growth factor, interleukin-12 and interferon γ (IFNγ), were measured in the peripheral blood and serum of patients before and after immunization, which enabled us to obtain a vaccination/baseline ratio (V/B ratio). An increased V/B ratio for NK cells, but not CD8 T cells, was significantly associated with prolonged PFS and OS. Patients exhibiting NK-cell responses were characterized by high levels of circulating IFNγ and E4BP4, an NK-cell transcription factor. Furthermore, the NK cell V/B ratio was inversely correlated with the TGFβ2 and VEGF V/B ratios. These results suggest that tumor-loaded DCs may increase the survival rate of patients with recurrent GB after effective tumor debulking, and emphasize the role of the NK-cell response in this therapeutic setting. PMID 23802079

A Phase I vaccine trial using dendritic cells pulsed with autologous oxidized lysate for recurrent ovarian cancer.
Jun 2013 | Kandalaft, Lana E; Chiang, Cheryl L; Tanyi, Janos; Motz, Greg; Balint, Klara; Mick, Rosemarie; Coukos, George
Ovarian cancer, like most solid tumors, is in dire need of effective therapies. The significance of this trial lies in its promise to spearhead the development of combination immunotherapy and to introduce novel approaches to therapeutic immunomodulation, which could enable otherwise ineffective vaccines to achieve clinical efficacy. PMID 23777306

The immunological response and post-treatment survival of DC-vaccinated melanoma patients are associated with increased Th1/Th17 and reduced Th3 cytokine responses.
Jun 2013 | Durán-Aniotz, Claudia; Segal, Gabriela; Salazar, Lorena; Pereda, Cristián; Falcón, Cristián; Tempio, Fabián; Aguilera, Raquel; González, Rodrigo; Pérez, Claudio; Tittarelli, Andrés; Catalán, Diego; Nervi, Bruno; Larrondo, Milton; Salazar-Onfray, Flavio; López, Mercedes N
Immunization with autologous dendritic cells (DCs) loaded with a heat shock-conditioned allogeneic melanoma cell lysate caused lysate-specific delayed type hypersensitivity (DTH) reactions in a number of patients. These responses correlated with a threefold prolonged long-term survival of DTH(+) with respect to DTH(-) unresponsive patients. Herein, we investigated whether the immunological reactions associated with prolonged survival were related to dissimilar cellular and cytokine responses in blood. PMID 23242374

Vaccination of diffuse large B- cell lymphoma patients with antigen-primed dendritic cells.
Jun 2013 | Abediankenari, Saeid; Janbabaei Mollae, Ghasem; Ghasemi, Maryam; Yousefzadeh, Yousef; Bahrami, Masoud; Alimoghaddam, Kamran
Dendritic cells (DCs) are professional antigen presenting cells that have a potential role in the initiating of immune responses. The cell vaccination is a new strategy in treatment of infectious diseases and cancers. In this study, we have generated monocyte-derived dendritic cells of lymphoma patient's peripheral blood mononuclear cells then; these cells were used as vaccine in lymphoma patients. We generated dendritic cell vaccine from lymphoma patient's blood monocytes with human interleukin-4, granulocyte monocyte colony stimulating factor and then, antigen-primed Dcs were administrated subcutaneously close to the inguinal lymph nodes after maturation of dendritic cells. After 7 days, we analyzed immune response in lymphoma patients with determining of LDH, Beta 2 Microglobulin, CD4+T cell percent, CD8+ Tcell percent and Tumor size before and after vaccination. Furthermore, phenotypic and functional analysis of dendritic cells was performed using anti CD83-FITC monoclonal antibodies. Before vaccination, the mean ± SD of LDH was 530.62±140.65 but after vaccination it was 459±109.45 that significantly different between experimental groups (P=0.002). In addition, the CD8+ T cells percentage significantly different between two groups (P=0.002). We concluded that the use of dendritic cell probably is one of the suitable noninvasive treatments for lymphoma patients that they have not response to chemical drugs. PMID 23737309

Dendritic cell immunotherapy combined with gemcitabine chemotherapy enhances survival in a murine model of pancreatic carcinoma.
May 2013 | Ghansah, Tomar; Vohra, Nasreen; Kinney, Kathleen; Weber, Amy; Kodumudi, Krithika; Springett, Gregory; Sarnaik, Amod A; Pilon-Thomas, Shari
Pancreatic cancer is an extremely aggressive malignancy with a dismal prognosis. Cancer patients and tumor-bearing mice have multiple immunoregulatory subsets including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC) that may limit the effectiveness of anti-tumor immunotherapies for pancreatic cancer. It is possible that modulating these subsets will enhance anti-tumor immunity. The goal of this study was to explore depletion of immunoregulatory cells to enhance dendritic cell (DC)-based cancer immunotherapy in a murine model of pancreatic cancer. Flow cytometry results showed an increase in both Tregs and MDSC in untreated pancreatic cancer-bearing mice compared with control. Elimination of Tregs alone or in combination with DC-based vaccination had no effect on pancreatic tumor growth or survival. Gemcitabine (Gem) is a chemotherapeutic drug routinely used for the treatment for pancreatic cancer patients. Treatment with Gem led to a significant decrease in MDSC percentages in the spleens of tumor-bearing mice, but did not enhance overall survival. However, combination therapy with DC vaccination followed by Gem treatment led to a significant delay in tumor growth and improved survival in pancreatic cancer-bearing mice. Increased MDSC were measured in the peripheral blood of patients with pancreatic cancer. Treatment with Gem also led to a decrease of this population in pancreatic cancer patients, suggesting that combination therapy with DC-based cancer vaccination and Gem may lead to improved treatments for patients with pancreatic cancer. PMID 23604104

Cancer immunotherapy: a paradigm shift for prostate cancer treatment.
May 2013 | Karan, Dev; Holzbeierlein, Jeffrey M; Van Veldhuizen, Peter; Thrasher, J Brantley
Prostate cancer remains a significant health problem for men in the Western world. Although treatment modalities are available, these do not confer long-term benefit and are accompanied by deleterious side effects. Immunotherapy represents a valuable alternative to conventional treatments by inducing tumour-specific immune responses that control the growth of cancer cells. Sipuleucel-T is approved by the FDA as an immunotherapeutic agent for the treatment of patients with asymptomatic or minimally symptomatic castration-resistant prostate cancer (CRPC). Although this approval has raised cost-versus-benefit issues, it has provided proof of concept for the therapeutic potential of active immunotherapy approaches for metastatic CRPC. Numerous clinical studies have demonstrated clinical benefit using immunotherapy compared to traditional chemotherapy and several active immunotherapy approaches (at various developmental stages)have demonstrated the potential to change the face of prostate cancer treatment. PMID 22641164

Autologous tumor lysate-pulsed dendritic cell immunotherapy for pediatric patients with newly diagnosed or recurrent high-grade gliomas.
May 2013 | Lasky, Joseph L; Panosyan, Eduard H; Plant, Ashley; Davidson, Tom; Yong, William H; Prins, Robert M; Liau, Linda M; Moore, Theodore B
Immunotherapy has the potential to improve clinical outcomes with little toxicity for pediatric patients with brain tumors. We conducted a pilot feasibility study of tumor lysate-pulsed dendritic cell (DC) vaccination in pediatric patients (1 to 18 years old) with newly diagnosed or recurrent high-grade glioma (HGG). A total of nine DC vaccine doses, each containing 1 × 10(6) cells per dose were administered to three out of the seven originally enrolled patients. Toxicities were limited to mild side-effects, except in one case of elevated alkaline phosphatase, which resolved without clinical consequences. Two patients with primary lesions amongst the three vaccinated were alive at the time of writing, both without evidence of disease. Pre- and post-vaccination tumor samples from a patient with an anaplastic oligoastrocytoma that recurred failed to demonstrate immune cell infiltration by immunohistochemistry. Peripheral cytokine levels were evaluated in one patient following DC vaccination and demonstrated some changes in relation to vaccination. DC vaccine is tolerable and feasible with some limitations for pediatric patients with HGG. Dendritic cell based immunotherapy may provide some clinical benefit in pediatric patients with glioma, especially for patients with minimal residual disease, but further investigation of this modality is required. PMID 23645755

Therapeutic regulation of myeloid-derived suppressor cells and immune response to cancer vaccine in patients with extensive stage small cell lung cancer.
Apr 2013 | Iclozan, Cristina; Antonia, Scott; Chiappori, Alberto; Chen, Dung-Tsa; Gabrilovich, Dmitry
Myeloid-derived suppressor cells (MDSC) are one of the major factors limiting the efficacy of immune therapy. In a clinical trial of patients with extensive stage small cell lung cancer (SCLC), we tested the possibility that targeting MDSC can improve the induction of immune responses by a cancer vaccine. Forty-one patients with extensive stage SCLC were randomized into three arms: arm A--control, arm B--vaccination with dendritic cells transduced with wild-type p53, and arm C--vaccination in combination with MDSC targeted therapy with all-trans-retinoic acid (ATRA). Interim results of the ongoing clinical trial are presented. Pre-treatment levels of MDSC populations in patients from all three arms were similar. Vaccine alone did not affect the proportion of MDSC, whereas in patients treated with ATRA, the MDSC decreased more than twofold (p = 0.02). Before the start of treatment, no patients had detectable p53-specific responses in IFN-γ ELISPOT. Sequential measurements did not show positive p53 responses in any of the 14 patients from arm A. After immunization, only 3 out of 15 patients (20 %) from arm B developed a p53-specific response (p = 0.22). In contrast, in arm C, 5 out of 12 patients (41.7 %) had detectable p53 responses (p = 0.012). The proportion of granzyme B-positive CD8(+) T cells was increased only in patients from arm C but not in arm B. Depletion of MDSC substantially improved the immune response to vaccination, suggesting that this approach can be used to enhance the effect of immune interventions in cancer. PMID 23589106

Autologous lysate-pulsed dendritic cell vaccination followed by adoptive transfer of vaccine-primed ex vivo co-stimulated T cells in recurrent ovarian cancer.
Apr 2013 | Kandalaft, Lana E; Powell, Daniel J; Chiang, Cheryl L; Tanyi, Janos; Kim, Sarah; Bosch, Marnix; Montone, Kathy; Mick, Rosemarie; Levine, Bruce L; Torigian, Drew A; June, Carl H; Coukos, George
Novel strategies for the therapy of recurrent ovarian cancer are warranted. We report a study of a combinatorial approach encompassing dendritic cell (DC)-based autologous whole tumor vaccination and anti-angiogenesis therapy, followed by the adoptive transfer of autologous vaccine-primed CD3/CD28-co-stimulated lymphocytes. Recurrent ovarian cancer patients for whom tumor lysate was available from prior cytoreductive surgery underwent conditioning with intravenous bevacizumab and oral metronomic cyclophosphamide, sequentially followed by (1) bevacizumab plus vaccination with DCs pulsed with autologous tumor cell lysate supernatants, (2) lymphodepletion and (3) transfer of 5 × 10(9) autologous vaccine-primed T-cells in combination with the vaccine. Feasibility, safety as well as immunological and clinical efficacy were evaluated. Six subjects received this vaccination. Therapy was feasible, well tolerated, and elicited antitumor immune responses in four subjects, who also experienced clinical benefits. Of these, three patients with residual measurable disease received outpatient lymphodepletion and adoptive T-cell transfer, which was well tolerated and resulted in a durable reduction of circulating regulatory T cells and increased CD8(+) lymphocyte counts. The vaccine-induced restoration of antitumor immunity was achieved in two subjects, who also demonstrated clinical benefits, including one complete response. Our findings indicate that combinatorial cellular immunotherapy for the treatment of recurrent ovarian cancer is well tolerated and warrants further investigation. Several modifications of this approach can be envisioned to optimize immunological and clinical outcomes. PMID 23482679

Chemotherapy acts as an adjuvant to convert the tumor microenvironment into a highly permissive state for vaccination-induced antitumor immunity.
Apr 2013 | Kang, Tae Heung; Mao, Chih-Ping; Lee, Sung Yong; Chen, Alexander; Lee, Ji-Hyun; Kim, Tae Woo; Alvarez, Ronald D; Roden, Richard B S; Pardoll, Drew; Hung, Chien-Fu; Wu, T-C
Multiple classes of pharmacologic agents have the potential to induce the expression and release of proinflammatory factors from dying tumor cells. As a result, these cells can in theory elicit an immune response through various defined mechanisms to permanently eradicate disseminated cancer. However, the impact of chemotherapy on the tumor-specific immune response in the context of the tumor microenvironment is largely unknown. Within the tumor microenvironment, the immune response promoted by chemotherapy is antagonized by an immune-suppressive milieu, and the balance of these opposing forces dictates the clinical course of disease. Here, we report that high antigen exposure within the tumor microenvironment following chemotherapy is sufficient to skew this balance in favor of a productive immune response. In elevating antigen exposure, chemotherapy can achieve long-term control of tumor progression without the need of an additional adjuvant. We found that chemotherapy initiated this phenomenon in the tumor microenvironment through an accumulation of dendritic cells, which stimulated CD8(+) T cells and the type I IFN pathway. From this conceptual base, we developed a simple approach to cancer therapy combining chemotherapy and vaccination that may be widely applicable. PMID 23418322

Vaccine strategies for glioblastoma: progress and future directions.
Feb 2013 | Jackson, Christopher; Ruzevick, Jacob; Brem, Henry; Lim, Michael
Recent advances in glioblastoma therapy have led to optimism that more effective therapies will improve outcomes. Immunotherapy is a promising approach that has demonstrated the potential to eradicate cancer cells with cellular-level accuracy while minimizing damage to surrounding healthy tissue. Several vaccination strategies have been evaluated for activity against glioblastoma in clinical trials. These include peptide vaccines, polyvalent dendritic cell vaccines, heat shock protein vaccines and adoptive immunotherapy. In this review, we highlight clinical trials representative of each of these approaches and discuss strategies for integrating these therapies into routine patient care. PMID 23413907

Comparison of glioma-associated antigen peptide-loaded versus autologous tumor lysate-loaded dendritic cell vaccination in malignant glioma patients.
Feb 2013 | Prins, Robert M; Wang, Xiaoyan; Soto, Horacio; Young, Emma; Lisiero, Dominique N; Fong, Brendan; Everson, Richard; Yong, William H; Lai, Albert; Li, Gang; Cloughesy, Timothy F; Liau, Linda M
Dendritic cell (DC) vaccination is emerging as a promising therapeutic option for malignant glioma patients. However, the optimal antigen formulation for loading these cells has yet to be established. The objective of this study was to compare the safety, feasibility, and immune responses of malignant glioma patients on 2 different DC vaccination protocols. Twenty-eight patients were treated with autologous tumor lysate (ATL)-pulsed DC vaccination, whereas 6 patients were treated with glioma-associated antigen (GAA) peptide-pulsed DCs. Safety, toxicity, feasibility, and correlative immune monitoring assay results were compared between patients on each trial. Because of HLA subtype restrictions on the GAA-DC trial, 6/15 screened patients were eligible for treatment, whereas 28/32 patients passed eligibility screening for the ATL-DC trial. Elevated frequencies of activated natural killer cells were observed in the peripheral blood from GAA-DC patients compared with the ATL-DC patients. In addition, a significant correlation was observed between decreased regulatory T lymphocyte (Treg) ratios (postvaccination/prevaccination) and overall survival (P = 0.004) in patients on both trials. In fact, Treg ratios were independently prognostic for overall survival in these patients, whereas tumor pathology was not in multivariate analyses. In conclusion, these results suggest that ATL-DC vaccination is associated with wider patient eligibility compared with GAA-DC vaccination. Decreased postvaccination/prevaccination Treg ratios and decreased frequencies of activated natural killer cells were associated with prolonged survival in patients from both trials, suggesting that these lymphocyte subsets may be relevant immune monitoring endpoints for immunotherapy protocols in malignant glioma patients. PMID 23377664

α-type-1 polarized dendritic cell-based vaccination in recurrent high-grade glioma: a phase I clinical trial.
Jan 2013 | Akiyama, Yasuto; Oshita, Chie; Kume, Akiko; Iizuka, Akira; Miyata, Haruo; Komiyama, Masaru; Ashizawa, Tadashi; Yagoto, Mika; Abe, Yoshiaki; Mitsuya, Koichi; Watanabe, Reiko; Sugino, Takashi; Yamaguchi, Ken; Nakasu, Yoko
High-grade gliomas including glioblastoma multiforme (GBM) are among the most malignant and aggressive of tumors, and have a very poor prognosis despite a temozolomide-based intensive treatment. Therefore, a novel therapeutic approach to controlling recurrence is needed. In the present study, we investigated the effect of activated dendritic cell (DC) (α-type-1 polarized DC)-based immunotherapy on high-grade glioma patients with the HLA-A2 or A24 genotype. PMID 23270484

Targeting cancer stem cells via dendritic-cell vaccination.
Dec 2012 | Teitz-Tennenbaum, Seagal; Wicha, Max S; Chang, Alfred E; Li, Qiao
Using syngeneic murine tumor models established in immunocompetent hosts, we showed that cancer stem cells are immunogenic and can be selectively targeted by dendritic cell-based vaccines. This new approach induced both humoral and cellular immune responses and conferred significantly superior antitumor immunity as compared with conventional vaccines. PMID 23243607

Immunotherapy in ovarian cancer.
Dec 2012 | Mantia-Smaldone, Gina M; Corr, Bradley; Chu, Christina S
Ovarian cancer is the most deadly gynecologic malignancy, with more than 15,000 deaths anticipated in 2012. While approximately 80% of patients will respond to frontline chemotherapy, more than 60% of patients will experience disease recurrence and only 44% will be alive at 5 y. Host anti-tumor immune responses are associated with a significant improvement in overall survival for women with ovarian cancer. By bolstering these responses, it may therefore be possible to significantly influence the prognosis of women with this lethal disease. In this review, we will focus on innovative immune-based strategies which are currently being investigated in the treatment of ovarian cancer. PMID 22906947

Dendritic cell-based immunotherapy in mesothelioma.
Nov 2012 | Cornelissen, Robin; Lievense, Lysanne A; Heuvers, Marlies E; Maat, Alexander P; Hendriks, Rudi W; Hoogsteden, Henk C; Hegmans, Joost P; Aerts, Joachim G
Mesothelioma is a rare thoracic malignancy with a dismal prognosis. Current treatment options are scarce and clinical outcomes are rather disappointing. Due to the immunogenic nature of mesothelioma, several studies have investigated immunotherapeutic strategies to improve the prognosis of patients with mesothelioma. In the last decade, progress in knowledge of the modulation of the immune system to attack the tumor has been remarkable, but the optimal strategy for immunotherapy has yet to be unraveled. Because of their potent antigen-presenting capacity, dendritic cells are acknowledged as a promising agent in immunotherapeutic approaches in a number of malignancies. This review gives an update and provides a future perspective in which immunotherapy may improve the outcome of mesothelioma therapy. PMID 23148753

Dendritic cell-based tumor vaccinations in epithelial ovarian cancer: a systematic review.
Nov 2012 | Tanyi, Janos L; Chu, Christina S
After decades of extensive research, epithelial ovarian cancer still remains a lethal disease. Multiple new studies have reported that the immune system plays a critical role in the growth and spread of ovarian carcinoma. This review summarizes the development of dendritic cell (DC) vaccinations specific for ovarian cancer. So far, DC-based vaccines have induced effective antitumor responses in animal models, but only limited results from human clinical trials are available. Although DC-based immunotherapy has proven to be clinically safe and efficient at inducing tumor-specific immune responses, its clear role in the therapy of ovarian cancer still needs to be clarified. The relatively disappointing low-response rates in early clinical trials point to the need for the development of more effective and personalized DC-based anticancer vaccines. This article reviews the basic mechanisms, limitations and future directions of DC-based anti-ovarian cancer vaccine development. PMID 23148752

Pre-clinical assessment of autologous DC-based therapy in ovarian cancer patients with progressive disease.
Nov 2012 | Hardwick, Nicola; Ledermann, Jonathan A; Aitkens, Egla; Chain, Benny
Dendritic cell-based vaccines offer promise for therapy of ovarian cancer. Previous studies have demonstrated that oxidation of several antigens, including ovarian cancer cells, using hypochlorous acid strongly enhances their immunogenicity and their uptake and presentation by dendritic cells. The response of T cells and dendritic cells to autologous tumour from patients with active disease has not previously been investigated. Monocyte-derived dendritic cells were generated from patients with active disease and activated by co-culture with oxidised tumour cells and the TLR agonist poly I:C. The dendritic cells showed an activated phenotype, but secreted high levels of TGFβ. Co-culture of the antigen-loaded dendritic cells with autologous T cells generated a population of effector T cells that showed a low level of specific lytic activity against autologous tumour, as compared to autologous mesothelium. The addition of neutralising antibody to TGFβ in DC/T cell co-cultures increased the levels of subsequent tumour killing in three samples tested. Co-culture of monocytes from healthy volunteers with the ovarian cell line SKOV-3 prior to differentiation into dendritic cells reduced the ability of dendritic cells to stimulate cytotoxic effector cells. The study suggests that co-culture of dendritic cells with oxidised tumour cells can generate effector cells able to kill autologous tumour, but that the high tumour burden in patients with active disease may compromise dendritic cell and/or T cell function. PMID 22476408

Integration of autologous dendritic cell-based immunotherapy in the standard of care treatment for patients with newly diagnosed glioblastoma: results of the HGG-2006 phase I/II trial.
Nov 2012 | Ardon, Hilko; Van Gool, Stefaan W; Verschuere, Tina; Maes, Wim; Fieuws, Steffen; Sciot, Raf; Wilms, Guido; Demaerel, Philippe; Goffin, Jan; Van Calenbergh, Frank; Menten, Johan; Clement, Paul; Debiec-Rychter, Maria; De Vleeschouwer, Steven
Dendritic cell (DC)-based tumor vaccination has rendered promising results in relapsed high-grade glioma patients. In the HGG-2006 trial (EudraCT 2006-002881-20), feasibility, toxicity, and clinical efficacy of the full integration of DC-based tumor vaccination into standard postoperative radiochemotherapy are studied in 77 patients with newly diagnosed glioblastoma. PMID 22527250

Enhanced therapeutic effect of B cell-depleting anti-CD20 antibodies upon combination with in-situ dendritic cell vaccination in advanced lymphoma.
Nov 2012 | Manzur, S; Cohen, S; Haimovich, J; Hollander, N
The present standard of care for B cell non-Hodgkin's lymphoma includes the anti-CD20 monoclonal antibody rituximab. Although combination treatments with chemotherapy and rituximab improved the duration of remissions and overall survival in indolent B cell lymphoma, the disease is essentially incurable. Thus, new therapeutic approaches are needed. One such approach is active immunization. Given that rituximab depletes both malignant and normal B cells, it is expected to impair humoral immune responses in vaccinated patients. Hence, optimal vaccination strategies for rituximab-treated patients require induction of effector T cells, which can be achieved by dendritic cell (DC) vaccines. We have demonstrated in a mouse model that chemotherapy combined with DC vaccines was therapeutically effective. However, efficacy was related to tumour size at the onset of treatment, decreasing in correlation with increasing tumour burdens. We therefore examined whether, in spite of its low efficacy in advanced disease, DC vaccination may synergize with anti-CD20 antibodies to enhance therapy. Lymphoma-bearing mice were treated with cyclophosphamide, anti-CD20 antibodies and an intratumoral DC vaccine. Results clearly demonstrated the enhanced therapeutic effect of this combination treatment. Thus, under conditions of disseminated disease, when either anti-CD20 antibody treatment or vaccination showed insufficient efficacy, their combination resulted in synergism that mediated long-term survival. We demonstrated further that the combination of antibody and vaccine induced T cell-mediated anti-tumour immune responses with long-term memory. Combination treatments including tumour cell-loaded DC vaccines may therefore provide a strategy for enhancing therapy in rituximab-treated patients. PMID 23121670

Complex evaluation of human monocyte-derived dendritic cells for cancer immunotherapy.
Oct 2012 | Vopenkova, Katerina; Mollova, Klara; Buresova, Ivana; Michalek, Jaroslav
Dendritic cell (DC) immunotherapy is capable of generating tumour-specific immune responses. Different maturation strategies were previously tested to obtain DC capable of anti-cancer responses in vitro, usually with limited clinical benefit. Mutual comparison of currently used maturation strategies and subsequent complex evaluation of DC functions and their stimulatory capacity on T cells was performed in this study to optimize the DC vaccination strategy for further clinical application. DC were generated from monocytes using granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4, pulsed with whole tumour cell lysate and then matured with one of five selected maturation strategies or cultured without additional maturation stimulus. DC were characterized with regard to their surface marker expression, cytokine profiles, migratory capacity, allogeneic and autologous T cell stimulatory capacity as well as their specific cytotoxicity against tumour antigens. We were able to demonstrate extensive variability among different maturation strategies currently used in DC immunotherapeutic protocols that may at least partially explain limited clinical benefit of some clinical trials with such DC. We identified DC matured with interferon-γ and lipopolysaccharide as the most attractive candidate for future clinical trials in cancer immunotherapy. PMID 22882679

NK cells: key to success of DC-based cancer vaccines?
Oct 2012 | Lion, Eva; Smits, Evelien L J M; Berneman, Zwi N; Van Tendeloo, Viggo F I
The cytotoxic and regulatory antitumor functions of natural killer (NK) cells have become attractive targets for immunotherapy. Manipulation of specific NK cell functions and their reciprocal interactions with dendritic cells (DCs) might hold therapeutic promise. In this review, we focus on the engagement of NK cells in DC-based cancer vaccination strategies, providing a comprehensive overview of current in vivo experimental and clinical DC vaccination studies encompassing the monitoring of NK cells. From these studies, it is clear that NK cells play a key regulatory role in the generation of DC-induced antitumor immunity, favoring the concept that targeting both innate and adaptive immune mechanisms may synergistically promote clinical outcome. However, to date, DC vaccination trials are only infrequently accompanied by NK cell monitoring. Here, we discuss different strategies to improve DC vaccine preparations via exploitation of NK cells and provide a summary of relevant NK cell parameters for immune monitoring. We underscore that the design of DC-based cancer vaccines should include the evaluation of their NK cell stimulating potency both in the preclinical phase and in clinical trials. PMID 22907975

Autologous dendritic cell vaccine for estrogen receptor (ER)/progestin receptor (PR) double-negative breast cancer.
Oct 2012 | Qi, Chun-Jian; Ning, Yong-Ling; Han, Ye-Shan; Min, Hai-Yan; Ye, Heng; Zhu, Yu-Lan; Qian, Ke-Qing
A wealth of preclinical information, as well as a modest amount of clinical information, indicates that dendritic cell vaccines have therapeutic potential. The aim of this work was to assess the immune response, disease progression, and post-treatment survival of ER/PR double-negative stage II/IIIA breast cancer patients vaccinated with autologous dendritic cells pulsed with autologous tumor lysates. PMID 22290073

Optimizing dendritic cell vaccine for immunotherapy in multiple myeloma: tumour lysates are more potent tumour antigens than idiotype protein to promote anti-tumour immunity.
Oct 2012 | Hong, S; Li, H; Qian, J; Yang, J; Lu, Y; Yi, Q
Dendritic cells (DCs) are the most potent antigen-presenting cells and are the mediators of T cell immunity. Many investigators have explored the potential of using DCs as a vaccine for tumour-derived antigens in immunotherapy of B cell malignancies, and the results have been disappointing. To search for better tumour antigens to improve the efficacy of DC-based immunotherapy in myeloma, we evaluated and compared the efficacy of the vaccination of DCs pulsed with idiotype (Id) or tumour lysate in the 5TGM1 myeloma mouse model. Our results showed that Id- or tumour lysate-pulsed DC vaccines protected mice efficiently against developing myeloma, retarded tumour growth, induced tumour regression against established tumour and protected surviving mice from tumour rechallenge. The therapeutic responses were associated with an induction of strong humoral immune responses, including anti-Id or anti-lysate antibodies, and cellular immune responses including myeloma-specific CD8(+) cytotoxic T lymphocytes, CD4(+) type 1 T helper cells and memory T cells in mice receiving Id- or tumour lysate-pulsed DC vaccines. In addition, our studies showed that tumour lysate-pulsed DCs were more potent vaccines than the Id-pulsed DC vaccines to promote anti-tumour immunity in the model. This information will be important for improving the strategies of DC-based immunotherapy for patients with myeloma and other B cell tumours. PMID 23039887

Dendritic cell vaccine modified by Ag85A gene enhances anti-tumor immunity against bladder cancer.
Oct 2012 | Zhang, Pei; Wang, Jinyan; Wang, Danan; Wang, Huan; Shan, Fengping; Chen, Liudan; Hou, Ying; Wang, Enhua; Lu, Chang-Long
The ability of dendritic cells to provide all the signals required for T-cell activation makes them an ideal cancer vaccine platform. With the use of established DC2.4 cell line, originated from C57BL/6 mice and developed by superinfecting GM-CSF transduced bone marrow cells with myc and raf oncogenes, we investigated whether the DC 2.4 cell line transfected with Ag85A gene could enhance immunity against bladder cancer. Both phenotypic and functional analyses of Ag85A-DCs were done with use of FCM and T cell proliferation test. The cytotoxicity of Ag85A-DCs loaded with tumor cell lysate was verified by LDH. Finally, the production of interferon gamma was assayed by both ELISA and FCM. The immunotherapeutic effect of DC vaccine on murine bladder cancer was assessed pharmacologically and pathologically. Our results showed that Ag85A gene transfected DCs expressed high levels of key surface markers such as CD80, CD86 and MHC-II. The CTL primed with MB49 lysate-pulsed Ag85A-DCs elicits higher activity against MB49 tumor cells and upregulated level of IFN-γ production. Furthermore, the significant inhibitive effect on tumor growth in mice was found in the group of Ag85A-DC vaccine. The infiltration of CD4(+) or CD8(+) T cell within established tumor treated by Ag85A-DC vaccine significantly increased as compared with control groups. It is therefore concluded that DCs engineered by Ag85A gene exerts enhanced anti-tumor immunity against bladder cancer and this study might provide a meaningful mode of action with the use of Ag85A engineered DC vaccination in anti-cancer immunotherapy. PMID 22884511

Metastatic melanoma patients treated with dendritic cell vaccination, Interleukin-2 and metronomic cyclophosphamide: results from a phase II trial.
Sep 2012 | Ellebaek, Eva; Engell-Noerregaard, Lotte; Iversen, Trine Zeeberg; Froesig, Thomas Moerch; Munir, Shamaila; Hadrup, Sine Reker; Andersen, Mads Hald; Svane, Inge Marie
Dendritic cells (DC) are the most potent antigen presenting cells and have proven effective in stimulation of specific immune responses in vivo. Competing immune inhibition could limit the clinical efficacy of DC vaccination. In this phase II trial, metronomic Cyclophosphamide and a Cox-2 inhibitor have been added to a DC vaccine with the intend to dampen immunosuppressive mechanisms. Twenty-eight patients with progressive metastatic melanoma were treated with autologous DCs pulsed with survivin, hTERT, and p53-derived peptides (HLA-A2(+)) or tumor lysate (HLA-A2(-)). Concomitantly the patients were treated with IL-2, Cyclophosphamide, and Celecoxib. The treatment was safe and tolerable. Sixteen patients (57 %) achieved stable disease (SD) at 1st evaluation and 8 patients had prolonged SD (7-13.7 months). The median OS was 9.4 months. Patients with SD had an OS of 10.5 months while patients with progressive disease (PD) had an OS of 6.0 months (p = 0.048) even though there were no differences in prognostic factors between the two groups. Despite the use of metronomic Cyclophosphamide, regulatory T cells did not decrease during treatment. Indirect IFN-γ ELISPOT assays showed a general increase in immune responses from baseline to the time of 4th vaccination. Induction of antigen-specific immune responses was seen in 9 out of 15 screened HLA-A2(+) patients. In conclusion, the number of patients obtaining SD more than doubled and 6-month survival significantly increased compared to a previous trial without Cyclophosphamide and Celecoxib. A general increase in immune responses against the tested peptides was observed. PMID 22426890

Targeting of the non-mutated tumor antigen HER2/neu to mature dendritic cells induces an integrated immune response that protects against breast cancer in mice.
Sep 2012 | Wang, Bei; Zaidi, Neeha; He, Li-Zhen; Zhang, Li; Kuroiwa, Janelle M Y; Keler, Tibor; Steinman, Ralph M
Given their relative simplicity of manufacture and ability to be injected repeatedly, vaccines in a protein format are attractive for breast and other cancers. However, soluble human epidermal growth factor receptor (HER2)/neu protein as a vaccine has not been immunogenic. When protein is directly targeted to antigen uptake receptors, such as DEC205 (DEC), efficient processing and presentation of antigen take place. The aim of this study was to determine the immunogenicity of a HER2 protein vaccine that directly targets to DEC+ dendritic cells (DCs) in a mouse breast cancer model. PMID 22397502

Dendritic cell-based vaccination in metastatic melanoma patients: phase II clinical trial.
Sep 2012 | Oshita, Chie; Takikawa, Masako; Kume, Akiko; Miyata, Haruo; Ashizawa, Tadashi; Iizuka, Akira; Kiyohara, Yoshio; Yoshikawa, Shusuke; Tanosaki, Ryuji; Yamazaki, Naoya; Yamamoto, Akifumi; Takesako, Kazutoh; Yamaguchi, Ken; Akiyama, Yasuto
Metastatic and chemoresistant melanoma can be a good target of immunotherapy because it is an intractable cancer with a very poor prognosis. Previously, we tested a dendritic cell (DC)-based phase I vaccine, and confirmed that it was safe. In the present study, we performed a phase II trial of a DC vaccine for metastatic melanoma patients with mainly the HLA-A24 genotype, and investigated the efficacy of the vaccine. Twenty-four patients with metastatic melanoma were enrolled into a phase II study of DC-based immunotherapy. The group included 19 HLA-A24-positive (A*2402) patients and 3 HLA-A2-positive (A*0201) patients. The protocol for DC production was similar to that in the phase I trial. Briefly, a cocktail of 5 melanoma-associated synthetic peptides (gp100, tyrosinase, MAGE-A2, MAGE-A3 and MART-1 or MAGE‑A1) restricted to HLA-A2 or A24 and KLH were used for DC pulsing. Finally, DCs were injected subcutaneously (s.c.) into the inguinal region in the dose range of 1-5x107 per shot. The DC ratio (lin-HLA-DR+) of the vaccine was 38.1±13.3% and the frequency of CD83+ DCs was 25.7±20.8%. Other parameters regarding DC processing were not different from phase I. Immune response-related parameters including the ELISPOT assay, DTH reaction to peptide or KLH, DC injection numbers were shown to be related to a good prognosis. The ELISPOT reaction was positive in 75% of the patients vaccinated. The increase of anti-melanoma antigen antibody titer before vaccination was also shown to be a prognosis factor, but that post-vaccination was not. Based on immunohistochemical analysis, CD8 and IL-17 were not involved in the prognosis. Adverse effects of more than grade III were not seen. Overall survival analysis revealed a significant survival prolongation effect in DC-given melanoma patients. These results suggest that peptide cocktail-treated DC vaccines may be a safe and effective therapy against metastatic melanoma in terms of prolongation of overall survival time. PMID 22895835

Quality of life during dendritic cell vaccination against metastatic renal cell carcinoma.
Aug 2012 | Leonhartsberger, Nicolai; Ramoner, Reinhold; Falkensammer, Claudia; Rahm, Andrea; Gander, Hubert; Höltl, Lorenz; Thurnher, Martin
Patients with metastatic renal cell carcinoma (RCC) undergoing cytokine or targeted therapies may show a remarkable decline in quality of life (QoL). We wanted to evaluate QoL in patients with metastatic RCC undergoing therapeutic vaccination with dendritic cells (DCs). In a cross-sectional analysis, QoL was therefore assessed in RCC patients participating in three consecutive clinical trials of DC vaccination. Before the first and after the third vaccination with DCs, patients completed a QoL questionnaire (EORTC QLQ-C30, version 3). Data were transformed into scale scores and analysed using SPSS 12.0 software. Mean values of the resulting scores obtained before and after DC vaccination were compared using students t test and Wilcoxon rank-sum test. P < 0.05 was considered statistically significant. The questionnaire was completed by 55 of 71 patients (compliance rate, 77.5%) who had a median age of 58.7 years (from 30 to 75 years). No significant reductions in functioning scales including physical, emotional and social criteria as well as symptom scores, which assess typical symptoms of tumour therapies, were observed indicating that QoL remained high during DC vaccination. Significant correlations were found between overall survival and functional as well as symptom scores. Our data indicate that DC vaccination, which is a personalised treatment modality, maintains QoL and thus represents an attractive nontoxic treatment option for patients with metastatic RCC. It will be important to identify the most effective conditions of DC vaccination including combinations with other therapeutics to maximise clinical efficacy while still preserving QoL. PMID 22278360

Morphologic evidence of anti-tumor specificity of T cells activated by denritic cells derived from peripheral blood mononuclear cells of thyroid cancer patients.
Aug 2012 | Lee, Dae-Heui
Recent studies suggest that immunization with autologous dendritic cells (DCs) results in protective immunity and rejection of established tumors in various human malignancies. The purpose of this study is to determine whether DCs are generated from peripheral blood mononuclear cells (PBMNs) by using cytokines such as F1t-3 ligand (FL), granulocyte macrophage-colony stimulating factor (GM-CSF), IL-4, and TNF-α, and whether cytotoxic T cells activated against the thyroid cancer tissues by the DCs. Peripheral blood was obtained from 2 patients with thyroid cancer. DCs were established from PBMNs by culturing in the presence of FL, GM-CSF, IL-4, and TNF-α for 14 days. At day 14, the differentiated DCs was analyzed morphologically. The immunophenotypic features of DCs such as CDla, CD83, and CD86 were analyzed by immunofluorelescence microscopy. At day 18, DCs and T cells were incubated with thyroid cancer tissues or normal thyroid tissues for additional 4 days, respectively. DCs generated from the PBMNs showed the typical morphology of DCs. Activated cytotoxic T lymphocytes (CTLs) were observed also. DCs and the CTLs were attached to the cancer tissues on scanning electron microscope. The DCs activated the CTLs, which able to specifically attack the thyroid cancer. This study provides morphologic evidence that the coculture of T cells/cancer tissues activated the T cells and differentiated CTLs. The CTLs tightly adhered to cancer tissues and lysed cancer tissues vigorously. Therefore DCs could be used as potential vaccines in the immunotherapy. PMID 22915989

HER-2 pulsed dendritic cell vaccine can eliminate HER-2 expression and impact ductal carcinoma in situ.
Aug 2012 | Sharma, Anupama; Koldovsky, Ursula; Xu, Shuwen; Mick, Rosemarie; Roses, Robert; Fitzpatrick, Elizabeth; Weinstein, Susan; Nisenbaum, Harvey; Levine, Bruce L; Fox, Kevin; Zhang, Paul; Koski, Gary; Czerniecki, Brian J
HER-2/neu overexpression plays a critical role in breast cancer development, and its expression in ductal carcinoma in situ (DCIS) is associated with development of invasive breast cancer. A vaccine targeting HER-2/neu expression in DCIS may initiate immunity against invasive cancer. PMID 22252842

Dendritic cell engineering for tumor immunotherapy: from biology to clinical translation.
Aug 2012 | Bhargava, Arpit; Mishra, Dinesh; Banerjee, Smita; Mishra, Pradyumna Kumar
Dendritic cells (DCs) are the most potent APCs, with the ability to orchestrate a repertoire of immune responses. DCs play a pivotal role in the initiation, programming and regulation of tumor-specific immune responses, as they are poised to take up, process and present tumor antigens to naive or effector T lymphocytes. Although, to an extent, DC-based immunotherapeutic strategies have successfully induced specific anti-tumor responses in animal models, their clinical efficacy has rarely been translated into the clinic. This article attempts to present a complete picture of recent developments of DC-based therapeutic strategies addressing multiple components of tumor immunoenvironment. It also showcases certain practical intricacies in order to explore novel strategies for providing new impetus to DC-based cancer vaccination. PMID 22853757

Cancer therapy and vaccination.
Jul 2012 | Aly, Hamdy A A
Cancer remains one of the leading causes of death worldwide, both in developed and in developing nations. It may affect people at all ages, even fetuses, but the risk for most varieties increases with age. Current therapeutic approaches which include surgery, chemotherapy and radiotherapy are associated with adverse side effects arising from lack of specificity for tumors. The goal of any therapeutic strategy is to impact on the target tumor cells with limited detrimental effect to normal cell function. Immunotherapy is cancer specific and can target the disease with minimal impact on normal tissues. Cancer vaccines are capable of generating an active tumor-specific immune response and serve as an ideal treatment due to their specificity for tumor cells and long lasting immunological memory that may safeguard against recurrences. Cancer vaccines are designed to either prevent (prophylactic) or treat established cancer (therapeutic). Identification of tumor-associated antigens (TAAs) and tumor-specific antigens (TSAs) has led to increased efforts to develop vaccination strategies. Vaccines may be composed of whole cells or cell extracts, genetically modified tumor cells to express costimulatory molecules, dendritic cells (DCs) loaded with TAAs, immunization with soluble proteins or synthetic peptides, recombinant viruses or bacteria encoding tumor-associated antigens, and plasmid DNA encoding TSAs or TAAs in conjunction with appropriate immunomodulators. All of these antitumor vaccination approaches aim to induce specific immunological responses and localized to TAAs, destroying tumor cells alone and leaving the vast majority of other healthy cells of the body untouched. PMID 22658969

[Dendritic cell-based therapeutic vaccination for acute myeloid leukemia].
Jun 2012 | Anguille, Sébastien; Van Tendeloo, Vigor; Berneman, Zwi
The long-term outlook for adult patients with acute myeloid leukemia (AML) remains dismal. The main reason for this state of affairs lies in the fact that the majority of AML patients will eventually relapse, even after obtaining complete remission following front-line chemotherapy. Relapses are generally attributed to the persistence of a small number of chemotherapy-resistant leukemic (stem) cells, a condition known as minimal residual disease (MRD). The eradication of MRD, with the eventual aim of reducing the risk of relapse, therefore represents a high-priority goal of modern AML therapy. It is now well established that the immune system plays a crucial role in the defense against AML. This knowledge has fuelled the development of immune-based approaches to control MRD and, ultimately, to prevent relapse. One of the promising strategies that have emerged in this regard involves the use of dendritic cells for therapeutic vaccination. This review article aims to introduce the reader into the conceptual and practical aspects of DC-based vaccination for AML. Next, we will review the first clinical results obtained with this immunotherapeutic approach in AML patients. Finally, we will briefly reflect on the potential place of DC vaccination in the future therapy of AML. PMID 22641288

Development of sipuleucel-T: autologous cellular immunotherapy for the treatment of metastatic castrate resistant prostate cancer.
Jun 2012 | Sims, Robert B
Sipuleucel-T, the first autologous cellular immunotherapy approved by the United States Food and Drug Administration, is designed to stimulate an immune response to prostate cancer. Sipuleucel-T is manufactured by culturing a patient's peripheral blood mononuclear cells, including autologous antigen presenting cells (APCs), with a recombinant protein comprising a tumor-associated antigen (prostatic acid phosphatase [PAP]) and granulocyte colony-macrophage stimulating factor (GM-CSF). A full course of treatment comprises 3 infusions of sipuleucel-T, given at approximately 2-week intervals. The pattern of APC activation is consistent with priming by the first infusion, and boosting by the second and third infusions. Preclinical and clinical studies have demonstrated evidence of a robust antigen-specific immune response that includes a progressive and persistent increase in antigen-specific cellular and humoral immune responses. Treatment with sipuleucel-T has demonstrated a survival benefit in Phase 3 studies of subjects with metastatic castrate resistant (hormone refractory) prostate cancer (mCRPC). Adverse events with sipuleucel-T were generally mild to moderate and resolved within 2 days. Serious adverse events, autoimmune events, and cerebrovascular events occurred at a similar rate to control subjects. As the first autologous cellular immunotherapy to demonstrate an improvement in overall survival in asymptomatic or minimally symptomatic mCRPC patients, sipuleucel-T represents a new treatment paradigm in oncology. PMID 22122856

Successful treatment of advanced ovarian cancer with thermochemotherapy and adjuvant immune therapy.
Jun 2012 | Kleef, R; Kekic, S; Ludwig, N
We report on a 4-year progression-free survival of a 54-year-old female first diagnosed in December 2007 with advanced bilateral ovarian cancer FIGO IIIc, disseminated peritoneal carcinosis and malignant diaphragm invasion. Treatment started in January 2008 with 6 cycles of Taxol 175 mg/m(2)/carboplatin AUC 5 in 3-week intervals. Twenty-four hours following each chemotherapy session, fever-range long-duration whole-body hyperthermia (WBH) was performed at the temperature plateau of 40°C body core temperature for 6 h. Three months after completion of chemotherapy, 4 more long-duration WBH procedures were performed in monthly intervals. Importantly, long-duration WBH was paralleled with intradermal vaccination of autologous dendritic cells. No other treatment was given to the patient. Four years following the first diagnosis, the patient is still in complete remission with no evidence of disease. PMID 22679425

Co-culture of apoptotic breast cancer cells with immature dendritic cells: a novel approach for DC-based vaccination in breast cancer.
Jun 2012 | Zheng, Jin; Liu, Qiang; Yang, Jiandong; Ren, Qinyou; Cao, Wei; Yang, Jingyue; Yu, Zhaocai; Yu, Fang; Wu, Yanlan; Shi, Hengjun; Liu, Wenchao
A dendritic cell (DC)-based vaccine strategy could reduce the risk of recurrence and improve the survival of breast cancer patients. However, while therapy-induced apoptosis of hepatocellular and colorectal carcinoma cells can enhance maturation and antigen presentation of DCs, whether this effect occurs in breast cancer is currently unknown. In the present study, we investigated the effect of doxorubicin (ADM)-induced apoptotic MCF-7 breast cancer cells on the activation of DCs. ADM-induced apoptotic MCF-7 cells could effectively induce immature DC (iDC) maturation. The mean fluorescence intensity (MFI) of DC maturity marker CD83 was 23.3 in the ADM-induced apoptotic MCF-7 cell group compared with 8.5 in the MCF-7 cell group. The MFI of DC co-stimulatory marker CD86 and HLA-DR were also increased after iDCs were treated with ADM-induced apoptotic MCF-7 cells. Furthermore, the proliferating autologous T-lymphocytes increased from 14.2 to 40.3% after incubated with DCs induced by apoptotic MCF-7 cells. The secretion of interferon-γ by these T-lymphocytes was also increased. In addition, cell-cell interaction between apoptotic MCF-7 cells and iDCs, but not soluble factors released by apoptotic MCF-7 cells, was crucial for the maturation of iDCs. These findings constitute a novel in vitro DC-based vaccine strategy for the treatment of breast cancer by ADM-induced apoptotic MCF-7 cells. PMID 22527124

Vaccination with dendritic cells loaded with tumor apoptotic bodies (Apo-DC) in patients with chronic lymphocytic leukemia: effects of various adjuvants and definition of immune response criteria.
May 2012 | Palma, Marzia; Hansson, Lotta; Choudhury, Aniruddha; Näsman-Glaser, Barbro; Eriksson, Ingrid; Adamson, Lars; Rossmann, Eva; Widén, Karin; Horváth, Rudolf; Kokhaei, Parviz; Vertuani, Simona; Mellstedt, Håkan; Osterborg, Anders
We previously demonstrated that autologous dendritic cells that have endocytosed apoptotic bodies of chronic lymphocytic leukemia (CLL) cells (Apo-DC) can stimulate antileukemic T cell responses in vitro. In this phase I study, we vaccinated 15 asymptomatic CLL patients at five time points with Apo-DC administered intradermally either alone (cohort I), or in combination with subcutaneous granulocyte-macrophage-colony-stimulating-factor (GM-CSF) (cohort II) or with GM-CSF and intravenous low-dose cyclophosphamide (cohort III). Aim of the study was to evaluate the safety and immunogenicity of Apo-DC alone or in combination with GM-CSF and low-dose cyclophosphamide in CLL patients. All patients completed the vaccination schedule without dose-limiting toxicity. No objective clinical responses were seen. Vaccine-induced leukemia-specific immune responses were evaluated by IFN-γ ELISpot and proliferation assays over a 52 weeks observation period and immune response criteria were defined. According to these criteria, 10/15 patients were defined as immune responders. The frequency of immune-responding patients was higher in cohorts II (3/5) and III (5/5) than in cohort I (2/5). In order to further characterize the induced immune response, estimation of secreted cytokines and CD107-degranulation assay were performed. Clustering of T and CLL cells was observed in CD107-degranulation assay and visualized by confocal microscopy. Additionally, assessment of regulatory T cells (T(regs)) revealed their significantly lower frequencies in immune responders versus non-responders (P < 0.0001). Cyclophosphamide did not reduce T(regs) frequency. In conclusion, vaccination with Apo-DC + GM-CSF and cyclophosphamide was safe and elicited anti-CLL immune responses that correlated inversely with T(regs) levels. Lack of clinical responses highlights the necessity to develop more potent vaccine strategies in B cell malignancies. PMID 22086161

Dendritic/tumor fusion cells as cancer vaccines.
May 2012 | Avigan, David; Rosenblatt, Jacalyn; Kufe, Donald
A promising cancer vaccine involves the fusion of dendritic cells (DCs) with tumor cells such that a broad array of tumor antigens are presented in the context of DC-mediated costimulation and stimulatory cytokines. In diverse animal models, vaccination with DC/tumor fusions results in protection from an otherwise lethal challenge of tumor cells and eradication of established disease. In phase I clinical studies, vaccination with DC/tumor fusions was well tolerated, and induced immunologic responses in the majority of patients and clinical responses in a subset. Vaccine efficacy may be blunted by the immunosuppressive milieu characteristic of patients with malignancy, including the increased presence of regulatory T cells, and inhibitory pathways such as the PD-1/PDL-1 pathway. A current focus of research interest lies in enhancing response to cancer vaccines, by combining vaccination with tumor cytoreduction, regulatory T-cell depletion, and blockade of critical inhibitory pathways. PMID 22595051

Induction of tolerogenic dendritic cells by IL-6-secreting CT26 colon carcinoma.
May 2012 | Alshamsan, Aws
One scenario by which tumors escape immune recognition is the constitutive activation of signal transducer and activator of transcription 3 (STAT3). This transcription factor mediates the production of tumor-derived factors that negatively influence target immune cells, such as dendritic cells, and polarize them toward immune-tolerance also through the induction of STAT3 activation. In the current study, the effect of p-STAT3-positive murine colon carcinoma cell line (CT26) on bone marrow-derived DCs was examined. The results showed a remarkable increase in p-STAT3 in dendritic cells (DCs) only after CT26-CM incubation. The induction of p-STAT3 in CT26-CM exposed DCs was attributed at least in part to the high levels of interleukin-6 secreted by CT26 in culture. This was also accompanied by a significant reduction in the response to the immunostimulatory adjuvant lipopolysaccharide by lowering the expression of co-stimulatory molecules CD86 and CD40. Taken together, the results suggest an inhibitory effect of CT26 colon carcinoma on DC maturation through induction of STAT3 phosphorylation. Therefore, tumor-induced p-STAT3 in DCs can be seen as a promising target for colon cancer immunotherapy. PMID 21999714

Phase I/II randomized trial of dendritic cell vaccination with or without cyclophosphamide for consolidation therapy of advanced ovarian cancer in first or second remission.
Apr 2012 | Chu, Christina S; Boyer, Jean; Schullery, Daniel S; Gimotty, Phyllis A; Gamerman, Victoria; Bender, James; Levine, Bruce L; Coukos, George; Rubin, Stephen C; Morgan, Mark A; Vonderheide, Robert H; June, Carl H
In spite of increased rates of complete response to initial chemotherapy, most patients with advanced ovarian cancer relapse and succumb to progressive disease. Immunotherapy may have potential for consolidation therapy. PMID 22021066

Dendritic cells the tumor microenvironment and the challenges for an effective antitumor vaccination.
Apr 2012 | Benencia, Fabian; Sprague, Leslee; McGinty, John; Pate, Michelle; Muccioli, Maria
Many clinical trials have been carried out or are in progress to assess the therapeutic potential of dendritic-cell- (DC-) based vaccines on cancer patients, and recently the first DC-based vaccine for human cancer was approved by the FDA. Herewith, we describe the general characteristics of DCs and different strategies to generate effective antitumor DC vaccines. In recent years, the relevance of the tumor microenvironment in the progression of cancer has been highlighted. It has been shown that the tumor microenvironment is capable of inactivating various components of the immune system responsible for tumor clearance. In particular, the effect of the tumor microenvironment on antigen-presenting cells, such as DCs, does not only render these immune cells unable to induce specific immune responses, but also turns them into promoters of tumor growth. We also describe strategies likely to increase the efficacy of DC vaccines by reprogramming the immunosuppressive nature of the tumor microenvironment. PMID 22505809

Monitoring of regulatory T cell frequencies and expression of CTLA-4 on T cells, before and after DC vaccination, can predict survival in GBM patients.
Apr 2012 | Fong, Brendan; Jin, Richard; Wang, Xiaoyan; Safaee, Michael; Lisiero, Dominique N; Yang, Isaac; Li, Gang; Liau, Linda M; Prins, Robert M
Dendritic cell (DC) vaccines have recently emerged as an innovative therapeutic option for glioblastoma patients. To identify novel surrogates of anti-tumor immune responsiveness, we studied the dynamic expression of activation and inhibitory markers on peripheral blood lymphocyte (PBL) subsets in glioblastoma patients treated with DC vaccination at UCLA. PMID 22485134

Immunotherapy using dendritic cells against multiple myeloma: how to improve?
Apr 2012 | Nguyen-Pham, Thanh-Nhan; Lee, Yoon-Kyung; Kim, Hyeoung-Joon; Lee, Je-Jung
Multiple myeloma (MM) is a good target disease in which one can apply cellular immunotherapy, which is based on the graft-versus-myeloma effect. This role of immune effector cells provides the framework for the development of immune-based therapeutic options that use antigen-presenting cells (APCs) with increased potency, such as dendritic cells (DCs), in MM. Current isolated idiotype (Id), myeloma cell lysates, myeloma dying cells, DC-myeloma hybrids, or DC transfected with tumor-derived RNA has been used for immunotherapy with DCs. Immunological inhibitory cytokines, such as TGF-β, IL-10, IL-6 and VEGF, which are produced from myeloma cells, can modulate antitumor host immune response, including the abrogation of DC function, by constitutive activation of STAT3. Therefore, even the immune responses have been observed in clinical trials, the clinical response was rarely improved following DC vaccinations in MM patients. We are going to discuss how to improve the efficacy of DC vaccination in MM. PMID 22481968

Cellular immunotherapy using dendritic cells against multiple myeloma.
Apr 2012 | Nguyen-Pham, Thanh-Nhan; Lee, Youn-Kyung; Lee, Hyun-Ju; Kim, Mi-Hyun; Yang, Deok-Hwan; Kim, Hyeoung-Joon; Lee, Je-Jung
Cellular therapy with dendritic cells (DCs) is emerging as a useful immunotherapeutic tool to treat multiple myeloma (MM). DC-based idiotype vaccination was recently suggested to induce idiotype-specific immune responses in MM patients. However, the clinical results so far have been largely disappointing, and the clinical effectiveness of such vaccinations in MM still needs to be demonstrated. DC-based therapies against MM may need to be boosted with other sources of tumor-associated antigens, and potent DCs should be recruited to increase the effectiveness of treatment. DCs with both high migratory capacity and high cytokine production are very important for effective DC-based cancer vaccination in order to induce high numbers of Th1-type CD4(+) T cells and CD8(+) cytotoxic T lymphocytes. The tumor microenvironment is also important in the regulation of tumor cell growth, proliferation, and the development of therapeutic resistance after treatment. In this review, we discuss how the efficacy of DC vaccination in MM can be improved. In addition, novel treatment strategies that target not only myeloma cells but also the tumor microenvironment are urgently needed to improve treatment outcomes. PMID 22479274

Cancer immunotherapy via dendritic cells.
Mar 2012 | Palucka, Karolina; Banchereau, Jacques
Cancer immunotherapy attempts to harness the power and specificity of the immune system to treat tumours. The molecular identification of human cancer-specific antigens has allowed the development of antigen-specific immunotherapy. In one approach, autologous antigen-specific T cells are expanded ex vivo and then re-infused into patients. Another approach is through vaccination; that is, the provision of an antigen together with an adjuvant to elicit therapeutic T cells in vivo. Owing to their properties, dendritic cells (DCs) are often called 'nature's adjuvants' and thus have become the natural agents for antigen delivery. After four decades of research, it is now clear that DCs are at the centre of the immune system owing to their ability to control both immune tolerance and immunity. Thus, DCs are an essential target in efforts to generate therapeutic immunity against cancer. PMID 22437871

Prostate cancer vaccines: moving therapeutic vaccination forward in the post-Provenge era.
Mar 2012 | Arlen, Philip M; Wood, Lauren V
The focus of extensive research in the area of prostate cancer vaccines has led to the approval of the first therapeutic vaccine by the US FDA, sipuleucel-T. As our understanding of immunotherapy has increased, novel approaches have been investigated that have shown considerable promise. As the field has continued to evolve, questions have arisen regarding the potential role of immunotherapy: which populations of patients are most likely to benefit from immunotherapy and how and when should these therapies be administered? In addition, what are the best tools that can be used as surrogates to monitor immune responses to cancer vaccines that truly can give meaningful insight toward improving clinical outcomes? Finally, how can combination approaches be applied to prostate cancer vaccines in terms of both standard of care and experimental therapies? This review will address many of these important concepts with regard to prostate cancer vaccine therapy. PMID 22380822

A gynecologic oncology group phase II trial of two p53 peptide vaccine approaches: subcutaneous injection and intravenous pulsed dendritic cells in high recurrence risk ovarian cancer patients.
Feb 2012 | Rahma, Osama E; Ashtar, Ed; Czystowska, Malgorzata; Szajnik, Marta E; Wieckowski, Eva; Bernstein, Sarah; Herrin, Vincent E; Shams, Mortada A; Steinberg, Seth M; Merino, Maria; Gooding, William; Visus, Carmen; Deleo, Albert B; Wolf, Judith K; Bell, Jeffrey G; Berzofsky, Jay A; Whiteside, Theresa L; Khleif, Samir N
Peptide antigens have been administered by different approaches as cancer vaccine therapy, including direct injection or pulsed onto dendritic cells; however, the optimal delivery method is still debatable. In this study, we describe the immune response elicited by two vaccine approaches using the wild-type (wt) p53 vaccine. PMID 21927947

Clinical and immunologic evaluation of dendritic cell-based immunotherapy in combination with gemcitabine and/or S-1 in patients with advanced pancreatic carcinoma.
Feb 2012 | Kimura, Yukino; Tsukada, Jun; Tomoda, Takeshi; Takahashi, Hidenori; Imai, Kazuhiro; Shimamura, Kanae; Sunamura, Makoto; Yonemitsu, Yoshikazu; Shimodaira, Shigetaka; Koido, Shigeo; Homma, Sadamu; Okamoto, Masato
In the current study, we have evaluated the clinical and immunological responses in patients with advanced pancreatic carcinoma who received dendritic cell (DC)-based immunotherapy in combination with gemcitabine and/or S-1. PMID 21792083

Immunotherapy for metastatic colorectal cancer: present status and new options.
Feb 2012 | Ellebaek, Eva; Andersen, Mads Hald; Svane, Inge Marie; Straten, Per Thor
Although no immunotherapeutic treatment is approved for colorectal cancer (CRC) patients, promising results from clinical trials suggest that several immunotherapeutic strategies may prove efficacious and applicable to this group of patients. This review describes the immunogenicity of CRC and presents the most interesting strategies investigated so far: cancer vaccination including antigen-defined vaccination and dendritic cell vaccination, chemo-immunotherapy, and adoptive cell transfer. Future treatment options as well as the possibility of combining existing therapies will be discussed along with the challenges presented by tumor escape mechanisms. PMID 22214467

[Prostate carcinoma: vaccination as a new option for treatment].
Jan 2012 | Bedke, J; Gouttefangeas, C; Stenzl, A
Immune therapy and tumor cell vaccination is a challenging option in prostate cancer therapy, especially as side effects rarely occur. This review highlights recent developments in vaccination therapy of prostate cancer. The FDA approved antigen presenting cell vaccine Sipuleucel-T is described and new strategies of immune therapy like RNA and peptide vaccination are discussed in detail. Currently the effect of prostate cancer vaccination has still limitations, at least partially due to the immune suppressive effects of the tumor microenvironment and regulatory T cells, which suppress the immune effector function. To overcome these hurdles the concept of immune checkpoint modulation, which has the aim to break tolerance mechanisms, is discussed. Potential clinical therapies of checkpoint modulation are outlined. PMID 21989588

Immunotherapy of lung adenocarcinoma patient with Peptide-pulsed dendritic cells: a case report.
Jan 2012 | Wojas-Krawczyk, Kamila; Krawczyk, Paweł; Buczkowski, Jarosław; Walkowska, Anna; Jankowska, Olga; Czekajska-Chehab, Elżbieta; Milanowski, Janusz
Immunotherapy with ex vivo generated dendritic cells (DCs) is reported to be of low toxicity and of diverse effectiveness in cancer treatment. The synthetic antigens are frequently used for immunotherapy especially for patients with stable disease after prior treatment. We described the effect of peptide-loaded DCs-based immunotherapy on patient with recurrent surgically resected adenocarcinoma with bronchoalveolar feature with co-existing of Takayasu arteritis and chronic hepatitis B. In January 2010, 61-year-old patient received subcutaneously four bi-weekly vaccinations of DCs loaded with MUC1 and MAGE-3 epitopes. Additionally, he received three bi-weekly booster vaccinations after 7 months from the first course of immunotherapy. Delayed-type hypersensitivity test was positive only for MAGE-3 antigen. The evidence expansion of MAGE-3-specific CD8(+) cells after first vaccination and after third vaccination during boosters injections was observed (from 0.08% before vaccination to 0.5% after first vaccination; from 0.05% before booster vaccination to 0.24% after third injection). Computed tomography scans performed after first course and after booster course of vaccination until April 2011 did not shown any presence of lung tumour or metastases. Based on clinical factors (no completed wedge-resection and recurrent character of cancer) as well as on the presence of the tumour-antigen-specific immunological response, we could speculated that immunotherapy prolonged disease free-survival in our patient. Over 16 months from first vaccination, the patient remains without symptoms of cancer. PMID 22143160

Clinical application of a dendritic cell vaccine raised against heat-shocked glioblastoma.
Jan 2012 | Jie, X; Hua, L; Jiang, W; Feng, F; Feng, G; Hua, Z
Establishment of a detection platform for glioblastoma-dendritic cell (DC) vaccine preparation and to determine the efficacy of the vaccine in a clinical trial. Autologous glioblastoma-DC vaccine was prepared from a glioblast specimen procured from surgical resection. The specimen was used to enrich the vaccine with peripherally blood-derived DCs after heat-shock induced, glioblastoma apoptosis. The control group received conventional treatment of surgery and radio-chemotherapy post-operation. The therapeutic group received a combination of glioblastoma-DC vaccine and conventional therapy. A comparison of the functional immune parameters, including tumor control, rate live time, Karnofsky scores, and complications occurring in each group were observed and recorded. The proportions of peripheral CD3(+), CD3(+)CD4(+), CD4(+)/CD8(+), and NK cells were significantly higher after DC vaccination than the control group (P < 0.05). Serum levels of IL-2, IL-12, and IFN-γ were significantly higher after DC vaccination than in the control group (P < 0.05). Nine months after vaccination, tumor control rate is significantly improved in the DC group compared with the control group (P < 0.05); survival rate was significantly higher in DC group than in control group (P < 0.05) and the time to relapse was significantly longer in DC group than that in control group (P < 0.05). Karnofsky scores were better in DC vaccination group 6 and 9 months post-treatment compared with the control group (P < 0.05). The combination of glioma DC vaccine and radiotherapy/chemotherapy post-operatively enhances the immune function of patients, increases the tumor control rate, prolongs the survival time and relapse duration, improves the quality of life, and therefore provides a more effective intervention of treating glioblastoma. PMID 21909820

Exosome-loaded dendritic cells elicit tumor-specific CD8+ cytotoxic T cells in patients with glioma.
Jan 2012 | Bu, Ning; Wu, Haiqin; Sun, Bingzhong; Zhang, Guilian; Zhan, Shuqin; Zhang, Ru; Zhou, Le
In this study, we demonstrate that tumor-derived exosome-loaded dendritic cells can elicit a specific CD8(+) cytotoxic T-lymphocyte (CTL) response against autologous tumor cells in patients with malignant glioma. Exosomes were purified by ultrafiltration centrifugation and sucrose gradient ultracentrifugation. Exosomes had antigen-presenting molecules (MHC-I, HSP70), tumor antigen (MAGE-1) and adherent molecule (ICAM-1). After incubation with exosomes, the dendritic cells (DCs) could activate the T lymphocytes to become glioma-specialized CTL. The CTL had vigorous cytotoxicity to glioma cells as opposed to autologous lymphoblast cells. These data demonstrate that tumor exosome-loaded DC can be an effective tool in inducing glioma-specific CD8(+) CTLs able to kill autologous glioma cells in vitro. In conclusion, exosomes are a natural and new source of tumor-rejection antigens, opening up new avenues for immunization against glioma. PMID 21336773

Therapeutical doses of temozolomide do not impair the function of dendritic cells and CD8+ T cells.
Jan 2012 | Xu, Xun; Stockhammer, Florian; Schmitt, Anita; Casalegno-Garduno, Rosaely; Enders, Anne; Mani, Jiju; Classen, Carl Friedrich; Linnebacher, Michael; Freund, Mathias; Schmitt, Michael
The median survival of patients with glioblastoma multiforme (GBM) remains poor. Innovative immunotherapies with dendritic cell (DC) vaccination might be combined with standard temozolomide (TMZ) treatment. Here, we evaluated the influence of TMZ on the phenotype and function of DCs and CD8+ T cells. DCs were generated from the peripheral blood of healthy volunteers (HVs) and GBM patients. DCs were analyzed by light microscopy and flow cytometry. Phagocytic activity was tested by FITC-dextran engulfment. Mixed lymphocyte peptide cultures were followed by enzyme-linked immunospot (ELISPOT) and flow cytometry assays. TMZ was added to DC and T cell cultures at concentrations up to 500 µM. Mature DCs were generated from HVs and GBM patients. Cells displayed a typical DC morphology and a mature DC phenotype. Expression of CD209 was even higher in DCs generated from patients under therapy than from HVs (75.2 vs. 51.1%). In contrast, CD40 (1.1 vs. 13.5%) and BDCA4 (26.5 vs. 52.9%) were lower expressed in GBM patients at time of diagnosis. Immature DCs showed high phagocytic activity. Addition of TMZ at concentrations up to 50 µM did neither impair the phenotype nor the function of DCs. In ELISPOT and flow cytometry assays, no impairment of CD8+ T cell responses to viral antigens could be observed. Taken together, TMZ does not impair the function of either DCs or the CD8+ T cells. PMID 22134728

Current vaccination strategies for prostate cancer.
Dec 2011 | Joniau, Steven; Abrahamsson, Per-Anders; Bellmunt, Joaquim; Figdor, Carl; Hamdy, Freddie; Verhagen, Paul; Vogelzang, Nicholas J; Wirth, Manfred; Van Poppel, Hendrik; Osanto, Susanne
The first therapeutic cancer vaccine demonstrating effectiveness in a phase 3 study was approved by the US Food and Drug Administration on 29 April 2010. The pivotal trial demonstrated overall survival (OS) benefit in patients treated with antigen-loaded leukapheresis cells compared with a control infusion. Results of other prostate cancer (PCa) vaccination strategies are awaited, as this approach may herald a new era in the care for patients with advanced PCa. PMID 22001436

A novel dendritic cell-based immunization approach for the induction of durable Th1-polarized anti-HER-2/neu responses in women with early breast cancer.
Dec 2011 | Koski, Gary K; Koldovsky, Ursula; Xu, Shuwen; Mick, Rosemarie; Sharma, Anupama; Fitzpatrick, Elizabeth; Weinstein, Susan; Nisenbaum, Harvey; Levine, Bruce L; Fox, Kevin; Zhang, Paul; Czerniecki, Brian J
Twenty-seven patients with HER-2/neu overexpressing ductal carcinoma in situ of the breast were enrolled in a neoadjuvant immunization trial for safety and immunogenicity of DC1-polarized dendritic cells (DC1) pulsed with 6 HER-2/neu promiscuous major histocompatibility complex class II-binding peptides and 2 additional human leukocyte antigen (HLA)-A2.1 class I-binding peptides. DC1 were generated with interferon-γ and a special clinical-grade bacterial endotoxin (lipopolysaccharide) and administered directly into groin lymph nodes 4 times at weekly intervals before scheduled surgical resection of ductal carcinoma in situ. Patients were monitored for the induction of new or enhanced antipeptide reactivity by interferon-γ ELISPOT and enzyme-linked immunosorbentassays performed on Th cells obtained from peripheral blood or excised sentinel lymph nodes. Responses by cytotoxic T lymphocyte against HLA-A2.1-binding peptides were measured using peptide-pulsed T2 target cells or HER-2/neu-expressing or nonexpressing tumor cell lines. DC1 showed surface phenotype indistinct from "gold standard" inflammatory cocktail-activated DC, but displayed a number of distinguishing functional characteristics including the secretion of soluble factors and enhanced "killer DC" capacity against tumor cells in vitro. Postimmunization, we observed sensitization of Th cells to at least 1 class II peptide in 22 of 25 (88%; 95% exact confidence interval, 68.8%-97.5%) evaluable patients, whereas 11 of 13 (84.6%; 95% exact confidence interval, 64%-99.8%) HLA-A2.1 patients were successfully sensitized to class I peptides. Perhaps most importantly, anti-HER-2/neu peptide responses were observed up to 52-month postimmunization. These data show that even in the presence of early breast cancer such DC1 are potent inducers of durable type I-polarized immunity, suggesting potential clinical value for development of cancer immunotherapy. PMID 22130160

New perspectives in glioma immunotherapy.
Nov 2011 | Daga, Antonio; Bottino, Cristina; Castriconi, Roberta; Gangemi, Rosaria; Ferrini, Silvano
Glioblastoma (GBM) is a deadly tumor, which in spite of surgery and radio/chemotherapy frequently undergoes relapses related to the infiltration of the normal parenchyma and to resistance to cytotoxic and radiation therapy. Immunotherapy may represent a promising approach, which may complement existing therapies with the aim of eliminating residual tumor cells, through their selective targeting by immune effector cells or antibodies. This goal can be achieved through different approaches, based either on the induction of an immune response of the host, or by the injection of in vitro generated effector cells or monoclonal antibodies. Recent advances in the immunobiology of GBM and of its stem cell compartment will help in the development of more effective immunotherapy protocols. To this aim, the identification of antigens and receptors involved in GBM/immune cell interactions and of GBM immune escape mechanisms will provide new targets and tools. In this review we will discuss active immunotherapy approaches, including molecular-defined, GBM cell-based and dendritic-cell based vaccines. In addition, cytokines such as interferons and several interleukins can be used to enhance the immune response, both as recombinant molecules and by gene transfer technologies. Monoclonal antibodies or other ligands specific for GBM- or neovasculature-associated targets are now available in different genetically modified formats and can be used as such or for the targeted delivery of active compounds. Finally the in vitro activation and expansion of specific or innate immunity effector cells endowed with anti-GBM properties may provide an additional weapon for adoptive imunotherapy approaches. PMID 21827420

Improved efficacy of therapeutic vaccination with dendritic cells pulsed with tumor cell lysate against hepatocellular carcinoma by introduction of 2 tandem repeats of microbial HSP70 peptide epitope 407-426 and OK-432.
Nov 2011 | Ge, Chiyu; Xing, Yun; Wang, Qi; Xiao, Wen; Lu, Yong; Hu, Xiangbing; Gao, Zhenqiu; Xu, Maolei; Ma, Yanjun; Cao, Rongyue; Liu, Jingjing
Therapeutic vaccination with dendritic cells (DCs) pulsed with tumor cell lysate vaccine (H-D) represents an attractive approach for hepatocellular carcinoma (HCC) treatment. However, the efficacy of this approach is not most satisfactory for the low levels of T helper 1 (Th1)-type cytokines secretion and weak T cell responses. In this study, in order to increase the potency of H-D, two tandem repeats of microbial HSP70 peptide epitope 407-426 (2mHSP70(407-426), M2) which has been demonstrated to be effective in enhancing DC maturation were applied. The DC vaccine (HM-D) which was HCC tumor cell lysate pulsed with M2 was developed. Nevertheless, the immunotherapeutic effect was still not satisfactory enough even some promotion was obtained. Therefore, OK-432 (OK), which is a useful anti-cancer agent and effectively in stimulating DC maturation, was introduced to HM-D. Our results demonstrated that treatment with the improved DC vaccine which was tumor cell lysate pulsed with M2 and OK (HMO-D), compared with H-D and HM-D, significantly increased cell surface markers (MHC-I and II, CD40, CD80, CD86 and CD11c) expression on DCs, enhanced Th1-type cytokines (IL-12, TNF-α and IFN-γ) production but not Th2-type cytokine (IL-5) production, induced remarkable high levels of lymphocytes proliferation and CD8(+) cytotoxic T-lymphocyte (CTL). Furthermore, immunization with HMO-D effectively reduced tumor progression and enhanced the survival of mice with H22 tumors. Besides, we also found that the capability of M2 in inducing the Th1 cytokines was stronger than OK. In view of these results, HMO-D vaccination provided a novel immunotherapeutic approach for the treatment of HCC. PMID 22015603

Long-term vaccine therapy with autologous whole tumor cell-pulsed dendritic cells for a patient with recurrent rectal carcinoma.
Nov 2011 | Onishi, Hideya; Morisaki, Takashi; Baba, Eishi; Nakamura, Mitsunari; Inaba, Syoichi; Kuroki, Hideo; Matsumoto, Kotaro; Katano, Mitsuo
We performed continuous dendritic cells (DCs) vaccination to treat a patient with chemotherapy-resistant recurrent rectal carcinoma and lung and bone metastases. A patient has received a total of 66 DC vaccinations at 14-day intervals for 3 years until his death. Necrotic whole tumor cells (WTC) were selected as the tumor-associated antigen source because they showed a greater capacity for DC maturation and interleukin-12 secretion than both necrotic tumor lysate alone and necrotic tumor cell fragment alone. After the sixth vaccination, both skin test and interferon-γ (IFN-γ) enzyme-linked immunospot (ELISPOT) response by peripheral blood T-cells to WTC-pulsed DCs were positive. Importantly, T-cell responses were positive towards DCs pulsed with several synthetic peptides including Carcinoembryonic antigen (CEA), Melanoma associated antigen (MAGE)1 and MAGE3. A biopsy specimen collected from the pelvic bone metastasis after the 6th vaccination showed marked necrotic change of the carcinoma cells, with many infiltrating mononuclear cells. The patient did not show any particular adverse reactions to vaccination such as autoimmune phenomena. Our experience of this case suggests that continuous long-term vaccination with autologous WTC-pulsed DCs can elicit in vivo T-cell response against multiple tumor-associated antigens and induce tumor regression in disease that has proven resistant to intensive chemo- or radiation therapy. PMID 22110233

Pilot clinical trial of type 1 dendritic cells loaded with autologous tumor lysates combined with GM-CSF, pegylated IFN, and cyclophosphamide for metastatic cancer patients.
Nov 2011 | Alfaro, Carlos; Perez-Gracia, Jose L; Suarez, Natalia; Rodriguez, Javier; Fernandez de Sanmamed, Miguel; Sangro, Bruno; Martin-Algarra, Salvador; Calvo, Alfonso; Redrado, Miriam; Agliano, Alice; Gonzalez, Alvaro; Rodriguez, Inmaculada; Bolaños, Elixabet; Hervás-Stubbs, Sandra; Perez-Calvo, Javier; Benito, Alberto; Peñuelas, Ivan; Vigil, Carmen; Richter, José; Martinez-Forero, Ivan; Melero, Ignacio
Twenty-four patients with metastatic cancer received two cycles of four daily immunizations with monocyte-derived dendritic cells (DC). DC were incubated with preheated autologous tumor lysate and subsequently with IFN-α, TNF-α, and polyinosinic:polycytidylic acid to attain type 1 maturation. One DC dose was delivered intranodally, under ultrasound control, and the rest intradermally in the opposite thigh. Cyclophosphamide (day -7), GM-CSF (days 1-4), and pegIFN alpha-2a (days 1 and 8) completed each treatment cycle. Pretreatment with cyclophosphamide decreased regulatory T cells to levels observed in healthy subjects both in terms of percentage and in absolute counts in peripheral blood. Treatment induced sustained elevations of IL-12 in serum that correlated with the output of IL-12p70 from cultured DC from each individual. NK activity in peripheral blood was increased and also correlated with the serum concentration of IL-12p70 in each patient. Circulating endothelial cells decreased in 17 of 18 patients, and circulating tumor cells markedly dropped in 6 of 19 cases. IFN-γ-ELISPOT responses to DC plus tumor lysate were observed in 4 of 11 evaluated cases. Tracing DC migration with [(111)In] scintigraphy showed that intranodal injections reached deeper lymphatic chains in 61% of patients, whereas with intradermal injections a small fraction of injected DC was almost constantly shown to reach draining inguinal lymph nodes. Five patients experienced disease stabilization, but no objective responses were documented. This combinatorial immunotherapy strategy is safe and feasible, and its immunobiological effects suggest potential activity in patients with minimal residual disease. A randomized trial exploring this hypothesis is currently ongoing. PMID 22048768

Third generation dendritic cell vaccines for tumor immunotherapy.
Nov 2011 | Frankenberger, Bernhard; Schendel, Dolores J
This review summarizes our studies of the past several years on the development of third generation dendritic cell (DC) vaccines. These developments have implemented two major innovations in DC preparation: first, young DCs are prepared within 3 days and, second, the DCs are matured with the help of Toll-like receptor agonists, imbuing them with the capacity to produce bioactive IL-12 (p70). Based on phenotype, chemokine-directed migration, facility to process and present antigens, and stimulatory capacity to polarize Th1 responses in CD4+ T cells, induce antigen-specific CD8+ CTL and activate natural killer cells, these young mDCs display all the important properties needed for initiating good antitumor responses in a vaccine setting. PMID 21439674

HER2-based recombinant immunogen to target DCs through FcγRs for cancer immunotherapy.
Nov 2011 | Zizzari, Ilaria Grazia; Veglia, Filippo; Taurino, Federica; Rahimi, Hassan; Quaglino, Elena; Belleudi, Francesca; Riccardo, Federica; Antonilli, Morena; Napoletano, Chiara; Bellati, Filippo; Benedetti-Panici, Pierluigi; Torrisi, Maria Rosaria; Frati, Luigi; Nuti, Marianna; Rughetti, Aurelia
Dendritic cell (DC)-based immunotherapy is an attractive approach to induce long lasting antitumor effector cells aiming to control cancer progression. DC targeting is a critical step in the design of DC vaccines in order to optimize delivery and processing of the antigen, and several receptors have been characterized for this purpose. In this study, we employed the FcγRs to target DCs both in vitro and in vivo. We designed a recombinant molecule (HER2-Fc) composed of the immunogenic sequence of the human tumor-associated antigen HER2 (aa 364-391) and the Fc domain of a human IgG(1). In a mouse model, HER2-Fc cDNA vaccination activated significant T cell-mediated immune responses towards HER2 peptide epitopes as detected by IFN-γ ELIspot and induced longer tumor latency as compared to Ctrl-Fc-vaccinated control mice. Human in vitro studies indicated that the recombinant HER2-Fc immunogen efficiently targeted human DCs through the FcγRs resulting in protein cross-processing and in the activation of autologous HER2-specific CD8(+) T cells from breast cancer patients. PMID 21845448

Combination therapy of renal cell carcinoma or breast cancer patients with dendritic cell vaccine and IL-2: results from a phase I/II trial.
Nov 2011 | Baek, Soyoung; Kim, Choung-Soo; Kim, Sung-Bae; Kim, Yong-Man; Kwon, Seog-Woon; Kim, YongMan; Kim, Hyunsoo; Lee, Hyunah
Ten cancer patients (Six renal cell carcinoma and four breast cancer patients) were treated in a phase I/II study with a vaccine composed of autologous dendritic cells (DCs) and IL-2 to evaluate the DC vaccine-related toxicity and antigen-specific immune alteration. PMID 22013914

Immunotherapy for glioma: getting closer to the clinical arena?
Nov 2011 | Finocchiaro, Gaetano; Pellegatta, Serena
During recent years different approaches have been explored to raise effective antitumor responses against brain tumors and particularly glioblastomas (GBMs). In most cases, cancer vaccines were based on autologous dendritic cells loaded with GBM peptides or whole tumor lysates. Many phase I-II studies showed that such strategy is feasible and nontoxic but failed to provide convincing evidence of its efficacy. This was due to study design and other biological issues: local immune suppression and insufficient characterization of appropriate epitopes appear as particularly relevant. PMID 22027543

Dendritic cell-based vaccines positively impact natural killer and regulatory T cells in hepatocellular carcinoma patients.
Oct 2011 | Bray, Sarah M; Vujanovic, Lazar; Butterfield, Lisa H
Immunotherapy of cancer must promote antitumor effector cells for tumor eradication as well as counteract immunoregulatory mechanisms which inhibit effectors. Immunologic therapies of cancer are showing promise, including dendritic cell-(DC-) based strategies. DC are highly malleable antigen-presenting cells which can promote potent antitumor immunity as well as tolerance, depending on the environmental signals received. Previously, we tested a peptide-pulsed DC vaccine to promote Alpha-fetoprotein (AFP-) specific anti-tumor immunity in patients with hepatocellular carcinoma (HCC), and reported on the CD8+ T cell responses induced by this vaccine and the clinical trial results. Here, we show that the peptide-loaded DC enhanced NK cell activation and decreased regulatory T cells (Treg) frequencies in vaccinated HCC patients. We also extend these data by testing several forms of DC vaccines in vitro to determine the impact of antigen loading and maturation signals on both NK cells and Treg from healthy donors and HCC patients. PMID 21969837

Immunotherapy in human glioblastoma.
Sep 2011 | Szabo, A T; Carpentier, A F
Glioblastoma patients spontaneously develop anti-tumour immune responses. However, the tumour itself develops several mechanisms that allow the tumor to escape the immune system. Clinical trials using infusion of activated autologous immune cells, or active immunotherapy with tumor antigens and dendritic cells have successfully induced anti-tumour immunity and some radiological responses. More recently, approaches targeting the mechanisms of tolerance have shown promising data in melanoma, and are currently under investigations in gliomas. However, large randomised trials are still needed to prove the usefulness of cancer vaccines in brain tumors. PMID 21885075

A phase I/II study of a MUC1 peptide pulsed autologous dendritic cell vaccine as adjuvant therapy in patients with resected pancreatic and biliary tumors.
Sep 2011 | Lepisto, Andrew J; Moser, Arthur J; Zeh, Herbert; Lee, Kenneth; Bartlett, David; McKolanis, John R; Geller, Brian A; Schmotzer, Amy; Potter, Douglas P; Whiteside, Theresa; Finn, Olivera J; Ramanathan, Ramesh K
Pancreatic and biliary cancers are relatively resistant to chemotherapy and radiation and may therefore provide an opportunity for testing the potential of immunotherapy. MUC1 is an epithelial cell glycoprotein that is highly overexpressed and aberrantly glycosylated in many adenocarcinomas, including pancreatic tumors, providing a tumor specific antigen and target. We performed a Phase I/II clinical trial of a MUC1 peptide-loaded DC vaccine in 12 pancreatic and biliary cancer patients following resection of their primary tumors. The primary endpoints were vaccine toxicity and immunogenicity and the secondary endpoint was clinical outcome. The vaccine was well tolerated and no toxicity was observed. Three patients had pre-existing MUC1 antibody responses that remained stable post vaccination. MUC1-specific T cell responses were difficult to evaluate due to increases in activity of all CD8 and CD4 T cells following each vaccination. Prior to vaccination, patients entered onto this trial had a significantly higher percentage of FoxP3+CD4+ T cells compared to age matched healthy controls. The percentage of these cells also increased transiently following each injection, returning to baseline or below before the next injection. Vaccinated patients have been followed for over four years and four of the twelve patients are alive, all without evidence of recurrence. Study of the immune parameters in long-term survivors several years after vaccination may yield the sought after immune correlates of clinical responses that analysis of immune responses shortly after vaccination has not revealed. PMID 19129927

Treatment of high-grade glioma in children and adolescents.
Sep 2011 | MacDonald, T J; Aguilera, D; Kramm, C M
Pediatric high-grade gliomas (HGGs)--including glioblastoma multiforme, anaplastic astrocytoma, and diffuse intrinsic pontine glioma--are difficult to treat and are associated with an extremely poor prognosis. There are no effective chemotherapeutic regimens for the treatment of pediatric HGG, but many new treatment options are in active investigation. There are crucial molecular differences between adult and pediatric HGG such that results from adult clinical trials cannot simply be extrapolated to children. Molecular markers overexpressed in pediatric HGG include PDGFRα and P53. Amplification of EGFR is observed, but to a lesser degree than in adult HGG. Potential molecular targets and new therapies in development for pediatric HGG are described in this review. Research into bevacizumab in pediatric HGG indicates that its activity is less than that observed in adult HGG. Similarly, tipifarnib was found to have minimal activity in pediatric HGG, whereas gefitinib has shown greater effects. After promising phase I findings in children with primary CNS tumors, the integrin inhibitor cilengitide is being investigated in a phase II trial in pediatric HGG. Studies are also ongoing in pediatric HGG with 2 EGFR inhibitors: cetuximab and nimotuzumab. Other novel treatment modalities under investigation include dendritic cell-based vaccinations, boron neutron capture therapy, and telomerase inhibition. While the results of these trials are keenly awaited, the current belief is that multimodal therapy holds the greatest promise. Research efforts should be directed toward building multitherapeutic regimens that are well tolerated and that offer the greatest antitumor activity in the setting of pediatric HGG. PMID 21784756

Immuno-cell therapy with antecedent surgery has superior actuarial survival to immuno-cell therapy without antecedent surgery for advanced cancers.
Sep 2011 | Shindo, Goki; Endo, Takayoshi; Onda, Masamitsu; Miyamoto, Yoju; Kaneko, Toru; Goto, Shigenori
Immuno-cell therapy using activated lymphocytes (ALs) and/or dendritic cells (DCs) is considered one of the less toxic supportive therapies compared with conventional chemotherapy and radiotherapy, especially for the treatment for advanced cancers. To improve the efficacy of immuno-cell therapy for such cancer, clinical data were analyzed in this preliminary study. PMID 21638124

Dendritic cells combining with cytokine-induced killer cells synergize chemotherapy in patients with late-stage non-small cell lung cancer.
Sep 2011 | Zhong, Runbo; Teng, Jiajun; Han, Baohui; Zhong, Hua
Lung cancer is the leading cause for cancer-related mortality and morbidity, and the survival of late-stage non-small cell lung cancer (NSCLC) remains poor. We hereby evaluate conventional chemotherapy followed by immunotherapy using dendritic cells and cytokine-induced killer cells in the treatment for late stage of NSCLC. PMID 21681372

Immunotherapy for prostate cancer: biology and therapeutic approaches.
Sep 2011 | Cha, Edward; Fong, Lawrence
Although prostate cancer was not historically considered to be a particularly immune-responsive cancer, recent clinical trials have demonstrated that immunotherapy for prostate cancer can lead to improvements in overall survival (OS). These studies include randomized controlled trials with sipuleucel-T and another with PROSTVAC-VF, both of which rely on stimulating the immune system to target prostate proteins. This review discusses the most promising developments over the past year in immune-based therapy for prostate cancer and the opportunities that lie ahead. Recent randomized immunotherapy trials in prostate cancer have demonstrated improvements in OS but without the concomitant improvements in progression-free survival. This uncoupling of survival from clinical response poses challenges to clinical management, because conventional measures of objective response cannot be used to identify patients benefiting from treatment. There is a significant need to identify immunologic or clinical surrogates for survival so that clinical benefit can be assessed in a timely manner. Immunotherapy is now an established treatment approach for prostate cancer, with multiple clinical trials demonstrating improvements in OS. Significant challenges to this modality remain, including determining best clinical setting for immunotherapy, identifying patients who benefit, and defining relevant clinical and immunologic end points. Nevertheless, the broader availability of novel immunotherapies will provide opportunities not only to target different components of the immune system but also to combine immunotherapies with other treatments for improved clinical efficacy. PMID 21825260

Current immunotherapeutic approaches in pancreatic cancer.
Sep 2011 | Koido, Shigeo; Homma, Sadamu; Takahara, Akitaka; Namiki, Yoshihisa; Tsukinaga, Shintaro; Mitobe, Jimi; Odahara, Shunichi; Yukawa, Toyokazu; Matsudaira, Hiroshi; Nagatsuma, Keisuke; Uchiyama, Kan; Satoh, Kenichi; Ito, Masaki; Komita, Hideo; Arakawa, Hiroshi; Ohkusa, Toshifumi; Gong, Jianlin; Tajiri, Hisao
Pancreatic cancer is a highly aggressive and notoriously difficult to treat. As the vast majority of patients are diagnosed at advanced stage of the disease, only a small population is curative by surgical resection. Although gemcitabine-based chemotherapy is typically offered as standard of care, most patients do not survive longer than 6 months. Thus, new therapeutic approaches are needed. Pancreatic cancer cells that develop gemcitabine resistance would still be suitable targets for immunotherapy. Therefore, one promising treatment approach may be immunotherapy that is designed to target pancreatic-cancer-associated antigens. In this paper, we detail recent work in immunotherapy and the advances in concept of combination therapy of immunotherapy and chemotherapy. We offer our perspective on how to increase the clinical efficacy of immunotherapies for pancreatic cancer. PMID 21922022

The dermis as a portal for dendritic cell-targeted immunotherapy of cutaneous melanoma.
Sep 2011 | Oosterhoff, D; Sluijter, B J R; Hangalapura, B N; de Gruijl, T D
Complete surgical excision at an early stage remains the only curative treatment for cutaneous melanoma with few available adjuvant therapy options. Nevertheless, melanoma is a relatively immunogenic tumor type and particularly amenable to immunotherapeutic approaches. A dense network of cutaneous dendritic cells (DC) may account for the reported efficacy of vaccination through the skin and provide an attractive target for the immunotherapy of melanoma. Several phenotypically distinct DC subsets are discernable in the skin, among others, epidermal Langerhans cells and dermal DC. Upon appropriate activation both subsets can efficiently migrate to melanoma-draining lymph nodes (LN) to prime T cell-mediated responses. Unfortunately, from an early stage, melanoma development is characterized by strong immune suppression, facilitating unchecked tumor growth and spread. Particularly the primary tumor site and the first-line tumor-draining LN, the so-called sentinel LN, bear the brunt of this melanoma-induced immune suppression-and these are exactly the sites where anti-melanoma effector T cell responses should be primed by DC in order to prevent early metastasis. Through local immunopotentiation or through DC-targeted vaccination, the dermis may be utilized as a portal to activate DC and kick-start or boost effective T cell-mediated anti-melanoma immunity, even in the face of this immune suppression. PMID 21681685

Improvement of dendritic cell therapy in glioblastoma multiforme WHO 4 by Newcastle disease virus
Sep 2011 | Nesselhut, J

2011 ASCO Annual Meeting; Oral Abstract Session, Developmental Therapeutics - Clinical Pharmacology and Immunotherapy

Background: Glioblastoma multiforme (GBM, WHO grade 4 glioma) is an aggressive disease with an unfavorable prognosis. The current first line treatment comprises radical operation and radiotherapy combined with temozolomide chemotherapy. The reported median overall survival time after primary diagnosis is less than 15 months. After failure of first-line therapy there is currently no effective therapy, and side effects from further treatments may potentially impair quality of life. We report that immunotherapy with monocyte-derived dendritic cells (MoDC) combined with oncolytic Newcastle Disease Virus (NDV) can improve the efficacy of dendritic cell based immune therapy for relapsed GBM. Methods: After isolating monocytes from peripheral blood of n=37 patients with stage IV GBM who failed first-line radio-chemotherapy (PFI: 8 months), MoDC were generated using standard protocols. In 19 patients, NDV was added to the MoDC on day 5. These patients were also pretreated with an infusion with NDV one day before vaccination. The MoDC were harvested on day 7 of culture and administered to the patients intradermally. Results: Improvement of the clinical response was observed in patients, who received combination of NDV with MoDC vs. MoDC alone (47% vs. 11%). The median survival after onset of DC-therapy was 3 months with MoDC alone and 10 months (23 months after primary diagnosis) in combination with NDV. The 1- year-survival rates after onset of DC therapy were 6% and 32%, respectively. The therapy was well tolerated without any major side effects. IFN-gamma Elispot analyses from patients who received NDV injections and NDV-primed MoDC show that MoDC primed with NDV can induce a specific CD4 and CD8 T-cell response against NDV whereas healthy donors show no specific T-cell response. Conclusions: The efficacy of dendritic-cell based therapy for GBM can be improved by combination with NDV and may prolong overall survival of patients after failure of first-line therapy. For a first time we demonstrate that NDV primed MoDC induces a NDV specific T-cell response in humans, which may lead to in-vivo lysis of NDV-infected tumor cells.

Route of administration modulates the induction of dendritic cell vaccine-induced antigen-specific T cells in advanced melanoma patients.
Sep 2011 | Lesterhuis, W Joost; de Vries, I Jolanda M; Schreibelt, Gerty; Lambeck, Annechien J A; Aarntzen, Erik H J G; Jacobs, Joannes F M; Scharenborg, Nicole M; van de Rakt, Mandy W M M; de Boer, Annemiek J; Croockewit, Sandra; van Rossum, Michelle M; Mus, Roel; Oyen, Wim J G; Boerman, Otto C; Lucas, Sophie; Adema, Gosse J; Punt, Cornelis J A; Figdor, Carl G
It is unknown whether the route of administration influences dendritic cell (DC)-based immunotherapy. We compared the effect of intradermal versus intranodal administration of a DC vaccine on induction of immunologic responses in melanoma patients and examined whether concomitant administration of interleukin (IL)-2 increases the efficacy of the DC vaccine. PMID 21771874

Immunotherapy for the treatment of prostate cancer.
Aug 2011 | Di Lorenzo, Giuseppe; Buonerba, Carlo; Kantoff, Philip W
Failure of immune surveillance has a prominent role in tumorigenesis. Cancerous cells can evade T-cell responses to tumor-associated antigens by multiple mechanisms. Active immunotherapy aims to stimulate the immune response against cancer cells. Unlike normal prostate tissue, prostate cancer is not ignored by the immune system, as shown by the presence of tumor infiltrating lymphocytes. This characteristic renders prostate cancer particularly suitable for immunotherapy. The existence of well-defined antigens, largely limited to prostate tissue, allows prostate cancer cells to be targeted without the risk of systemic autoimmune reactions, as autoimmunity specifically directed at the prostate is the goal of prostate cancer immunotherapy. Active immunotherapy directed towards prostate cancer can be conducted using multiple strategies, involving dendritic cells, whole-cell vaccines, viral vectors, DNA-based and peptide-based agents, as well as immunostimulatory agents. The only FDA-approved immunotherapy for prostate cancer is the dendritic-cell-based agent Sipuleucel-T, which yielded an advantage in overall survival, but not in progression-free survival in a phase III trial. We present the clinical developments in the field of immunotherapy and critically analyze methodological issues related to the evaluation of tumor responses to immunotherapy, trial design, and surrogate end points. PMID 21606971

Pulsing with blast cell lysate or blast-derived total RNA reverses the dendritic cell-mediated cytotoxic activity of cytokine-induced killer cells against allogeneic acute myelogenous leukemia cells.
Aug 2011 | Schöttker, Björn; Schmidt-Wolf, Ingo G H
Immunotherapeutic strategies may be a treatment option in patients with refractory acute myelogenous leukemia (AML) or, in cases of complete remission after conventional therapy regimens, may help to reduce disease recurrence or delay time to progression. Evidence suggests a key role of dendritic cells (DCs) in cancer immunotherapy due to their capacity to present tumour antigens to effector cells. We generated cytokine-induced killer (CIK) cells from healthy donors and examined their responses in vitro in an LDH release assay against three cell lines and allogeneic HLA non-matched blasts from three patients with de novo AML after coincubation with autologous peripheral blood monocyte-derived DCs. Although DCs were unable to enhance CIK cell effects against all three cell lines tested, the cytotoxic activity against the patients' AML cells increased after coculture with mature DCs, which was significant in two of three patients. However, neither prior pulsing of the DCs with blast cell lysates nor with leukemic cell-derived total RNA further enhanced the lytic capacity of the CIK cells. On the contrary, pulsing reduced or even reversed the cytotoxic activity of the effector cells. This decrease of allogeneic cytotoxicity led us to conclude that monocyte-derived DCs may be useful in autologous or allogeneic vaccine strategies for the treatment of AML or in priming donor lymphocytes in vitro, but unfractionated antigens as pulsing agents may have inhibitory effects on T cell efficiency and their employment in immunotherapeutic strategies for AML seems questionable. PMID 21863132

Cancer-testis antigen, BORIS based vaccine delivered by dendritic cells is extremely effective against a very aggressive and highly metastatic mouse mammary carcinoma.
Aug 2011 | Mkrtichyan, Mikayel; Ghochikyan, Anahit; Davtyan, Hayk; Movsesyan, Nina; Loukinov, Dmitry; Lobanenkov, Victor; Cribbs, David H; Laust, Amanda K; Nelson, Edward L; Agadjanyan, Michael G
Here, we analyze for the first time the immunological and therapeutic efficacy of a dendritic cell (DC) vaccine based on a cancer-testis antigen, Brother of regulator of imprinted sites (BORIS), an epigenetically acting tumor-promoting transcription factor. Vaccination of mice with DC loaded with truncated form of BORIS (DC/mBORIS) after 4T1 mammary tumor implantation induced strong anti-cancer immunity, inhibited tumor growth (18.75% of mice remained tumor-free), and dramatically lowered the number of spontaneous clonogenic metastases (50% of mice remained metastases-free). Higher numbers of immune effector CD4 and CD8 T cells infiltrated the tumors of vaccinated mice vs. control animals. Vaccination significantly decreased the number of myeloid-derived suppressor cells (MDSCs) infiltrating the tumor sites, but not MDSCs in the spleens of vaccinated animals. These data suggest that DC-based mBORIS vaccination strategies have significant anti-tumor activity in a therapeutic setting and will be more effective when combined with agents to attenuate tumor-associated immune suppression. PMID 21641588

Prostate cancer immunotherapy.
Aug 2011 | May, Kenneth F; Gulley, James L; Drake, Charles G; Dranoff, Glenn; Kantoff, Philip W
The interaction between the immune system and prostate cancer has been an area of research interest for several decades. The recent U.S. Food and Drug Administration approval of 2 first-in-class proof-of-concept immunotherapies (sipuleucel-T and ipilimumab) has stimulated broader interest in manipulating immunity to fight cancer. In the context of prostate cancer, the immunotherapy strategies that have garnered the most interest are the therapeutic vaccination strategies, exemplified by sipuleucel-T and PROSTVAC-VF, and immune checkpoint blockade of CTLA-4 and PD-1. Improved understanding of the immune responses generated by these strategies and development of predictive biomarkers for patient selection will guide rational combinations of these treatments and provide building blocks for future immunotherapies. PMID 21700764

Challenges in dendritic cells-based therapeutic vaccination in HIV-1 infection Workshop in dendritic cell-based vaccine clinical trials in HIV-1.
Aug 2011 | García, Felipe; Routy, Jean-Pierre
Therapeutic immunization has been proposed as an approach that might help limit the need for lifelong combined antiretroviral therapy (cART). One approach for therapeutic vaccination which has been explored during the last few years is the administration of autologous monocyte-derived DCs (MD-DCs) loaded ex vivo with a variety of antigens. It has been shown in experimental murine models as well as in cancer patients and in patients with chronic infections that this approach can induce and potentiate antigen-specific T-cell response (and to induce a potent protective immunity). Contrary to the wide experience with this strategy in cancer, in HIV-1 infection the experience is limited and the design of the clinical trials varies greatly between groups. This variability affects all the steps of the process, from preparation of immunogen and DCs to clinical trial design and immune monitoring. Although both the study designs and the DC preparation (the maturation stimuli and the identity and source of HIV-1 antigens used to pulse DCs) varied in most of the studies that were published so far, overall the results indicate that DC immunotherapy elicits some degree of immunological response. To address this situation and to allow comparison between trials a panel of experts working in DC-based clinical trials in HIV-1 infection met in Barcelona at the end of 2010. During this meeting, the participants shared the data of their current research activities in this field in order to unify criteria for the future. This report summarizes the present situation of the field and the discussions and conclusions of this meeting. PMID 21791232

Optimizing DC vaccination by combination with oncolytic adenovirus coexpressing IL-12 and GM-CSF.
Aug 2011 | Zhang, Song-Nan; Choi, Il-Kyu; Huang, Jing-Hua; Yoo, Ji-Young; Choi, Kyung-Ju; Yun, Chae-Ok
Dendritic cell (DC)-based vaccination is a promising strategy for cancer immunotherapy. However, clinical trials have indicated that immunosuppressive microenvironments induced by tumors profoundly suppress antitumor immunity and inhibit vaccine efficacy, resulting in insufficient reduction of tumor burdens. To overcome these obstacles and enhance the efficiency of DC vaccination, we generated interleukin (IL)-12- and granulocyte-macrophage colony-stimulating factor (GM-CSF)-coexpressing oncolytic adenovirus (Ad-ΔB7/IL12/GMCSF) as suitable therapeutic adjuvant to eliminate immune suppression and promote DC function. By treating tumors with Ad-ΔB7/IL12/GMCSF prior to DC vaccination, DCs elicited greater antitumor effects than in response to either treatment alone. DC migration to draining lymph nodes (DLNs) dramatically increased in mice treated with the combination therapy. This result was associated with upregulation of CC-chemokine ligand 21 (CCL21(+)) lymphatics in tumors treated with Ad-ΔB7/IL12/GMCSF. Moreover, the proportion of CD4(+)CD25(+) T-cells and vascular endothelial growth factor (VEGF) expression was decreased in mice treated with the combination therapy. Furthermore, combination therapy using immature DCs also showed effective antitumor effects when combined with Ad-ΔB7/IL12/GMCSF. The combination therapy had a remarkable therapeutic efficacy on large tumors. Taken together, oncolytic adenovirus coexpressing IL-12 and GM-CSF in combination with DC vaccination has synergistic antitumor effects and can act as a potent adjuvant for promoting and optimizing DC vaccination. PMID 21468000

A phase I/II clinical trial investigating the adverse and therapeutic effects of a postoperative autologous dendritic cell tumor vaccine in patients with malignant glioma.
Jul 2011 | Chang, Chen-Nen; Huang, Yin-Cheng; Yang, Den-Mei; Kikuta, Kenichiro; Wei, Kuo-Jen; Kubota, Toshihiko; Yang, Wen-Kuang
Previous clinical trials of dendritic cell (DC)-based immunotherapy in patients with glioblastoma multiforme (GBM) have reported induction of systemic immune responses and prolonged survival. From 2003 to 2005, we performed a clinical trial in which patients with malignant glioma underwent surgery for maximal cytoreduction followed by a 6-month 10-injection course of autologous DC-tumor vaccine therapy, each injection containing 1-6×10(7) DC. Of the 17 treated patients (16 with World Health Organization grade IV and one with grade III glioma), eight (47.1%) had an initial transient elevation in aspartate aminotransferase (AST)/alanine aminotransferase (ALT). Vaccination caused some tumor shrinkage and increased concentration of tumor-infiltrating CD8(+) lymphocytes. Median survival and 5-year survival were 525 days and 18.8%, respectively, for 16 patients with grade IV glioma (381 days and 12.5% for eight newly diagnosed; 966 days and 25% for eight relapsed patients) compared to 380 days and 0% for 63 historical control patients. We concluded that autologous DC-tumor immunotherapy benefits patients with malignant glioma but may cause transient but reversible elevation of serum AST/ALT levels. PMID 21715171

Dendritic cell-based vaccination of patients with advanced pancreatic carcinoma: results of a pilot study.
Jul 2011 | Bauer, Christian; Dauer, Marc; Saraj, Samira; Schnurr, Maximilian; Bauernfeind, Franz; Sterzik, Alexander; Junkmann, Jana; Jakl, Veronika; Kiefl, Rosemarie; Oduncu, Fuat; Emmerich, Bertold; Mayr, Doris; Mussack, Thomas; Bruns, Christiane; Rüttinger, Dominik; Conrad, Claudius; Jauch, Karl-Walter; Endres, Stefan; Eigler, Andreas
Dendritic cell (DC)-based vaccination can induce antitumor T cell responses in vivo. This clinical pilot study examined feasibility and outcome of DC-based tumor vaccination for patients with advanced pancreatic adenocarcinoma. PMID 21547597

Dendritic cells in cancer immunotherapy: vaccines or autologous transplants?
Jul 2011 | Kalinski, Pawel; Edington, Howard; Zeh, Herbert J; Okada, Hideho; Butterfield, Lisa H; Kirkwood, John M; Bartlett, David L
Dendritic cells (DCs) are the most powerful immunostimulatory cells specialized in the induction and regulation of immune responses. Their properties and the feasibility of their large-scale ex vivo generation led to the application of ex vivo-educated DCs to bypass the dysfunction of endogenous DCs in cancer patients and to induce therapeutic anti-cancer immunity. While multiple paradigms of therapeutic application of DCs reflect their consideration as cancer "vaccines", numerous features of DC-based vaccination resemble those of autologous transplants, resulting in challenges and opportunities that distinguish them from classical vaccines. In addition to the functional heterogeneity of DC subsets and plasticity of the individual DC types, the unique features of DCs are the kinetic character of their function, limited functional stability, and the possibility to imprint in maturing DCs distinct functions relevant for the induction of effective cancer immunity, such as the induction of different effector functions or different homing properties of tumor-specific T cells (delivery of "signal 3" and "signal 4"). These considerations highlight the importance of the application of optimized, potentially patient-specific conditions of ex vivo culture of DCs and their delivery, with the logistic and regulatory implications shared with transplantation and other surgical procedures. PMID 21717071

Engineering the brain tumor microenvironment enhances the efficacy of dendritic cell vaccination: implications for clinical trial design.
Jul 2011 | Mineharu, Yohei; King, Gwendalyn D; Muhammad, A K M G; Bannykh, Serguei; Kroeger, Kurt M; Liu, Chunyan; Lowenstein, Pedro R; Castro, Maria G
Glioblastoma multiforme (GBM) is a deadly primary brain tumor. Clinical trials for GBM using dendritic cell (DC) vaccination resulted in antitumor immune responses. Herein, we tested the hypothesis that combining in situ (intratumoral) Ad-Flt3L/Ad-TK-mediated gene therapy with DC vaccination would increase therapeutic efficacy and antitumor immunity. PMID 21632862

Mature autologous dendritic cell vaccines in advanced non-small cell lung cancer: a phase I pilot study.
Jul 2011 | Perroud, Maurício W; Honma, Helen N; Barbeiro, Aristóteles S; Gilli, Simone Co; Almeida, Maria T; Vassallo, José; Saad, Sara To; Zambon, Lair
Overall therapeutic outcomes of advanced non-small-cell lung cancer (NSCLC) are poor. The dendritic cell (DC) immunotherapy has been developed as a new strategy for the treatment of lung cancer. The purpose of this study was to evaluate the feasibility, safety and immunologic responses in use in mature, antigen-pulsed autologous DC vaccine in NSCLC patients. PMID 21682877

Randomized trial of autologous cellular immunotherapy with sipuleucel-T in androgen-dependent prostate cancer.
Jul 2011 | Beer, Tomasz M; Bernstein, Guy T; Corman, John M; Glode, L Michael; Hall, Simon J; Poll, Wayne L; Schellhammer, Paul F; Jones, Lori A; Xu, Yi; Kylstra, Jelle W; Frohlich, Mark W
Sipuleucel-T, an autologous cellular immunotherapy, was investigated in a randomized, double-blind, controlled trial to determine its biologic activity in androgen-dependent prostate cancer (ADPC). PMID 21558406

Sipuleucel-T: autologous cellular immunotherapy for men with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer.
Jun 2011 | Sims, Robert B
Sipuleucel T is an autologous cellular immunotherapy designed to stimulate an immune response in men diagnosed with asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. Sipuleucel T improves overall survival and provides an additional treatment option for this patient population. PMID 21716715

Recent advances in immunotherapy for the treatment of prostate cancer.
Jun 2011 | Sonpavde, Guru; Agarwal, Neeraj; Choueiri, Toni K; Kantoff, Philip W
Prostate cancer vaccines attempt to induce cancer-specific systemic immune responses and represent a new class of targeted therapies, many of which are non-toxic. Several vaccine technologies are in development. PMID 21675925

Immunotherapy for prostate cancer: recent advances, lessons learned, and areas for further research.
Jun 2011 | Gulley, James L; Drake, Charles G
A surge of interest in therapeutic cancer vaccines has arisen in the wake of recent clinical trials suggesting that such vaccines can result in statistically significant and clinically meaningful improvements in overall survival-with substantially limited side effects compared with chemotherapy-in patients with metastatic castration-resistant prostate cancer. One of these trials led to the registration of sipuleucel-T, the first therapeutic vaccine to be approved for cancer patients. In this review we highlight emerging patterns from clinical trials that suggest a need for more-appropriate patient populations (i.e., with lower tumor volume and less-aggressive disease) and endpoints (i.e., overall survival) for studies of immunotherapy alone, as well as biologically plausible explanations for these findings. We also explore the rationale for ongoing and planned studies combining therapeutic vaccines with other modalities. Finally, we attempt to put these findings into a practical clinical context and suggest fertile areas for future study. Although our discussion focuses on prostate cancer, the concepts we address most likely have broad applicability to immunotherapy for other cancers as well. PMID 21680544

Phase I/II trial of a dendritic cell vaccine transfected with DNA encoding melan A and gp100 for patients with metastatic melanoma.
Jun 2011 | Steele, J C; Rao, A; Marsden, J R; Armstrong, C J; Berhane, S; Billingham, L J; Graham, N; Roberts, C; Ryan, G; Uppal, H; Walker, C; Young, L S; Steven, N M
This trial tested a dendritic cell (DC) therapeutic cancer vaccine in which antigen is loaded using a novel non-viral transfection method enabling the uptake of plasmid DNA condensed with a cationic peptide. Proof of principle required the demonstration of diverse T lymphocyte responses following vaccination, including multiple reactivities restricted through both major histocompatibility complex (MHC) class I and II. Patients with advanced melanoma were offered four cycles of vaccination with autologous DC expressing melan A and gp100. Disease response was measured using Response Evaluation Criteria in Solid Tumours. Circulating MHC class I- and II-restricted responses were measured against peptide and whole antigen targets using interferon-γ ELIspot and enzyme-linked immunosorbent assay assays, respectively. Responses were analyzed across the trial population and presented descriptively for some individuals. Twenty-five patients received at least one cycle. Vaccination was well tolerated. Three patients had reduction in disease volume. Across the trial population, vaccination resulted in an expansion of effector responses to both antigens, to the human leukocyte antigen A2-restricted modified epitope, melan A ELAGIGILTV, and to a panel of MHC class I- and II-restricted epitopes. Vaccination with mature DC non-virally transfected with DNA encoding antigen had biological effect causing tumour regression and inducing diverse T lymphocyte responses. PMID 21307889

Cancer stem cells: perspectives of new therapeutical approaches for breast cancer.
May 2011 | Nicolini, A; Ferrari, P; Fini, M; Borsari, V; Fallahi, P; Antonelli, A; Carpi, A; Miccoli, P
Currently stem cells are hypothesized to play a central role in the origin, spread and resistance to treatment of breast cancer. Common anticancer therapy is effective but transient, with tumor relapse and metastatic disease often occurring. For therapy to be more effective, debulking of differentiated tumors must occur followed by targeting of the remaining surviving often quiescent tumor stem cells. New therapeutics aimed at cancer stem cells are achieved through non immunological and immunological methods. The former include elective ABC drug transporters or the heat shock protein 90 inhibition, targeting the self-renewal signalling pathways or the EMT program, differentiation therapy, or other interventions to eliminate BrCSCs. The latter include targeting specific antigens expressed on BrCSCs, dendritic cells (DCs) based vaccination and blockers of the extrinsic signals at CSC niche. Here all these novel approaches related to breast cancer stem cells are described. PMID 21622284

hTERT mRNA dendritic cell vaccination: complete response in a pancreatic cancer patient associated with response against several hTERT epitopes.
May 2011 | Suso, Else M Inderberg; Dueland, Svein; Rasmussen, Anne-Marie; Vetrhus, Turid; Aamdal, Steinar; Kvalheim, Gunnar; Gaudernack, Gustav
Immunotherapy targeting the hTERT subunit of telomerase has been shown to induce robust immune responses in cancer patients after vaccination with single hTERT peptides. Vaccination with dendritic cells (DCs) transfected with hTERT mRNA has the potential to induce strong immune responses to multiple hTERT epitopes and is therefore an attractive approach to more potent immunotherapy. Blood samples from such patients provide an opportunity for identification of new, in vivo processed T-cell epitopes that may be clinically relevant. A 62-year-old female patient underwent radical surgery for a pancreatic adenocarcinoma. After relapse, she obtained stable disease on gemcitabine treatment. Due to severe neutropenia, the chemotherapy was terminated. The patient has subsequently been treated with autologous DCs loaded with hTERT mRNA for 3 years. Immunomonitoring was performed at regular intervals following start of vaccination and clinical outcome measured by CT and PET/CT evaluation. The patient developed an immune response against several hTERT-derived Th and CTL epitopes. She presently shows no evidence of active disease based on PET/CT scans. No serious adverse events were experienced and the patient continues to receive regular booster injections. We here provide evidence for the induction of hTERT-specific immune responses following vaccination of a pancreas cancer patient with DCs loaded with hTERT mRNA. These responses are associated with complete remission. A thorough analysis of this patient immune response has provided a unique opportunity to identify novel epitopes, associated with clinical effects. These will be included in future hTERT vaccines. PMID 21365467

PD-1 blockade by CT-011, anti-PD-1 antibody, enhances ex vivo T-cell responses to autologous dendritic cell/myeloma fusion vaccine.
May 2011 | Rosenblatt, Jacalyn; Glotzbecker, Brett; Mills, Heidi; Vasir, Baldev; Tzachanis, Dimitrios; Levine, James D; Joyce, Robin M; Wellenstein, Kerry; Keefe, Whitney; Schickler, Michael; Rotem-Yehudar, Rinat; Kufe, Donald; Avigan, David
We have developed a cancer vaccine in which autologous tumor is fused with dendritic cells (DCs) resulting in the presentation of tumor antigens in the context of DC-mediated costimulation. In clinical trials, immunologic responses have been observed, however responses may be muted by inhibitory pathways. The PD1/PDL1 pathway is an important element contributing to tumor-mediated immune suppression. In this study, we demonstrate that myeloma cells and DC/tumor fusions strongly express PD-L1. Compared with a control population of normal volunteers, increased PD-1 expression was observed on T cells isolated from patients with myeloma. It is interesting to note that after autologous transplantation, T-cell expression of PD-1 returned to levels seen in normal controls. We examined the effect of PD-1 blockade on T-cell response to DC/tumor fusions ex vivo. Presence of CT-011, an anti-PD1 antibody, promoted the vaccine-induced T-cell polarization towards an activated phenotype expressing Th1 compared with Th2 cytokines. A concomitant decrease in regulatory T cells and enhanced killing in a cytotoxicity assay was observed. In summary, we demonstrate that PD-1 expression is increased in T cells of patients with active myeloma, and that CT-011 enhances activated T-cell responses after DC/tumor fusion stimulation. PMID 21577144

Dendritic cell based tumor vaccination in prostate and renal cell cancer: a systematic review and meta-analysis.
May 2011 | Draube, Andreas; Klein-González, Nela; Mattheus, Stefanie; Brillant, Corinne; Hellmich, Martin; Engert, Andreas; von Bergwelt-Baildon, Michael
More than 200 clinical trials have been performed using dendritic cells (DC) as cellular adjuvants in cancer. Yet the key question whether there is a link between immune and clinical response remains unanswered. Prostate and renal cell cancer (RCC) have been extensively studied for DC-based immunotherapeutic interventions and were therefore chosen to address the above question by means of a systematic review and meta-analysis. PMID 21533099

Enhanced stimulation of anti-ovarian cancer CD8(+) T cells by dendritic cells loaded with nanoparticle encapsulated tumor antigen.
Apr 2011 | Hanlon, Douglas J; Aldo, Paulomi B; Devine, Lesley; Alvero, Ayesha B; Engberg, Anna K; Edelson, Richard; Mor, Gil
Dendritic cell (DC)-based cancer therapies are favored approaches to stimulate anti-tumor T-cell responses. Unfortunately, tolerance to tumor antigens is difficult to overcome. Biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NP) are effective reagents in the delivery of drugs and tumor-associated antigens (TAA). In this study, we assessed the capacity of a PLGA NP-based delivery system to augment CD8 T-cell responses to ovarian cancer TAA. PMID 21241402

Dendritic cells and cutaneous T-cell lymphomas.
Apr 2011 | Ni, X; Duvic, M
Dendritic cells (DCs) are potent antigen-presenting cells that help orchestrate the innate and adaptive immune systems to induce tolerance and immunity. They are diversified in their phenotypes, stages of maturation, degrees of activation, and functions. Several subtypes of DCs exist among human lymphoid tissues, non-lymphoid tissues, and in peripheral blood. In the skin, three types of DCs are described: Langerhans cells (LCs), dermal dendritic cells (DDCs), and plasmacytoid dendritic cells (pDCs). In the peripheral blood, myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells are well described. Dysfunctional DCs are found in many autoimmune disorders, allergies, and cancers. In this paper, we focus on DCs as related to cutaneous T cell lymphomas (CTCLs). Abnormal DC number and defective DC function are found in the blood of patients with advanced stage Sézary syndrome (SS), a leukemic variant of CTCLs. Extracorporeal photopheresis (ECP), an effective therapy for erythrodermic CTCLs, is thought to work by inducing apoptosis of tumor cells and monocytes-derived DCs. DC vaccination has been carried out successfully in some patients with CTCLs when combined with immune modifiers like toll like receptor agonists, which may enhance the function of DCs. However, DCs may perform a dual role in the pathogenesis of CTCLs. Immature DCs (langerhans cells) could promote the survival of malignant T cells. Further understanding of DCs and their role in CTCLs can help us to uncover the pathogenesis of this disease and to further explore the therapeutic uses of DCs. PMID 21505396

Immune response in patients with newly diagnosed glioblastoma multiforme treated with intranodal autologous tumor lysate-dendritic cell vaccination after radiation chemotherapy.
Apr 2011 | Fadul, Camilo E; Fisher, Jan L; Hampton, Thomas H; Lallana, Enrico C; Li, Zhongze; Gui, Jiang; Szczepiorkowski, Zbigniew M; Tosteson, Tor D; Rhodes, C Harker; Wishart, Heather A; Lewis, Lionel D; Ernstoff, Marc S
Patients with glioblastoma multiforme (GBM) are profoundly immunosuppressed and may benefit from restoration of an antitumor immune response in combination with conventional radiation therapy and temozolomide (TMZ). The optimal strategies to evaluate clinically relevant immune responses to treatment have yet to be determined. The primary objective of our study was to determine immunologic response to cervical intranodal vaccination with autologous tumor lysate-loaded dendritic cells (DCs) in patients with GBM after radiation therapy and TMZ. We used a novel hierarchical clustering analysis of immune parameters measured before and after vaccination. Secondary objectives were to assess treatment feasibility and to correlate immune response with progression-free survival (PFS) and overall survival. Ten eligible patients received vaccination. Tumor-specific cytotoxic T-cell response measured after vaccination was enhanced for the precursor frequency of CD4+ T and CD4+ interferon γ-producing cells. Hierarchical clustering analysis of multiple functional outcomes discerned 2 groups of patients according to their immune response, and additionally showed that patients in the top quintile for at least one immune function parameter had improved survival. There were no serious adverse events related to DC vaccination. All patients were alive at 6 months after diagnosis and the 6-month PFS was 90%. The median PFS was 9.5 months and overall survival was 28 months. In patients with GBM, immune therapy with DC vaccination after radiation and TMZ resulted in tumor-specific immune responses that were associated with prolonged survival. Our data suggest that DC vaccination in combination with radiation and chemotherapy in patients with GBM is feasible, safe, and may induce tumor-specific immune responses. PMID 21499132

Targeting of IL-2 and GM-CSF immunocytokines to a tumor vaccine leads to increased anti-tumor activity.
Apr 2011 | Fournier, Philippe; Aigner, Maximilian; Schirrmacher, Volker
Fusion proteins combining antibodies with cytokines such as IL-2 and GM-CSF appear to be promising reagents for tumor therapy. In this study, we combined such immunocytokines with the tumor vaccine ATV-NDV consisting of irradiated tumor cells infected with Newcastle disease virus (NDV). The two fusion proteins bsF-GMCSF and tsHN-IL2-GM-CSF, binding, respectively, to the viral fusion protein (F) or to hemagglutinin-neuraminidase (HN) expressed on the surface of the vaccine cells and containing GM-CSF or GM-CSF and IL-2-activities were produced by recombinant antibody technology. The purified molecules showed the expected binding specificity and biological activity inherent to the respective cytokine. Using a newly established in vitro tumor neutralisation assay (TNA), we showed improved antitumoral effect through tumor growth inhibition when human peripheral blood mononuclear cells from healthy donors were stimulated with immunocytokine modified versus non-modified tumor vaccine cells. These effects induced by the fusion proteins, in the presence of a suboptimal T cell activation signal 1 provided by bsHN-CD3, occured only when these were bound to the tumor vaccine. Furthermore, it was shown that CD14+ monocytes could be activated by the GM-CSF cytokine fused within the recombinant proteins and that they contributed essentially to the antitumor effect in the TNA. The data presented here suggest an easy way for a broad clinical development and application of tumor-targeted IL-2- and GM-CSF-based immunocytokines based on the associated increase of anti-tumor activity mediated by T cells and monocytes. PMID 21424118

Heat-shock induction of tumor-derived danger signals mediates rapid monocyte differentiation into clinically effective dendritic cells.
Apr 2011 | Aguilera, Raquel; Saffie, Carlos; Tittarelli, Andrés; González, Fermín E; Ramírez, Marcos; Reyes, Diego; Pereda, Cristián; Hevia, Daniel; García, Tamara; Salazar, Lorena; Ferreira, Arturo; Hermoso, Marcela; Mendoza-Naranjo, Ariadna; Ferrada, Carlos; Garrido, Paola; López, Mercedes N; Salazar-Onfray, Flavio
This study characterizes, biologically and clinically, a novel type of dendritic cells (DC) produced in the short term and called tumor antigen-presenting cells (TAPCells). In particular, we identified factors present in a lysate derived from heat-shocked allogeneic melanoma cells (TRIMEL) that are associated with TAPCells' enhanced capability to induce CD8(+) T-cell responses in vitro and in vaccinated melanoma patients. PMID 21292818

Chronic myeloid leukemia lysate-loaded dendritic cells induce T-cell responses towards leukemia progenitor cells.
Apr 2011 | Westers, Theresia M; van den Ancker, Willemijn; Bontkes, Hetty J; Janssen, Jeroen J W M; van de Loosdrecht, Arjan A; Ossenkoppele, Gert J
Treatment of chronic myeloid leukemia with tyrosine kinase inhibitors, such as imatinib mesylate, dasatinib and nilotinib, results in high rates of cytogenetic and molecular responses. However, in many patients, minimal residual disease is detected by molecular techniques. Since chronic myeloid leukemia cells are particularly good targets for immune surveillance mechanisms, we explored active specific immunotherapy using leukemia lysate-loaded dendritic cells in vitro. Our data show the potency of dendritic cell-based vaccination strategies for the induction of T cell-mediated responses to eradicate minimal residual disease. PMID 21463196

IL-15 and type I interferon are required for activation of tumoricidal NK cells by virus-infected dendritic cells.
Apr 2011 | Boudreau, Jeanette E; Stephenson, Kyle B; Wang, Fuan; Ashkar, Ali A; Mossman, Karen L; Lenz, Laurel L; Rosenthal, Kenneth L; Bramson, Jonathan L; Lichty, Brian D; Wan, Yonghong
There is increasing evidence that natural killer (NK) cells play an important role in antitumor immunity following dendritic cell (DC) vaccination. Little is known, however, about the optimal stimulation of DCs that favors NK activation in tumor-bearing hosts. In this study, we demonstrate that treatment with toll-like receptor (TLR) ligands and infection with a mutant vesicular stomatitis virus (VSV-ΔM51) both induced DC maturation. Further, inoculation of these DCs led to robust NK-mediated protection against tumor challenge. Strikingly, only VSV-ΔM51-infected DCs were capable of suppressing the growth of established tumors, suggesting that additional signals provided by viral infection may be required to activate tumoricidal NK cells in tumor-bearing hosts. VSV-ΔM51 infection of DCs induced greater type I interferon (IFN I) production than TLR ligand treatment, and disruption of the IFN I pathway in DCs eliminated their ability to induce NK activation and tumor protection. However, further studies indicated that IFN I alone was not sufficient to activate NK cells, especially in the presence of a tumor, and DC-derived IL-15 was additionally required for tumoricidal NK activation. These results suggest that induction of IFN I by VSV-ΔM51 allows DCs to overcome tumor-associated immunosuppression and facilitate IL-15-mediated priming of tumoricidal NK cells. Thus, the mode of DC maturation should be carefully considered when designing DC-based cancer immunotherapies. PMID 21307131

[Study on the specific immunity induced by dendritic cell vaccine loading allogenic microvascular endothelial cell bEnd.3 antigen against U14 cervical cancer cell in mice].
Mar 2011 | Zhao, Jun; Lu, Jing; Liu, Ya-qin; Yang, Hong-yan; Huang, You-tian; Zhao, Ji-min; Li, Shan; Zhai, Jing-ming; Zhao, Ming-yao; Zhang, Xi; Dong, Zi-ming
To explore the specific cellular and humoral immunity induced by dendritic cells (DC) vaccine loading allogenic microvascular endothelial cell bEnd.3 antigen against U14 cervical cancer cell of mice. PMID 21429436

Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy.
Mar 2011 | Prins, Robert M; Soto, Horacio; Konkankit, Vera; Odesa, Sylvia K; Eskin, Ascia; Yong, William H; Nelson, Stanley F; Liau, Linda M
To assess the feasibility, safety, and toxicity of autologous tumor lysate-pulsed dendritic cell (DC) vaccination and toll-like receptor (TLR) agonists in patients with newly diagnosed and recurrent glioblastoma. Clinical and immune responses were monitored and correlated with tumor gene expression profiles. PMID 21135147

Dendritic cell vaccination against ovarian cancer--tipping the Treg/TH17 balance to therapeutic advantage?
Mar 2011 | Cannon, Martin J; Goyne, Hannah; Stone, Pamela J B; Chiriva-Internati, Maurizio
The pathology of ovarian cancer is characterized by profound immunosuppression in the tumor microenvironment. Mechanisms that contribute to the immunosuppressed state include tumor infiltration by regulatory T cells (Treg), expression of B7-H1 (PDL-1), which can promote T cell anergy and apoptosis through engagement of PD-1 expressed by effector T cells, and expression of indoleamine 2,3-dioxygenase (IDO), which can also contribute to effector T cell anergy. Expression of both B7-H1 and IDO has been associated with differentiation and recruitment of Treg, and clinical studies have shown that each of these mechanisms correlates independently with increased morbidity and mortality in patients with ovarian cancer. In a remarkable counterpoint to these observations, ovarian tumor infiltration with T(H)17 cells correlates with markedly improved clinical outcomes. In this Future Perspectives review, we argue that dendritic cell (DC) vaccination designed to drive tumor-antigen-specific T(H)17 T cell responses, combined with adjuvant treatments that abrogate immunosuppressive mechanisms operative in the tumor microenvironment, offers the potential for clinical benefit in the treatment of ovarian cancer. We also discuss pharmacological approaches to modulation of MAP kinase signaling for manipulation of the functional plasticity of DC, such that they may be directed to promote T(H)17 responses following DC vaccination. PMID 21271951

Changes in peripheral blood level of regulatory T cells in patients with malignant melanoma during treatment with dendritic cell vaccination and low-dose IL-2.
Feb 2011 | Bjoern, J; Brimnes, M K; Andersen, M H; Thor Straten, P; Svane, I M
In this study, changes in peripheral blood regulatory T cell (Treg) levels were evaluated in 46 progressive patients with melanoma treated with a dendritic cell-based vaccine and concomitant low-dose IFN-α and IL-2. The regulatory subset of CD4 T cells, characterized by CD25(high) , was prospectively analysed in fresh blood, and treatment-associated quantitative and qualitative changes were analysed. By the 4th vaccine, patients showed a marked increase in CD4+ CD25(high) T cell subset from 6% to 22% (P<0.001). At the 6th vaccine, a general decline was observed and a significantly (P=0.01) lower level of CD4+ CD25(high) Treg cells was reached in the group of patients who attained disease stabilization (9.5%) compared to patients with continued progressive disease (14.5%). However, when FoxP3 was employed for retrospective analysis of Tregs on frozen blood, this difference did not reach significance (P=0.09). The vast majority of the Treg produced IL-10 and, to a varying extent, TGF-β. In addition, sorted CD4+ CD25(high) CD127⁻ Tregs were able to suppress proliferation of peripheral blood mononuclear cells in a dose-dependent manner, thus suggesting a regulatory functionality. These findings emphasize the need for strategies to effectively eliminate Treg cells to optimize the clinical effectiveness of cancer immunotherapy. PMID 21204893

An autologous dendritic cell canine mammary tumor hybrid-cell fusion vaccine.
Jan 2011 | Bird, R Curtis; Deinnocentes, Patricia; Church Bird, Allison E; van Ginkel, Frederik W; Lindquist, Joni; Smith, Bruce F
Mammary cancer is among the most prevalent canine tumors and frequently resulting in death due to metastatic disease that is highly homologous to human breast cancer. Most canine tumors fail to raise effective immune reactions yet, some spontaneous remissions do occur. Hybrid canine dendritic cell-tumor cell fusion vaccines were designed to enhance antigen presentation and tumor immune recognition. Peripheral blood-derived autologous dendritic cell enriched populations were isolated from dogs based on CD11c(+) expression and fused with canine mammary tumor (CMT) cells for vaccination of laboratory Beagles. These hybrid cells were injected into popliteal lymph nodes of normal dogs, guided by ultrasound, and included CpG-oligonucleotide adjuvants. Three rounds of vaccination were delivered. Significant IgG responses were observed in all vaccinated dogs compared to vehicle-injected controls. Canine IgG antibodies recognized shared CMT antigens as was demonstrated by IgG-recognition of three unrelated/independently derived CMT cell lines, and recognition of freshly isolated, unrelated, primary biopsy-derived CMT cells. A bias toward an IgG2 isotype response was observed after two vaccinations in most dogs. Neither significant cytotoxic T cell responses were detected, nor adverse or side-effects due to vaccination or due to the induced immune responses noted. These data provide proof-of-principle for this cancer vaccine strategy and demonstrate the presence of shared CMT antigens that promote immune recognition of mammary cancer. PMID 21069323

Resistance to the proapoptotic effects of interferon-gamma on melanoma cells used in patient-specific dendritic cell immunotherapy is associated with improved overall survival.
Jan 2011 | Cornforth, A N; Fowler, A W; Carbonell, D J; Dillman, R O
The use of whole cell tumor vaccines and various means of loading antigen onto dendritic cells have been under investigation for over a decade. Induction of apoptosis and the exposure of immune-stimulating proteins are thought to be beneficial for the use in immunotherapy protocols, but conclusive evidence in the clinical setting has been lacking. Incubation of melanoma cell lines with interferon-gamma (IFN-γ) increased phosphatidylserine and calreticulin exposure, but not in the IFN-γ-resistant cell line Lu-1205. Short-term autologous melanoma cell lines used for loading dendritic cells for immunotherapy showed differential response to the pro-apoptotic effects of IFN-γ. These IFN-γ-treated tumor cells (TCs) were irradiated and used for loading antigen for dendritic cell therapy. A log-rank comparison of survival for patients whose TCs were found to be either sensitive (upregulated phosphatidylserine and calreticulin) or insensitive to IFN-γ revealed a strongly significant correlation to progression-free (p = 0.003) and overall survival (p = 0.002) favorably in those patients whose cell lines were resistant to the proapoptotic effect of IFN-γ. These results suggest that the use of IFN-γ in anti-melanoma dendritic cell-based immunotherapy may only be beneficial when the cells do not undergo apoptosis in response to IFN-γ and support the contention that the use of some apoptotic cells in vaccines may be detrimental. PMID 20960187

Wild-type and modified gp100 peptide-pulsed dendritic cell vaccination of advanced melanoma patients can lead to long-term clinical responses independent of the peptide used.
Jan 2011 | Lesterhuis, W Joost; Schreibelt, Gerty; Scharenborg, Nicole M; Brouwer, H Mary-lène H; Gerritsen, Marie-Jeanne P; Croockewit, Sandra; Coulie, Pierre G; Torensma, Ruurd; Adema, Gosse J; Figdor, Carl G; de Vries, I Jolanda M; Punt, Cornelis J A
Dendritic cell (DC)-based immunotherapy is explored worldwide in cancer patients. Several strategies have been employed to load DC with antigen, including peptide loading. To increase immunogenicity of peptides, major histocompatibility complex (MHC) class I binding affinity and stability of peptide-MHC complexes at the cell surface may be improved by modification of the amino acid sequence. In this study, we compared the capacity of DC loaded with wild-type versus modified gp100 peptides with higher binding affinities to induce an immune and clinical response in advanced melanoma patients. Metastatic HLA-A2.1(+) melanoma patients were vaccinated intravenously (on average 25 × 10(6) DC) and intradermally (on average 11 × 10(6) DC) with mature DC loaded with keyhole limpet hemocyanin (KLH) together with tyrosinase peptide and either wild-type (15 patients) or modified (12 patients) gp100 peptides. All vaccinated patients showed a pronounced proliferative T cell or humoral response against KLH. Gp100-specific T cell responses were monitored in post-treatment delayed type hypersensitivity (DTH) skin biopsies by tetramer and functional analysis. Antigen-specific T cells were found in 2 of 15 patients vaccinated with wild-type gp100-loaded DC, versus 1 of 12 patients vaccinated with modified peptide-loaded DC. These three patients also had the best clinical response, with long-term (>8 years) complete responses in two patients, one in each group. We conclude that vaccination with peptide-loaded DC can result in long-term clinical responses in a minority of metastatic melanoma patients, and that the use of modified as compared to wild-type gp100 peptides for DC loading does not result in a relevant enhanced immune responses. PMID 21069321

Recent developments in cancer vaccines.
Jan 2011 | Palucka, Karolina; Ueno, Hideki; Banchereau, Jacques
The adoptive transfer of cancer Ag-specific effector T cells in patients can result in tumor rejection, thereby illustrating the immune system potential for cancer therapy. Ideally, one would like to directly induce efficient tumor-specific effector and memory T cells through vaccination. Therapeutic vaccines have two objectives: priming Ag-specific T cells and reprogramming memory T cells (i.e., a transformation from one type of immunity to another, for example, regulatory to cytotoxic). Recent successful phase III clinical trials showing benefit to the patients revived cancer vaccines. Dendritic cells (DCs) are essential in generation of immune responses, and as such represent targets and vectors for vaccination. We have learned that different DC subsets elicit different T cells. Similarly, different activation methods result in DCs able to elicit distinct T cells. We contend that a careful manipulation of activated DCs will allow cancer immunotherapists to produce the next generation of highly efficient cancer vaccines. PMID 21248270

Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with {alpha}-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma.
Jan 2011 | Okada, Hideho; Kalinski, Pawel; Ueda, Ryo; Hoji, Aki; Kohanbash, Gary; Donegan, Teresa E; Mintz, Arlan H; Engh, Johnathan A; Bartlett, David L; Brown, Charles K; Zeh, Herbert; Holtzman, Matthew P; Reinhart, Todd A; Whiteside, Theresa L; Butterfield, Lisa H; Hamilton, Ronald L; Potter, Douglas M; Pollack, Ian F; Salazar, Andres M; Lieberman, Frank S
A phase I/II trial was performed to evaluate the safety and immunogenicity of a novel vaccination with α-type 1 polarized dendritic cells (αDC1) loaded with synthetic peptides for glioma-associated antigen (GAA) epitopes and administration of polyinosinic-polycytidylic acid [poly(I:C)] stabilized by lysine and carboxymethylcellulose (poly-ICLC) in HLA-A2(+) patients with recurrent malignant gliomas. GAAs for these peptides are EphA2, interleukin (IL)-13 receptor-α2, YKL-40, and gp100. PMID 21149657

Vaccination with dendritic cell/tumor fusion cells results in cellular and humoral antitumor immune responses in patients with multiple myeloma.
Jan 2011 | Rosenblatt, Jacalyn; Vasir, Baldev; Uhl, Lynne; Blotta, Simona; Macnamara, Claire; Somaiya, Poorvi; Wu, Zekui; Joyce, Robin; Levine, James D; Dombagoda, Dilani; Yuan, Yan Emily; Francoeur, Karen; Fitzgerald, Donna; Richardson, Paul; Weller, Edie; Anderson, Kenneth; Kufe, Donald; Munshi, Nikhil; Avigan, David
We have developed a tumor vaccine in which patient-derived myeloma cells are chemically fused with autologous dendritic cells (DCs) such that a broad spectrum of myeloma-associated antigens are presented in the context of DC-mediated costimulation. We have completed a phase 1 study in which patients with multiple myeloma underwent serial vaccination with the DC/multiple myeloma fusions in conjunction with granulocyte-macrophage colony-stimulating factor. DCs were generated from adherent mononuclear cells cultured with granulocyte-macrophage colony-stimulating factor, interleukin-4, and tumor necrosis factor-α and fused with myeloma cells obtained from marrow aspirates. Vaccine generation was successful in 17 of 18 patients. Successive cohorts were treated with 1 × 10(6), 2 × 10(6), and 4 × 10(6) fusion cells, respectively, with 10 patients treated at the highest dose level. Vaccination was well tolerated, without evidence of dose-limiting toxicity. Vaccination resulted in the expansion of circulating CD4 and CD8 lymphocytes reactive with autologous myeloma cells in 11 of 15 evaluable patients. Humoral responses were documented by SEREX (Serologic Analysis of Recombinant cDNA Expression Libraries) analysis. A majority of patients with advanced disease demonstrated disease stabilization, with 3 patients showing ongoing stable disease at 12, 25, and 41 months, respectively. Vaccination with DC/multiple myeloma fusions was feasible and well tolerated and resulted in antitumor immune responses and disease stabilization in a majority of patients. PMID 21030562

[WT1 peptide pulsed dendritic cell therapy with activated T lymphocytes therapy for advanced cancers].
Jan 2011 | Kato, Yoichi
We assessed the efficacy of WT1 peptide pulsed dendritic cell (DC) therapy for various advanced cancers. All patients were vaccinated 5 times for 10 weeks with autologous monocytes derived DC and activated T lymphocytes. We treated a total of 26 patients who had HLA-A2402 or/and HLA-A0201. We evaluated 20 of the 26 patients who finished 5-time vaccination (10 men and 10 women, aged 48-81 years, Mean 64 years) and were diagnosed as follows: 3-pancreas cancer, 2-colorectal, 2-breast, 2-esophageal, 2-lung, 2-uterus, 2-ovarian and 5 others. In Clinical response (RECIST), the result was assessed as CR/PR/SD/PD, 0/7/8/5, respectively. Furthermore, the 7 PRs were resulted from 2-colorectal, and one of each was lung, laryngeal, axis, pancreas and smooth muscle sarcoma cancer. The 4 of 7 PR patients were treated with chemotherapy. PMID 21224534

Gene carriers and transfection systems used in the recombination of dendritic cells for effective cancer immunotherapy.
Jan 2011 | Chen, Yu-Zhe; Yao, Xing-Lei; Tabata, Yasuhiko; Nakagawa, Shinsaku; Gao, Jian-Qing
Dendritic cells (DCs) are the most potent antigen-presenting cells. They play a vital role in the initiation of immune response by presenting antigens to T cells and followed by induction of T-cell response. Reported research in animal studies indicated that vaccine immunity could be a promising alternative therapy for cancer patients. However, broad clinical utility has not been achieved yet, owing to the low transfection efficiency of DCs. Therefore, it is essential to improve the transfection efficiency of DC-based vaccination in immunotherapy. In several studies, DCs were genetically engineered by tumor-associated antigens or by immune molecules such as costimulatory molecules, cytokines, and chemokines. Encouraging results have been achieved in cancer treatment using various animal models. This paper describes the recent progress in gene delivery systems including viral vectors and nonviral carriers for DC-based genetically engineered vaccines. The reverse and three-dimensional transfection systems developed in DCs are also discussed. PMID 21197274

Immunogenicity of dendritic cells pulsed with CEA peptide or transfected with CEA mRNA for vaccination of colorectal cancer patients.
Dec 2010 | Lesterhuis, W Joost; De Vries, I Jolanda M; Schreibelt, G; Schuurhuis, Danita H; Aarntzen, Erik H; De Boer, Annemiek; Scharenborg, Nicole M; Van De Rakt, Mandy; Hesselink, Erik J; Figdor, Carl G; Adema, Gosse J; Punt, Cornelis J A
Dendritic cells (DCs) are the professional antigen-presenting cells of the immune system. We have demonstrated that vaccination of autologous ex vivo cultured DCs results in the induction of tumor-specific immune responses in cancer patients, which correlates with clinical response. Optimization of antigen loading is one of the possibilities for further improving the efficacy of DC vaccination. Theoretically, transfection of DCs with RNA encoding a tumor-specific antigen may induce a broader immune response as compared to the most widely used technique of peptide pulsing. PMID 21187495

Guiding the "misguided" - functional conditioning of dendritic cells for the DC-based immunotherapy against tumours.
Dec 2010 | Huang, Fang-Ping; Chen, Yu-Xiao; To, Christina Kw
The concept of DC-based tumour vaccine has been tested both clinically and experimentally for the past two decades. Even though only limited success has been achieved to date, DC vaccination remains a promising immunological approach against tumours and deserves further exploration. It aims to elicit and establish specific immunity to destroy tumours. By such an approach, DC are used not only as a vector to deliver tumour antigens, but also as a "natural adjuvant" to boost vaccine efficacy. Tumours are however of mutated "self", to which the host immune system is essentially tolerated in the absence of external perturbation otherwise. Such a live cell-based approach is unfortunately extremely sensitive to, hence its efficacy inevitably limited by, the tumour microenvironment. Certain immunosuppressive mechanisms triggered by the tumour cells are therefore major obstacles against successful DC vaccination. Attempts have since been made in order to overcome these hurdles. This brief review summarises some of the earlier and current findings, and compares the effectiveness of various approaches used in these studies. It focuses particularly on strategies aimed at enhancing DC immunogenicity, through molecular modifications and functional conditioning of the cell vectors, targeting both the positive and negative regulators of DC functions. By dissecting the roles of DC in immunity versus tolerance induction, and the very mechanisms underlying autoimmunity, we examine further and try to explain how the suppressed or "misguided" immunity may be alternatively switched-on and more effectively redirected for cancer therapy. PMID 21182072

Sipuleucel-T: in metastatic castration-resistant prostate cancer.
Dec 2010 | Plosker, Greg L
Sipuleucel-T is an autologous active cellular immunotherapy used in the treatment of men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (CRPC). It is the first therapeutic cancer vaccine to receive US FDA approval. Approximately 3 days prior to each infusion of sipuleucel-T, patients undergo a leukapheresis procedure for collection of autologous peripheral blood mononuclear cells. Preparation of sipuleucel-T involves enrichment for antigen-presenting cells from the leukapheresis product and activation ex vivo with a recombinant fusion protein (PA2024). In the randomized, double-blind, placebo-controlled IMPACT study in patients with metastatic CRPC, sipuleucel-T was associated with a 22% relative reduction in the risk of death (hazard ratio 0.78; p = 0.03), which was the primary endpoint of the trial. After a median follow-up period of 34.1 months, median survival was 4.1 months longer with sipuleucel-T than placebo (25.8 vs 21.7 months). There was no significant between-group difference for the median time to objective disease progression (a secondary endpoint). Almost all patients treated with sipuleucel-T in clinical trials reported an adverse event, although these were mild or moderate in severity (grade 1 or 2) in most patients. The most common adverse events (e.g. infusion-related events, such as chills and fever) generally occurred within the first day after administration of sipuleucel-T and resolved within 2 days. PMID 21175243

Induction of cellular immune responses in patients with stage-I multiple myeloma after vaccination with autologous idiotype-pulsed dendritic cells.
Dec 2010 | Röllig, Christoph; Schmidt, Christian; Bornhäuser, Martin; Ehninger, Gerhard; Schmitz, Marc; Auffermann-Gretzinger, Susanne
Idiotype vaccines have shown both biological efficacy and clinical benefit in lymphoma. Circulating idiotype proteins (Id) in multiple myeloma patients offer a suitable target for immunotherapy. So far, specific immune responses after vaccination with Ids have been evaluated mostly in advanced myeloma. We explored the potential of dendritic-cell (DC)-based immunotherapy in 9 patients with stage-I disease. Mature monocyte-derived Id-pulsed DCs and keyhole limpet hemocyanin (KLH) were administered at dose levels between 2 and 20×10⁶ cells. Patients received 5 immunizations every 4 weeks. A median number of 6.8×10⁶ DCs were administered per vaccination. Five out of 9 patients (56%) developed Id-specific T cells as showed in proliferation assays and 8 out of 9 patients (89%) showed specific T-cell-mediated cytokine release after Id stimulation. The cytokine-secretion did not show a distinct Th1-type or Th2-type pattern. The M protein dropped slightly in 3 out of 9 patients. We could show that DC-based Id vaccination is a feasible way of inducing specific T-cell responses in stage-I myeloma patients. Further trials are needed to increase the rate of responses and to define the role of DC-based vaccination in the era of new pharmacologic therapies. PMID 21150718

New approaches to the development of adenoviral dendritic cell vaccines in melanoma.
Dec 2010 | Butterfield, Lisa H; Vujanovic, Lazar
Considerable research in the field of immunotherapy for melanoma has demonstrated that this tumor type can be responsive to therapeutic immune activation strategies. In early clinical trials, vaccine strategies using dendritic cells (DCs) and adenovirus (Ad) vectors (AdVs) were safe and immunogenic, and induced clinical responses in a minority of patients. Research from the past several years has yielded an improved mechanistic understanding of DC biology, AdV effects on DCs and the crosstalk that occurs between antigen-loaded DCs and specific lymphocyte subsets. This knowledge base is being combined with technological advances in cytokine delivery, AdV design and in vivo DC targeting. These developments are leading to novel AdV-transduced DC-based therapeutic modalities that may further advance melanoma immunotherapy. Interactions between AdVs and DCs, initial clinical trial results, and new developments in DC engineering and in AdV biology are reviewed. PMID 21154122

Vaccination with dendritic cells charged with apoptotic/necrotic B16 melanoma induces the formation of subcutaneous lymphoid tissue.
Dec 2010 | Mac Keon, Soledad; Gazzaniga, Silvina; Mallerman, Julieta; Bravo, Alicia I; Mordoh, José; Wainstok, Rosa
Antigen presentation by dendritic cells (DC) is of key importance for the initiation of the primary immune response. Mice vaccinated with DC charged with apoptotic/necrotic B16 cells (DC-Apo/Nec) are protected against B16 challenge. The aim of this study was to assess vaccine cell migration in our system and to find out if there is an immunological response taking place at the vaccination site. The formation of a pseudocapsule, peripheral node addresin expression in small venules, and the recruitment of a wide variety of cellular populations, including macrophages, polymorphonuclear lymphocytes, and CD8+ and CD4+ T lymphocytes found in association with DC, evidenced the formation of tertiary lymphoid tissue in the vaccination site in our experimental system. PMID 20937314

[Auto-dendritic cell vaccines pulsed with PSA, PSMA and PAP peptides for hormone-refractory prostate cancer].
Nov 2010 | Zhuang, Zhi-Xiang; Shen, Li-Qin; Shi, Yang; Lu, Xiao; Shi, Hong-Zhen
To investigate the clinical safety and effects of auto-dendritic cells pulsed with HLA-A201-binding peptides prostate-specific antigen (PSA) , prostate-specific membrane antigen (PSMA) and prostatic acid phosphatase (PAP) in the treatment of hormone-refractory metastatic prostate cancer (HRPC). PMID 21090344

Improved clinical outcome in indolent B-cell lymphoma patients vaccinated with autologous tumor cells experiencing immunogenic death.
Nov 2010 | Zappasodi, Roberta; Pupa, Serenella M; Ghedini, Gaia C; Bongarzone, Italia; Magni, Michele; Cabras, Antonello D; Colombo, Mario P; Carlo-Stella, Carmelo; Gianni, Alessandro M; Di Nicola, Massimo
Increasing evidence argues that the success of an anticancer treatment may rely on immunoadjuvant side effects including the induction of immunogenic tumor cell death. Based on the assumption that this death mechanism is a similar prerequisite for the efficacy of an active immunotherapy using killed tumor cells, we examined a vaccination strategy using dendritic cells (DC) loaded with apoptotic and necrotic cell bodies derived from autologous tumors. Using this approach, clinical and immunologic responses were achieved in 6 of 18 patients with relapsed indolent non-Hodgkin's lymphoma (NHL). The present report illustrates an impaired ability of the neoplastic cells used to vaccinate nonresponders to undergo immunogenic death on exposure to a cell death protocol based on heat shock, γ-ray, and UVC ray. Interestingly, when compared with doxorubicin, this treatment increased surface translocation of calreticulin and cellular release of high-mobility group box 1 and ATP in histologically distinct NHL cell lines. In contrast, treated lymphoma cells from responders displayed higher amounts of calreticulin and heat shock protein 90 (HSP90) compared with those from nonresponders and boosted the production of specific antibodies when loaded into DCs for vaccination. Accordingly, the extent of calreticulin and HSP90 surface expression in the DC antigenic cargo was significantly associated with the clinical and immunologic responses achieved. Our results indicate that a positive clinical effect is obtained when immunogenically killed autologous neoplastic cells are used for the generation of a DC-based vaccine. Therapeutic improvements may thus be accomplished by circumventing the tumor-impaired ability to undergo immunogenic death and prime the antitumor immune response. PMID 20884630

A randomized trial of ex vivo CD40L activation of a dendritic cell vaccine in colorectal cancer patients: tumor-specific immune responses are associated with improved survival.
Nov 2010 | Barth, Richard J; Fisher, Dawn A; Wallace, Paul K; Channon, Jacqueline Y; Noelle, Randolph J; Gui, Jiang; Ernstoff, Marc S
To determine whether an autologous dendritic cell (DC) vaccine could induce antitumor immune responses in patients after resection of colorectal cancer metastases and whether these responses could be enhanced by activating DCs with CD40L. PMID 20884622

Dendritic cells transfected with Her2 antigen-encoding RNA replicons cross-prime CD8 T cells and protect mice against tumor challenge.
Nov 2010 | Edlich, Birgit; Hogdal, Leah J; Rehermann, Barbara; Behrens, Sven-Erik
Antigen-specific T cells can be induced by direct priming and cross-priming. To investigate cross-priming as a vaccination approach dendritic cells were transfected with cytopathogenic viral RNA-replicons that expressed domains of the tumor-associated Her2-antigen and injected into MHC-discordant mice that did not allow direct priming. Upon tumor challenge 75% of the vaccinated, but none of the mock-vaccinated mice remained tumor-free. The anti-tumor effect required T cells and correlated with the vigor of the cross-primed CD8 T cell response. Her2-specific antibodies were not detected. This study highlights the potential of T cell cross-priming in cancer immunotherapy. PMID 20887827

Dendritic cell-based immunotherapy for prostate cancer.
Nov 2010 | Jähnisch, Hanka; Füssel, Susanne; Kiessling, Andrea; Wehner, Rebekka; Zastrow, Stefan; Bachmann, Michael; Rieber, Ernst Peter; Wirth, Manfred P; Schmitz, Marc
Dendritic cells (DCs) are professional antigen-presenting cells (APCs), which display an extraordinary capacity to induce, sustain, and regulate T-cell responses providing the opportunity of DC-based cancer vaccination strategies. Thus, clinical trials enrolling prostate cancer patients were conducted, which were based on the administration of DCs loaded with tumor-associated antigens. These clinical trials revealed that DC-based immunotherapeutic strategies represent safe and feasible concepts for the induction of immunological and clinical responses in prostate cancer patients. In this context, the administration of the vaccine sipuleucel-T consisting of autologous peripheral blood mononuclear cells including APCs, which were pre-exposed in vitro to the fusion protein PA2024, resulted in a prolonged overall survival among patients with metastatic castration-resistant prostate cancer. In April 2010, sipuleucel-T was approved by the United States Food and Drug Administration for prostate cancer therapy. PMID 21076523

RIG-I helicase-independent pathway in sendai virus-activated dendritic cells is critical for preventing lung metastasis of AT6.3 prostate cancer.
Nov 2010 | Kato, Tomonori; Ueda, Yasuji; Kinoh, Hiroaki; Yoneyama, Yasuo; Matsunaga, Akinao; Komaru, Atsushi; Harada, Yui; Suzuki, Hiroyoshi; Komiya, Akira; Shibata, Satoko; Hasegawa, Mamoru; Hayashi, Hideki; Ichikawa, Tomohiko; Yonemitsu, Yoshikazu
We recently demonstrated highly efficient antitumor immunity against dermal tumors of B16F10 murine melanoma with the use of dendritic cells (DCs) activated by replication-competent, as well as nontransmissible-type, recombinant Sendai viruses (rSeV), and proposed a new concept, "immunostimulatory virotherapy," for cancer immunotherapy. However, there has been little information on the efficacies of this method: 1) in more clinically relevant situations including metastatic diseases, 2) on other tumor types and other animal species, and 3) on the related molecular/cellular mechanisms. In this study, therefore, we investigated the efficacy of vaccinating DCs activated by fusion gene-deleted nontransmissible rSeV on a rat model of lung metastasis using a highly malignant subline of Dunning R-3327 prostate cancer, AT6.3. rSeV/dF-green fluorescent protein (GFP)-activated bone marrow-derived DCs (rSeV/dF-GFP-DC), consistent with results previously observed in murine DCs. Vaccination of rSeV/dF-GFP-DC was highly effective at preventing lung metastasis after intravenous loading of R-3327 tumor cells, compared with the effects observed with immature DCs or lipopolysaccharide-activated DCs. Interestingly, neither CTL activity nor DC trafficking showed any apparent difference among groups. Notably, rSeV/dF-DCs expressing a dominant-negative mutant of retinoic acid-inducible gene I (RIG-I) (rSeV/dF-RIGIC-DC), an RNA helicase that recognizes the rSeV genome for inducing type I interferons, largely lost the expression of proinflammatory cytokines without any impairment of antitumor activity. These results indicate the essential role of RIG-I-independent signaling on antimetastatic effect induced by rSeV-activated DCs and may provide important insights to DC-based immunotherapy for advanced malignancies. PMID 21076616

Dendritic cell vaccine in addition to FOLFIRI regimen improve antitumor effects through the inhibition of immunosuppressive cells in murine colorectal cancer model.
Nov 2010 | Kim, Hye-Sung; Park, Hye-Mi; Park, Jung-Sun; Sohn, Hyun-Jung; Kim, Sung-Guh; Kim, Hyung-Jin; Oh, Seong-Taek; Kim, Tai-Gyu
Although chemotherapy is still one of the best treatments for most cancers, immunotherapies such as dendritic cell (DC) vaccines have emerged as an alternative protocol for destroying residual tumors. In this study, we investigated antitumor effects of the combined therapy using DC vaccine and irinotecan plus infusional 5-fluorouracil and leucovorin (FOLFIRI) which have been clinically used for the treatment of colorectal cancer. A maximum tolerated dose of FOLFIRI was preliminarily determined for MC38/CEA2 colorectal cancer model. Vaccination with DC expressing carcinoembryonic antigen (CEA) enhanced antitumor effect after FOLFIRI treatment. The combined therapy also increased CEA-specific Th1 and cytotoxic T-cell responses. Interestingly, although FOLFIRI treatment rather showed a rebound in the number of myeloid-derived suppressor cells (MDSC) and regulatory T-cells (Treg) after 14 days, additional DC vaccine could inhibit the rebound of these immunosuppressive cells. Furthermore, mice cured by the combined therapy showed antigen-specific T-cell responses and resistance against challenge of MC38/CEA2 compared with mice cured with FOLFIRI. These results demonstrated that DC vaccine in addition to FOLFIRI regimen could improve antitumor effects through the inhibition of immunosuppressive tumor environments in murine colorectal cancer model, and may provide knowledge useful for the design of chemo-immunotherapeutic strategies for the treatment of colorectal carcinoma in clinical trials. PMID 20883737

Personalized cancer vaccines.
Nov 2010 | Jain, Kewal K
Personalized medicine has extended to management of cancer and implies prescription of specific therapeutics best suited for an individual patient and the type of tumor. These principles have been applied to cancer vaccines. PMID 20979567

Chemokine-mediated distribution of dendritic cell subsets in renal cell carcinoma.
Nov 2010 | Middel, Peter; Brauneck, Sven; Meyer, Werner; Radzun, Heinz-Joachim
Renal cell carcinoma (RCC) represents one of the most immunoresponsive cancers. Antigen-specific vaccination with dendritic cells (DCs) in patients with metastatic RCC has been shown to induce cytotoxic T-cell responses associated with objective clinical responses. Thus, clinical trials utilizing DCs for immunotherapy of advanced RCCs appear to be promising; however, detailed analyses concerning the distribution and function of DC subsets in RCCs are lacking. PMID 20969772

A pilot study on the immunogenicity of dendritic cell vaccination during adjuvant oxaliplatin/capecitabine chemotherapy in colon cancer patients.
Oct 2010 | Lesterhuis, W J; de Vries, I J M; Aarntzen, E A; de Boer, A; Scharenborg, N M; van de Rakt, M; van Spronsen, D-J; Preijers, F W; Figdor, C G; Adema, G J; Punt, C J A
Dendritic cell (DC) vaccination has been shown to induce anti-tumour immune responses in cancer patients, but so far its clinical efficacy is limited. Recent evidence supports an immunogenic effect of cytotoxic chemotherapy. Pre-clinical data indicate that the combination of chemotherapy and immunotherapy may result in an enhanced anti-cancer activity. Most studies have focused on the immunogenic aspect of chemotherapy-induced cell death, but only few studies have investigated the effect of chemotherapeutic agents on the effector lymphocytes of the immune system. PMID 20924373

Dendritic cells-mediated CTLs targeting hepatocellular carcinoma stem cells.
Oct 2010 | Sun, Jian-cong; Pan, Ke; Chen, Min-shan; Wang, Qi-jing; Wang, Hui; Ma, Hai-qing; Li, Yong-qiang; Liang, Xiao-ting; Li, Jian-jun; Zhao, Jing-jing; Chen, Yi-bing; Pang, Xiong-hao; Liu, Wang-li; Cao, Yun; Guan, Xin-yuan; Lian, Qi-zhou; Xia, Jian-chuan
Immunotherapy, especially using dendritic cells (DCs)-based vaccine, appears promising in the treatment of hepatocellular carcinoma (HCC) following surgery. However, the therapeutic efficacy of current DC vaccines loaded with HCC antigen is limited in clinical practice. One important reason might be that the DC vaccines for the treatment of HCC were not aimed at targeting the hepatocellular carcinoma cancer stem cells (HCCCSCs). Therefore, establishing an immunotherapy to kill HCC stem cells could be a novel therapeutic strategy. In this study, we have developed an immunotherapy to target CD133(+) HCC cells in the treatment of HCC. This study had three main findings; (1) CD133(+)HCC cells RNA loaded DCs could induce special CD8(+) cytotoxic T lymphocytes (CD133(+)Huh7-CTLs) response against CD133(+) Huh7 cells in vitro. (2) Huh7 cells-induced tumor growth in vivo was effectively inhibited by CD133(+)Huh7-CTLs. (3) the great inhibition potential of CD133(+)Huh7-CTLs to Huh7-induced tumor growth might not be only associated with anti-tumor cytokines such as IFNγ, but also to CD133(+)Huh7-DCs induced specific CTLs. This study shows an experimental proof that CD133(+)HCC cells RNA loaded DC vaccine has potential in treating HCC and may provide a new therapy for clinical post operative adjuvant therapy in future. PMID 20581468

Comparative analysis of cytotoxic T lymphocyte response induced by dendritic cells loaded with hepatocellular carcinoma -derived RNA or cell lysate.
Oct 2010 | Pan, Ke; Zhao, Jing-jing; Wang, Hui; Li, Jian-jun; Liang, Xiao-ting; Sun, Jian-cong; Chen, Yi-bing; Ma, Hai-qing; Liu, Qing; Xia, Jian-chuan
The choice of the tumor antigen preparation used for dendritic cell (DC) loading is important for optimizing DC vaccines. In the present study, we compared DCs pulsed with hepatocellular carcinoma (HCC) total RNA or cell lysates for their capacity to activate T cells. We showed here that HCC total RNA pulsed-DCs induced effector T lymphocyte responses which showed higher killing ability to HCC cell lines, as well as higher frequency of IFN-γ producing of CD4+ and CD8+ T cells when compared with lysate pulsed-DCs. Both of RNA and lysate loading did not influence the changes of mature DC phenotype and the capacity of inducing T cell proliferation. However, HCC lysate loading significantly inhibited the production of inflammatory cytokines IL-12p70, IFN-γ and enhanced the secretion of anti-inflammatory cytokines IL-10 of mature DCs. Our results indicated that DCs loaded with HCC RNA are superior to that loaded with lysate in priming anti-HCC CTL response, suggesting that total RNA may be a better choice for DCs-based HCC immunotherapy. PMID 20975822

Dendritic-cell tumor vaccines.
Oct 2010 | Rolinski, J; Hus, I
Most cancers remain incurable. Introduction of novel therapeutic methods, including new cytostatic regimens and targeted therapies, such as monoclonal antibodies and tyrosine kinase inhibitors, have increased remission rates as well as improved patient survival, but the ability to cure many cancer patients remains elusive. It is thus necessary to further develop alternative strategies to improve patient prognosis. The majority of patients who respond to induction therapy inevitably relapse, mainly because of the proliferation of residual malignant cells that have escaped control by induction chemotherapy. Therefore the eradication of minimal residual disease may be crucial to prevent a relapse and achieve a long-term remission. It seems that an advantageous treatment option may be cellular immunotherapy with dendritic-cell vaccines which might induce long-term specific anticancer responses with immune memory cells, which could contribute to effective and lasting elimination of malignant cells. PMID 20970677

Genetically modified dendritic cells in cancer immunotherapy: a better tomorrow?
Oct 2010 | Shurin, Michael R; Gregory, Melissa; Morris, John C; Malyguine, Anatoli M
Dendritic cells (DC) are powerful antigen-presenting cells that induce and maintain primary cytotoxic T lymphocyte (CTL) responses directed against tumor antigens. Consequently, there has been much interest in their application as antitumor vaccines. PMID 20955111

Dendritic cell vaccination in combination with anti-CD25 monoclonal antibody treatment: a phase I/II study in metastatic melanoma patients.
Oct 2010 | Jacobs, Joannes F M; Punt, Cornelis J A; Lesterhuis, W Joost; Sutmuller, Roger P M; Brouwer, H Mary-Lène H; Scharenborg, Nicole M; Klasen, Ina S; Hilbrands, Luuk B; Figdor, Carl G; de Vries, I Jolanda M; Adema, Gosse J
The success of cancer immunotherapy depends on the balance between effector T cells and suppressive immune regulatory mechanisms within the tumor microenvironment. In this study we investigated whether transient monoclonal antibody-mediated depletion of CD25(high) regulatory T cells (Treg) is capable of enhancing the immunostimulatory efficacy of dendritic cell vaccines. PMID 20736326

Multicenter phase II study of matured dendritic cells pulsed with melanoma cell line lysates in patients with advanced melanoma.
Oct 2010 | Ribas, Antoni; Camacho, Luis H; Lee, Sun Min; Hersh, Evan M; Brown, Charles K; Richards, Jon M; Rodriguez, Maria Jovie; Prieto, Victor G; Glaspy, John A; Oseguera, Denise K; Hernandez, Jackie; Villanueva, Arturo; Chmielowski, Bartosz; Mitsky, Peggie; Bercovici, Nadège; Wasserman, Ernesto; Landais, Didier; Ross, Merrick I
Several single center studies have provided evidence of immune activation and antitumor activity of therapeutic vaccination with dendritic cells (DC) in patients with metastatic melanoma. The efficacy of this approach in patients with favorable prognosis metastatic melanoma limited to the skin, subcutaneous tissues and lung (stages IIIc, M1a, M1b) was tested in a multicenter two stage phase 2 study with centralized DC manufacturing. PMID 20875102

Phase I study of autologous dendritic cell tumor vaccine in patients with non-small cell lung cancer.
Sep 2010 | Um, Soo-Jung; Choi, Young Jin; Shin, Ho-Jin; Son, Cheol Hun; Park, You-Soo; Roh, Mee Sook; Kim, Yun Seong; Kim, Young Dae; Lee, Soo-Keol; Jung, Min Ho; Lee, Min Ki; Son, Choonhee; Choi, Pil Jo; Chung, Jooseop; Kang, Chi-Dug; Lee, Eun-Yup
A dendritic cell vaccine has been developed as a novel strategy for generating antitumor immunity in the treatment of cancer. The purpose of this study was to assess the maximal tolerated dose, safety, and immunologic response of a new dendritic cell vaccine (DC-Vac) into which tumor lysate was loaded by electroporation and pulse in patients with advanced non-small cell lung cancer (NSCLC). PMID 20223553

Vaccination with autologous dendritic cells pulsed with multiple tumor antigens for treatment of patients with malignant melanoma: results from a phase I/II trial.
Sep 2010 | Trepiakas, Redas; Berntsen, Annika; Hadrup, Sine Reker; Bjørn, Jon; Geertsen, Poul F; Straten, Per Thor; Andersen, Mads H; Pedersen, Anders E; Soleimani, Amir; Lorentzen, Torben; Johansen, Julia S; Svane, Inge Marie
Dendritic cells are regarded as the most effective antigen presenting cells and coordinators of the immune response and therefore suitable as vaccine basis. Here we present results from a clinical study in which patients with malignant melanoma (MM) with verified progressive disease received vaccination with autologous monocyte-derived mature dendritic cells (DC) pulsed with p53, survivin and telomerase-derived peptides (HLA-A2+ patients) or with autologous/allogeneic tumor lysate (HLA-A2(−) patients) in combination with low-dose interleukin (IL)-2 and interferon (IFN)-alpha2b. PMID 20429791

IFN{gamma} markedly cooperates with intratumoral dendritic cell vaccine in dog tumor models.
Sep 2010 | Mito, Kai; Sugiura, Kikuya; Ueda, Kana; Hori, Takako; Akazawa, Takashi; Yamate, Jyoji; Nakagawa, Hiroshi; Hatoya, Shingo; Inaba, Muneo; Inoue, Norimitsu; Ikehara, Susumu; Inaba, Toshio
Dendritic cell (DC)-based immunotherapy can trigger effective immune responses against cancer in human patients. Although accompanied by little toxicity, further improvements are needed to optimize immune responses for fully satisfactory clinical outcomes. IFNγ, a potent inducer of T helper type 1 immune responses, is considered an important tool to realize improvements. In this study, we sought to clarify the effect of IFNγ on the maturation and activation of DCs and the clinical outcome of DC-based cancer therapy in dogs. In vitro experiments indicated that IFNγ significantly enhanced the expression of immune stimulatory molecules and interleukin-12 by DCs derived from canine monocytes. IFNγ also significantly strengthened DC-mediated growth suppression against tumor cell lines. DC inoculation with concomitant delivery of IFNγ into primary or recurrent tumors elicited significant clinical responses, including four complete responses and two partial responses against malignant tumors, also eliciting partial responses against benign but actively growing tumors. Together, our results indicate that combining IFNγ and DCs could induce strong immune responses against tumors, significantly improving clinical outcomes. The present study of dogs bearing common types of cancer in humans offers a unique line of support for the development of human cancer therapies. PMID 20823157

Harnessing naturally occurring tumor immunity: a clinical vaccine trial in prostate cancer.
Sep 2010 | Frank, Mayu O; Kaufman, Julia; Tian, Suyan; Suárez-Fariñas, Mayte; Parveen, Salina; Blachère, Nathalie E; Morris, Michael J; Slovin, Susan; Scher, Howard I; Albert, Matthew L; Darnell, Robert B
Studies of patients with paraneoplastic neurologic disorders (PND) have revealed that apoptotic tumor serves as a potential potent trigger for the initiation of naturally occurring tumor immunity. The purpose of this study was to assess the feasibility, safety, and immunogenicity of an apoptotic tumor-autologous dendritic cell (DC) vaccine. PMID 20824184

Dendritic cell vaccination of patients with metastatic colorectal cancer.
Sep 2010 | Burgdorf, Stefan K
Colorectal cancer is with more than 4000 new cases every year the third most common cancer in Denmark. Metastases are most often found in the liver, and 20-25% of the patients have synchronous metastases to the liver at time of primary diagnosis. Other frequent sites for metastases are lungs and lymph nodes. Without treatment the median survival for patients with metastatic colorectal cancer is 7-9 months. Patients receiving systemic or regional chemotherapy now have a median survival of approximately 20 months. Up to 40% of the patients undergoing intended curative surgery subsequently relapse with local or distant disease, and approximately 80% of the relapses appear within the first 3 years. If the cancer metastasises, and the chances of radical surgery are eliminated, the prognosis is poor. The aim of the present study was to evaluate the clinical and immunological effects of treating patients with disseminated colorectal cancer with a dendritic cell based cancer vaccine (MelCancerVac). The vaccine consisted of dendritic cells generated from autologous mononuclear cells pulsed with an allogeneic tumor cell lysate, selected for its high expression of cancer associated antigens. A clinical phase I study evaluating tolerability and toxicity of the treatment was established. Six patients with progressive disease were included and the analysis revealed that the treatment was well tolerated and not associated with toxicity. A subsequent clinical phase II study evaluating the activity of the treatment with CT-scan based measurements of tumors (RECIST), self reported quality of life (SF-36), and clinical evaluation was established. Out of twenty included patients with progressive disease, seventeen received intervention with the vaccine. Stable disease was achieved in four patients and two of these remained stable throughout the entire study period. Quality of life remained for most parameters included in the evaluation high and stable. The immunological consequences of the treatment were evaluated with plasma- and serum-levels of inflammatory and non-inflammatory markers (the following 10 cytokines: GM-CSF, INF-gamma, IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and TNF-alpha, and in addition the inflammatory chemokines MIP-1beta, Eotaxin and IP-10) and biomarkers CEA and TIMP-1. These analyses showed that the vaccine induced increasing levels of Th1 cytokines such as GM-CSF, TNF-alpha, IFN-gamma, and IL-2 in patients achieving stable disease. Patients with progressive disease had increasing levels of CEA and TIMP-1, while patients achieving stable disease maintained relatively stable levels. Conclusively, treatment with this dendritic cell based cancer vaccine was non-toxic and safe, clinical response in terms of stable disease was achieved in 24% of the patients, and the patients maintained a high quality of life during treatment. The immunological analyses indicated that the treatment resulted in favourable anticancer responses in the patients' immune system in terms of polarisation towards a Th1 dominated response potentially directed against tumor cells. Since no partial or complete responses were observed and since the number of patients was relatively low these results have to be interpreted with caution. Moreover, phase II study designs do not lead to final conclusions regarding clinical efficacy, which must be validated in larger prospective, randomised and controlled studies. PMID 20816019

Tumor cell lysate-pulsed dendritic cells induce a T cell response against colon cancer in vitro and in vivo.
Aug 2010 | Wu, Yu-gang; Wu, Guang-zhou; Wang, Liang; Zhang, Yan-Yun; Li, Zhong; Li, De-Chun
To investigate whether tumor cell lysate-pulsed (TP) dendritic cells (DCs) induce cytotoxic T lymphocyte (CTL) activity against colon cancer in vitro and in vivo. Hematopoietic progenitor cells were magnetically isolated from BALB/c mice bone marrow cells. These cells were cultured with cytokines GM-CSF, IL-4, and TNFalpha to induce their maturation. They were analyzed by morphological observation and phenotype analysis. DCs were pulsed with tumor cell lysate obtained by rapid freezing and thawing at a 1:3 DC:tumor cell ratio. CTL activity and interferon gamma (IFNgamma) secretion was evaluated ex vivo. In order to determine whether or not vaccination with CT26 TP DCs induce the therapeutic potential in the established colon tumor model, CT26 colon tumor cells were implanted subcutaneously (s.c.) in the midflank of naïve BALB/c mice. Tumor-bearing mice were injected with vaccination with CT26 TP DCs on days 3 and 10. Tumor growth was assessed every 2-3 days. Finally, CTL activity and IFNgamma secretion were evaluated in immunized mice. Hematopoietic progenitor cells from mice bone marrow cells cultured with cytokines for 8 days showed the character of typical mature DCs. Morphologically, these cells were large with oval or irregularly shaped nuclei and with many small dendrites. Phenotypically, FACS analysis showed that they expressed high levels of MHC II, CD11b, CD80, and CD86 antigen, and were negative for CD8alpha. However, immature DCs cultured with cytokines for 5 days did not have typical DCs phenotypic markers. Ex vivo primed T cells with CT26 TP DCs were able to induce effective CTL activity against CT26 tumor cells, but not B16 tumor cells (E:T = 100:1, 60.36 +/- 7.11% specific lysis in CT26 group vs. 17.36 +/- 4.10% specific lysis in B16 group), and produced higher levels of IFNgamma when stimulated with CT26 tumor cells but not when stimulated with B16 tumor cells (1210.33 +/- 72.15 pg/ml in CT26 group vs. 182.25 +/- 25.51 pg/ml in B16 group, P < 0.01). Vaccination with CT26 TP DCs could induce anti-tumor immunity against CT26 colon tumor in murine therapeutic models (tumor volume on day 19: CT26 TP DCs 342 +/- 55 mm(3) vs. the other control groups, P < 0.05). In addition, all splenic CD3(+) T cells obtained from mice vaccinated with CT26 TP DCs produced high levels of IFNgamma and shown specific cytotoxic activity against CT26 tumor cells, but no cytotoxic activity when stimulated with B16 tumor cells. Tumor cell lysate-pulsed DCs can induce tumor-specific CTL activity against colon cancer in vitro and in vivo. PMID 19669608

Optimizing dendritic cell-based immunotherapy in multiple myeloma: intranodal injections of idiotype-pulsed CD40 ligand-matured vaccines led to induction of type-1 and cytotoxic T-cell immune responses in patients.
Aug 2010 | Yi, Qing; Szmania, Susann; Freeman, John; Qian, Jianfei; Rosen, Nancy A; Viswamitra, Sanjaya; Cottler-Fox, Michele; Barlogie, Bart; Tricot, Guido; van Rhee, Frits
Vaccination with idiotype (Id) protein-pulsed dendritic cells (DCs) has been explored in multiple myeloma and the results have been disappointing. To improve the efficacy of DC vaccination in myeloma, we investigated the use of Id- and keyhole limpet haemocyanin (KLH)-pulsed, CD40 ligand-matured DCs administered intranodally. Nine patients with smouldering or stable myeloma without treatment were enrolled and DC vaccines were administered at weekly intervals for a total of four doses. Following vaccination, all patients mounted Id-specific gamma-interferon T-cell response. Interleukin-4 response was elicited in two, and skin delayed-type hypersensitivity reaction occurred in seven patients. More importantly, Id-specific cytotoxic T-cell responses were also detected in five patients. Most if not all patients mounted a positive T-cell response to KLH following vaccination. At 1-year follow-up, six of the nine patients had stable disease, while three patients had slowly progressive disease even during the vaccination period. At 5-year follow-up, four of the six patients continued with stable disease. No major side effects were noted. In summary, intranodal administration of Id-pulsed CD40 ligand-matured DCs was able to induce Id-specific T and B-cell responses in patients. Current efforts are geared towards breaking tumour-mediated immune suppression and improving clinical efficacy of this immunotherapy. PMID 20618329

Induction of complete and molecular remissions in acute myeloid leukemia by Wilms' tumor 1 antigen-targeted dendritic cell vaccination.
Aug 2010 | Van Tendeloo, Viggo F; Van de Velde, Ann; Van Driessche, Ann; Cools, Nathalie; Anguille, Sébastien; Ladell, Kristin; Gostick, Emma; Vermeulen, Katrien; Pieters, Katrien; Nijs, Griet; Stein, Barbara; Smits, Evelien L; Schroyens, Wilfried A; Gadisseur, Alain P; Vrelust, Inge; Jorens, Philippe G; Goossens, Herman; de Vries, I Jolanda; Price, David A; Oji, Yusuke; Oka, Yoshihiro; Sugiyama, Haruo; Berneman, Zwi N
Active immunization using tumor antigen-loaded dendritic cells holds promise for the adjuvant treatment of cancer to eradicate or control residual disease, but so far, most dendritic cell trials have been performed in end-stage cancer patients with high tumor loads. Here, in a phase I/II trial, we investigated the effect of autologous dendritic cell vaccination in 10 patients with acute myeloid leukemia (AML). The Wilms' tumor 1 protein (WT1), a nearly universal tumor antigen, was chosen as an immunotherapeutic target because of its established role in leukemogenesis and superior immunogenic characteristics. Two patients in partial remission after chemotherapy were brought into complete remission after intradermal administration of full-length WT1 mRNA-electroporated dendritic cells. In these two patients and three other patients who were in complete remission, the AML-associated tumor marker returned to normal after dendritic cell vaccination, compatible with the induction of molecular remission. Clinical responses were correlated with vaccine-associated increases in WT1-specific CD8+ T cell frequencies, as detected by peptide/HLA-A*0201 tetramer staining, and elevated levels of activated natural killer cells postvaccination. Furthermore, vaccinated patients showed increased levels of WT1-specific IFN-gamma-producing CD8+ T cells and features of general immune activation. These data support the further development of vaccination with WT1 mRNA-loaded dendritic cells as a postremission treatment to prevent full relapse in AML patients. PMID 20631300

Advances in cellular therapy for the treatment of thyroid cancer.
Jul 2010 | Papewalis, Claudia; Ehlers, Margret; Schott, Matthias
Up to now, there are no curative therapies available for the subset of metastasized undifferentiated/anaplastic thyroid carcinomas. This review describes the possible use of immunocompetent cells which may help to restore the antitumor immune recognition for treating an existing tumor or preventing its recurrence. The most prominent experimental strategy is the use of dendritic cells (DCs) which are highly potent in presenting tumor antigens. Activated DCs subsequently migrate to draining lymph nodes where they present antigens to naïve lymphocytes and induce cytotoxic T cells (CTL). Alternatively to DC therapy, adoptive cell transfer may be performed by either using natural killer cells or ex vivo maturated CTLs. Within this review article we will focus on recent advances in the understanding of anti-tumor immune responses, for example, in thyroid carcinomas including the advances which have been made for the identification of potential tumor antigens in thyroid malignancies. PMID 20671939

Tumor antigen presentation by dendritic cells.
Jul 2010 | Petersen, Troels R; Dickgreber, Nina; Hermans, Ian F
Tumor cells are generally regarded as poor stimulators of naive T cells. In contrast, dendritic cells (DCs) are highly specialized in this function, and are therefore likely to be important intermediaries in the process of stimulating T cell responses to tumors. While providing solid evidence that DCs participate in antitumor immunity has proved difficult, several lines of evidence point in this direction. First, animal models involving bone marrow chimeras have shown that cells of hematopoeitic origin are required to elicit T cell responses to whole-tumor vaccines. Second, compared with other cells of hematopoeitic origin, DCs are particularly well-equipped to cross-present exogenous antigens to CD8+ T cells, a critical function if intermediary cells are involved. Third, tumor-infiltrating DCs purified from tumor samples have the capacity to cross-present tumor antigens in vitro. Finally, priming of anti-tumor T cell responses can be abrogated in new in vivo models in which DCs can be specifically depleted. It is therefore significant that DCs in cancer patients are often kept in an immature or dysfunctional state, thereby preventing stimulation of tumor-specific T cells. This review describes the different steps required for DCs to elicit T cell responses to tumor-associated antigens, and highlights processes that are amenable to intervention as therapy. We conclude that effective anti-tumor activity may be dependent on the ability to re-program DCs resident in the host, perhaps even when transferred autologous DCs generated ex vivo are used as vaccines. In this context, recruiting the activity of cells of the innate immune system to condition host DCs may help elicit more effective T cell-mediated responses. PMID 20666707

Human myeloid dendritic cells for cancer therapy: does maturation matter?
Jul 2010 | Skalova, Katerina; Mollova, Klara; Michalek, Jaroslav
Dendritic cells form the connection between innate and adoptive mechanisms of the immune system. As antigen-presenting cells, dendritic cells are capable of presenting tumour antigen and effectively stimulating immune response targeted against a tumour. A number of preclinical and clinical studies document dendritic cells' potential in anti-cancer treatment. Increasing knowledge of dendritic cell biology is leading to improved methods for their preparation for clinical application. Unfortunately, there is to date no consensus specifying optimal conditions for dendritic cell preparation in vitro. This review summarizes the methods used for preparing myeloid dendritic cells derived from monocytic precursors while focusing on cytokine cocktails used for their growth, maturation, and functional adjustment. PMID 20665974

Toll-like receptor expression and function in human dendritic cell subsets: implications for dendritic cell-based anti-cancer immunotherapy.
Jul 2010 | Schreibelt, Gerty; Tel, Jurjen; Sliepen, Kwinten H E W J; Benitez-Ribas, Daniel; Figdor, Carl G; Adema, Gosse J; de Vries, I Jolanda M
Dendritic cells (DCs) are central players of the immune response. To date, DC-based immunotherapy is explored worldwide in clinical vaccination trials with cancer patients, predominantly with ex vivo-cultured monocyte-derived DCs (moDCs). However, the extensive culture period and compounds required to differentiate them into DCs may negatively affect their immunological potential. Therefore, it is attractive to consider alternative DC sources, such as blood DCs. Two major types of naturally occurring DCs circulate in peripheral blood, myeloid DCs (mDCs) and plasmacytoid (pDCs). These DC subsets express different surface molecules and are suggested to have distinct functions. Besides scavenging pathogens and presenting antigens, DCs secrete cytokines, all of which is vital for both the acquired and the innate immune system. These immunological functions relate to Toll-like receptors (TLRs) expressed by DCs. TLRs recognize pathogen-derived products and subsequently provoke DC maturation, antigen presentation and cytokine secretion. However, not every TLR is expressed on each DC subset nor causes the same effects when activated. Considering the large amount of clinical trials using DC-based immunotherapy for cancer patients and the decisive role of TLRs in DC maturation, this review summarizes TLR expression in different DC subsets in relation to their function. Emphasis will be given to the therapeutic potential of TLR-matured DC subsets for DC-based immunotherapy. PMID 20204387

Personalized dendritic cell-based tumor immunotherapy.
Jul 2010 | Janikashvili, Nona; Larmonier, Nicolas; Katsanis, Emmanuel
Advances in the understanding of the immunoregulatory functions of dendritic cells (DCs) in animal models and humans have led to their exploitation as anticancer vaccines. Although DC-based immunotherapy has proven clinically safe and efficient to induce tumor-specific immune responses, only a limited number of objective clinical responses have been reported in cancer patients. These relatively disappointing results have prompted the evaluation of multiple approaches to improve the efficacy of DC vaccines. The topic of this review focuses on personalized DC-based anticancer vaccines, which in theory have the potential to present to the host immune system the entire repertoire of antigens harbored by autologous tumor cells. We also discuss the implementation of these vaccines in cancer therapeutic strategies, their limitations and the future challenges for effective immunotherapy against cancer. PMID 20161666

Prostate cancer as a model for tumour immunotherapy.
Jul 2010 | Drake, Charles G
Advances in basic immunology have led to an improved understanding of the interactions between the immune system and tumours, generating renewed interest in approaches that aim to treat cancer immunologically. As clinical and preclinical studies of tumour immunotherapy illustrate several immunological principles, a review of these data is broadly instructive and is particularly timely now that several agents are beginning to show evidence of efficacy. This is especially relevant in the case of prostate cancer, as recent approval of sipuleucel-T by the US Food and Drug Administration marks the first antigen-specific immunotherapy approved for cancer treatment. Although this Review focuses on immunotherapy for prostate cancer, the principles discussed are applicable to many tumour types, and the approaches discussed are highlighted in that context. PMID 20651745

Global sensitivity analysis and model-based reactive scheduling of targeted cancer immunotherapy.
Jul 2010 | Kiran, Kanchi Lakshmi; Lakshminarayanan, S
Intra-patient variability is a key challenge in cancer treatment. This makes it necessary to find the factors affecting tumor growth and accordingly schedule therapies over the treatment horizon for the patient. In this work, model-based studies are performed to investigate these issues for optimal immunotherapeutic intervention. Dendritic cell therapy is a targeted immunotherapy where the dendritic cells and its activating agents such as interleukin are engineered, stimulated to recognize and specifically eradicate tumors. A mathematical model that integrates tumor dynamics and dendritic cell therapy is used to perform the analysis. Global sensitivity analysis of the model is done using high dimensional model reduction (HDMR) technique and the key parameters altering the tumor growth are identified. The variations in these key parameters are deemed to result in intra-patient variability during the treatment phase. Then, reactive scheduling is used to schedule dendritic cell interventions with and without interleukin interventions under the varying conditions of the patient. Moreover, the key parameters obtained from HDMR are verified using the reactive scheduling and nominal scheduling approaches. Besides saving costs, the in silico analysis done in this paper may be useful to the oncology community in designing experiments to clinically measure the influential parameters. It can also be used as a decision making tool to determine the required intervention dosage during the treatment. PMID 20639123

Potent anti-tumor responses to immunization with dendritic cells loaded with tumor tissue and an NKT cell ligand.
Jul 2010 | Petersen, Troels R; Sika-Paotonu, Dianne; Knight, Deborah A; Dickgreber, Nina; Farrand, Kathryn J; Ronchese, Franca; Hermans, Ian F
Cancer immunotherapy is well tolerated and specific, but its efficacy remains variable. To enhance anti-tumor CD8(+) T-cell responses induced by immunization with antigen-loaded dendritic cells (DCs), we explored the impact of eliciting a potent source of T-cell help from activated invariant natural killer (NK)-like T cells (iNKT cells) using the specific glycolipid ligand alpha-galactosylceramide (alpha-GalCer). As cytokines released by iNKT cells may drive proliferation of CD4(+)CD25(+) regulatory T cells (Tregs), we assessed this immunization strategy in animals treated with anti-CD25 antibody to inactivate Treg function. Combining DC immunization with iNKT cell activation was found to significantly enhance anti-tumor activity, which was improved further by the prior inactivation of Tregs. The improved anti-tumor activity with Treg inactivation was associated with a prolonged proliferative burst of responding CD8(+) T cells. We could find no evidence that inclusion of alpha-GalCer in the vaccine enhanced Treg numbers, or that the 'helper' function of iNKT cells was improved in the absence of Treg activity. Rather, the two activities appeared to act independently to improve the tumor-specific T-cell response. Inactivating regulatory T cells and eliciting iNKT cell activation are therefore two useful strategies that can be used in combination to improve anti-tumor immunization with antigen-loaded DCs. PMID 20142835

Anti-HER2 vaccines: new prospects for breast cancer therapy.
Jun 2010 | Ladjemi, Maha Zohra; Jacot, William; Chardès, Thierry; Pèlegrin, André; Navarro-Teulon, Isabelle
Each year, breast cancer accounts for more than 400,000 new cancer cases and more than 130,000 cancer deaths in Europe. Prognosis of nonmetastatic breast cancer patients is directly related to the extent of the disease, mainly nodal spreading and tumor size, and to the molecular profile, particularly HER2 over-expression. In patients with HER2-over-expressing tumors, different studies have shown cellular and/or humoral immune responses against HER2 associated with a lower tumor development at early stages of the disease. These findings have led to the hypothesis that the generation of an anti-HER2 immune response should protect patients from HER2-over-expressing tumor growth. Taken together with the clinical efficiency of trastuzumab-based anti-HER2 passive immunotherapy, these observations allowed to envisage various vaccine strategies against HER2. The induction of a stable and strong immunity by cancer vaccines is expected to lead to establishment of immune memory, thereby preventing tumor recurrence. However, an immunological tolerance against HER2 antigen exists representing a barrier to effective vaccination against this oncoprotein. As a consequence, the current challenge for vaccines is to find the best conditions to break this immunological tolerance. In this review, we will discuss the different anti-HER2 vaccine strategies currently developed; considering the strategies having reached the clinical phases as well as those still in preclinical development. The used antigen can be either composed of tumoral allogenic cells or autologous cells, or specific to HER2. It can be delivered by dendritic cells or in a DNA, peptidic or proteic form. Another area of research concerns the use of anti-idiotypic antibodies mimicking HER2. PMID 20532501

Generation of myeloma-specific T cells using dendritic cells loaded with MUC1- and hTERT- drived nonapeptides or myeloma cell apoptotic bodies.
Jun 2010 | Ocadlikova, D; Kryukov, F; Mollova, K; Kovarova, L; Buresdova, I; Matejkova, E; Penka, M; Buchler, T; Hajek, R; Michalek, J
Dendritic cells are able to induce anti-tumor immune responses by presenting tumor-specific antigens to T-lymphocytes. Various tumor-associated antigens have been studied in multiple myeloma in an effort to find a strong antigen capable of generating clinically meaningful responses in vaccinated patients. The aim of our study was to generate myeloma-specific cytotoxic T lymphocytes in vitro using dendritic cells loaded with peptide antigens or apoptotic bodies. Peripheral blood mononuclear cells from HLA-A2+ healthy donors were used for isolation and culture of dendritic cells (DCs) and T lymphocytes. DCs were loaded with hTERT- and MUC1-derived nonapeptides or apoptotic bodies from myeloma cells. Repeated stimulation of T lymphocytes led to their activation characterized by interferon-gamma production. Activated T lymphocytes were separated immunomagnetically and expanded in vitro. Specific cytotoxicity of the expanded T lymphocytes was tested against a myeloma cell line. There was evidence of cytotoxicity for all three types of antigens used for T lymphocyte priming and expansion. No statistically significant differences were observed in T lymphocyte cytotoxicity for any of the antigens. We present a method for the priming and expansion of myeloma-specific T lymphocytes using dendritic cells loaded with different types of tumor antigens. Cytotoxic T lymphocytes and/or activated dendritic cells generated by the described methods can be applied for cellular immunotherapy against multiple myeloma and other malignancies. PMID 20568900

Alpha-type 1-polarized dendritic cells loaded with apoptotic allogeneic myeloma cell line induce strong CTL responses against autologous myeloma cells.
Jun 2010 | Yang, Deok-Hwan; Kim, Mi-Hyun; Hong, Cheol Yi; Lee, Youn-Kyung; Jin, Chun-Ji; Pham, Thanh-Nhan Nguyen; Ahn, Jae-Sook; Bae, Woo-Kyun; Kim, Yeo-Kyeoung; Chung, Ik-Joo; Kim, Hyeoung-Joon; Kalinski, Pawel; Lee, Je-Jung
To induce a potent cytotoxic T lymphocyte (CTL) response, various tumor antigens should be loaded onto dendritic cells (DCs). In multiple myeloma (MM), it is difficult to obtain a sufficient number of autologous tumor cells as a source of tumor antigens in the clinical setting. We investigated the feasibility of immunotherapy in patients with MM, using myeloma-specific CTLs generated in vitro by alpha-type 1-polarized DCs (alphaDC1s) loaded with the ultraviolet B-irradiated allogeneic myeloma cell line, ARH77. alphaDC1s significantly increased the expression of several costimulatory molecules without differences in loading with tumor antigens. alphaDC1s showed a high production of interleukin-12 during maturation and after subsequent stimulation with CD40L but were not significantly affected by loading tumor antigens. Myeloma-specific CTLs against autologous myeloma cells from MM patients were induced by alphaDC1s pulsed with apoptotic ARH77 cells. Our data indicate that autologous DCs loaded with an allogeneic myeloma cell line can generate potent myeloma-specific CTL responses against autologous myeloma cells and might provide a practical method for cellular immunotherapy in patients with MM. PMID 20238114

Consolidative dendritic cell-based immunotherapy elicits cytotoxicity against malignant mesothelioma.
Jun 2010 | Hegmans, Joost P; Veltman, Joris D; Lambers, Margaretha E; de Vries, I Jolanda M; Figdor, Carl G; Hendriks, Rudi W; Hoogsteden, Henk C; Lambrecht, Bart N; Aerts, Joachim G
We previously demonstrated that dendritic cell-based immunotherapy induced protective antitumor immunity with a prolonged survival rate in mice. However, the clinical relevance is still in question. To examine this, we designed a clinical trial using chemotherapy followed by antigen-pulsed dendritic cell vaccination in mesothelioma patients. PMID 20167848

Polarized dendritic cells as cancer vaccines: directing effector-type T cells to tumors.
Jun 2010 | Kalinski, Pawel; Okada, Hideho
Ex vivo generation and antigen loading of dendritic cells (DCs) from cancer patients helps to bypass the dysfunction of endogenous DCs. It also allows to control the process of DC maturation and to imprint in maturing DCs several functions essential for induction of effective forms of cancer immunity. Recent reports from several groups including ours demonstrate that distinct conditions of DC generation and maturation can prime DCs for preferential interaction with different (effector versus regulatory) subsets of immune cells. Moreover, differentially-generated DCs have been shown to imprint different effector mechanisms in CD4(+) and CD8(+) T cells (delivery of "signal three") and to induce their different homing properties (delivery of "signal four"). These developments allow for selective induction of tumor-specific T cells with desirable effector functions and tumor-relevant homing properties and to direct the desirable types of immune cells to tumors. PMID 20409732

Cutting edge: delay and reversal of T cell tolerance by intratumoral injection of antigen-loaded dendritic cells in an autochthonous tumor model.
May 2010 | Higham, Eileen M; Shen, Ching-Hung; Wittrup, K Dane; Chen, Jianzhu
The tumor environment exerts a powerful suppressive influence on infiltrating tumor-reactive T cells. It induces tolerance of adoptively transferred effector T cells as they enter tumors and maintains the tolerance of persisting tumor-infiltrating T cells. In an autochthonous prostate cancer model, in which tumor-reactive CD8 T cells are trackable, we demonstrate that both depletion of endogenous dendritic cells (DCs) and intratumoral injection of Ag-loaded mature DCs delayed the tolerization of tumor-infiltrating effector CD8 T cells. Intratumoral injection of Ag-loaded DCs also reactivated tolerized CD8 T cells in the tumor tissue. The observed effects lasted as long as the injected DCs persisted. These findings are consistent with a critical role of DCs in modulating T cell reactivity in the tumor environment. They also suggest new potential strategies to extend the functionality of transferred effector T cells and to restore function to tolerized tumor-infiltrating T cells for cancer immunotherapy. PMID 20427765

INGN-225: a dendritic cell-based p53 vaccine (Ad.p53-DC) in small cell lung cancer: observed association between immune response and enhanced chemotherapy effect.
May 2010 | Chiappori, Alberto A; Soliman, Hatem; Janssen, William E; Antonia, Scott J; Gabrilovich, Dmitry I
Novel approaches are needed for patients with small cell lung cancer (SCLC), as response after relapse is poor with standard therapies. p53 gene mutations often occur, resulting in tumoral protein overexpression and allowing for their recognition by p53-specific cytotoxic T cells. PMID 20420527

Dendritic cells pulsed with an anti-idiotype antibody mimicking Her-2/neu induced protective antitumor immunity in two lines of Her-2/neu transgenic mice.
May 2010 | Saha, Asim; Chatterjee, Sunil K
Her-2/neu proto-oncogene is overexpressed in 20-30% of human breast cancers and is associated with high recurrence risk. To test the efficacy of immune-based strategies in eliciting an antitumor response, we have evaluated the vaccine potential of an anti-idiotype (Id) antibody, 6D12 in tolerant hosts. Immunization of human Her-2/neu transgenic mice with 6D12-pulsed dendritic cells (DC) could reverse Her-2/neu unresponsiveness and result in the induction of Her-2/neu-specific humoral and cellular immune responses and protection against tumors expressing Her-2/neu. Furthermore, the tumor rejection in 6D12-pulsed DC immunized mice was associated with development of memory response. Vaccination of transgenic female FVB-neuN mice that carry the rat Her-2/neu oncogene, markedly delayed tumor onset and developed significantly fewer spontaneous mammary tumors compared with mice treated with control vaccine. Tumor growth inhibition was associated with the induction of Her-2/neu-specific immune responses. These data suggest the potential use of anti-Id antibody 6D12 as a vaccine for immunotherapy of Her-2/neu-positive human cancer. PMID 20236626

Increase of circulating CD4+CD25highFoxp3+ regulatory T cells in patients with metastatic renal cell carcinoma during treatment with dendritic cell vaccination and low-dose interleukin-2.
Apr 2010 | Berntsen, Annika; Brimnes, Marie Klinge; thor Straten, Per; Svane, Inge Marie
Regulatory T cells (Treg) play an important role in the maintenance of immune tolerance and may be one of the obstacles of successful tumor immunotherapy. In this study, we analyzed the impact of administration of dendritic cell (DC) vaccination in combination with low-dose interleukin (IL)-2 in patients with metastatic renal cell carcinoma on the frequency of CD4+CD25highFoxp3+ Treg cells in peripheral blood. We found that the treatment increased the frequency of Treg cells more than 7-fold compared with pretreatment levels (P<0.0001). The frequency of Treg cells decreased when patients had been off IL-2 treatment for only 8 days, but remained higher than pretreatment levels. A functional assay showed that isolated Treg cells were capable of inhibiting proliferation of responder cells. Also, in vitro studies showed that coculture of mature DCs, autologous T cells and IL-2 leads to an increase in the number of Treg cells whereas IL-21 does not stimulate the induction of Treg cells. These findings demonstrate that even low doses of IL-2 in combination with DC vaccination are able to expand CD4+CD25+Foxp3+ Treg cells in vivo in metastatic renal cell carcinoma patients. Further, the results indicate that the IL-2-induced effect on Treg cells is reversible and declines shortly after termination of IL-2 treatment. Our data suggest that approaches combining DC-mediated immunotherapy and depletion of Treg cells may be necessary to enhance the ability of vaccination therapy to elicit effective antitumor responses in cancer patients. Also, adjuvant IL-21 administration may lead to immune enhancement without simultaneous induction of Treg cells. PMID 20386464

What's the place of immunotherapy in malignant mesothelioma treatments?
Apr 2010 | Grégoire, Marc
Malignant pleural mesothelioma (MPM) is a rare malignancy of the pleura with a very poor prognosis. Treatments evaluated for malignant mesothelioma, including chemotherapy, radiotherapy and surgery are of limited efficacy. However, the fact that the tumors of some patients with MPM regress spontaneously or respond to immunotherapy suggests that the immune system may respond to MPM under some circumstances. In this respect, animal studies have demonstrated immunoreactivity of MPM to different immunotherapies. In the case of MPM, several clinical studies have demonstrated a correlation between the presence of a lymphocyte infiltrate and a better prognosis and humoral response directed against specific antigens related to tumor. Thus, MPM immunotherapy is undoubtedly a highly promising but also very challenging approach to the treatment of this disease that has slipped through the defense lines of the immune system. This article reviews past and recent developments of the clinical strategies that concern immunotherapy of mesothelioma. PMID 20179421

Current status of immunological therapies for prostate cancer.
Apr 2010 | Antonarakis, Emmanuel S; Drake, Charles G
Considerable progress has been made in prostate cancer immunotherapy over the last year, and two agents have completed phase III testing. This review will discuss the most promising immune-directed strategies in development for prostate cancer, outlining interventions that mitigate tumor-induced tolerance and highlighting several combination immunotherapy approaches. PMID 20179598

Building on dendritic cell subsets to improve cancer vaccines.
Apr 2010 | Palucka, Karolina; Ueno, Hideki; Zurawski, Gerard; Fay, Joseph; Banchereau, Jacques
T cells can reject established tumors when adoptively transferred into patients, thereby demonstrating that the immune system can be harnessed for cancer therapy. However, such passive immunotherapy is unlikely to maintain memory T cells that might control tumor outgrowth on the long term. Active immunotherapy with vaccines has the potential to induce tumor-specific effector and memory T cells. Vaccines act through dendritic cells (DCs) which induce, regulate, and maintain T cell immunity. Clinical trials testing first generation DC vaccines pulsed with tumor antigens provided a proof-of-principle that therapeutic immunity can be elicited. The increased knowledge of the DC system, including the existence of distinct DC subsets is leading to new trials which aim at improved immune and clinical outcomes. PMID 20226644

Antigen-specific polyclonal cytotoxic T lymphocytes induced by fusions of dendritic cells and tumor cells.
Apr 2010 | Koido, Shigeo; Homma, Sadamu; Hara, Eiichi; Namiki, Yoshihisa; Ohkusa, Toshifumi; Gong, Jianlin; Tajiri, Hisao
The aim of cancer vaccines is induction of tumor-specific cytotoxic T lymphocytes (CTLs) that can reduce the tumor mass. Dendritic cells (DCs) are potent antigen-presenting cells and play a central role in the initiation and regulation of primary immune responses. Thus, DCs-based vaccination represents a potentially powerful strategy for induction of antigen-specific CTLs. Fusions of DCs and whole tumor cells represent an alternative approach to deliver, process, and subsequently present a broad spectrum of antigens, including those known and unidentified, in the context of costimulatory molecules. Once DCs/tumor fusions have been infused back into patient, they migrate to secondary lymphoid organs, where the generation of antigen-specific polyclonal CTL responses occurs. We will discuss perspectives for future development of DCs/tumor fusions for CTL induction. PMID 20379390

Differential effects of Paclitaxel on dendritic cell function.
Apr 2010 | John, Justin; Ismail, Mohammed; Riley, Catherine; Askham, Jonathan; Morgan, Richard; Melcher, Alan; Pandha, Hardev
The potential utility of dendritic cells (DC) as cancer vaccines has been established in early trials in human cancers. The concomitant administration of cytotoxic agents and DC vaccines has been previously avoided due to potential immune suppression by chemotherapeutics. Recent studies show that common chemotherapy agents positively influence adaptive and innate anti-tumour immune responses. PMID 20302610

The choice of the antigen in the dendritic cell-based vaccine therapy for prostate cancer.
Mar 2010 | Matera, Lina
Tumor antigens (TA) are promising candidates for targeted treatment of prostate cancer (PCa). Critical issues in the preparation of dendritic cell (DC)-based TA vaccines are the DC maturation state and the appropriateness of the TA. Prostate-specific antigen (PSA) and prostate acide pshosphatase (PAP) presented by DC have produced encouraging results and PAP-loaded DCs are at late-stage development for PCa patients. TAs indispensable for tumor survival and propagation are now emerging as first choice TAs for future vaccines. The increased expression and enzymatic activity of prostate specific membrane antigen (PSMA) and prostate stem cell antigen (PSCA) by aggressive prostate tumors is indicative of a unique, selective advantage on the part of cells expressing them. Human telomerase reverse transcriptase (hTERT) and survivin are both involved in tumor cell survival and considered universal TAs. The T cell epitope potential of peptides derived from these TAs has been defined by computer-assisted prediction programs and has been tested in vitro and in vivo in terms of their ability to recruit cytotoxic T lymphocytes (CTL) and to be recognised as CTL targets. Results, reviewed here, show that anti-tumor immunity can be induced in vivo by DC loaded with both whole TAs and TA peptides. The promising, but still limited clinical success suggests further exploration of this immune therapy in the more appropriate setting of minimal disease. In advanced stages, vaccine can still be effective when combined with systemic or local cytoreductive therapies, which may overcome antigen specific tolerance and subvert the tumor immunosuppressive environment. PMID 19954892

Dendritic Cells-based Vaccine and Immune Monitoring for Hepatocellular Carcinoma.
Mar 2010 | Lee, Dae-Heui
Human tumors, including those of the hepatobiliary system, express a number of specific antigens that can be recognized by T cells, and may provide potential targets for cancer immunotherapy. Dendritic cells (DCs) are rare leucocytes that are uniquely potent in their ability to capture, process and present antigens to T cells. The ability to culture sufficient numbers of DCs from human bone marrow or blood progenitors has attracted a great deal of interest in their potential utilization in human tumor vaccination. CD34(+) peripheral blood stem cells (PBSCs) were obtained from a patient with a hepatocellular carcinoma. The PBSCs were cultured in the X-VIVO 20 medium supplemented with the Flt-3 Ligand (FL), GM-CSF, IL-4 and TNF-alpha for 12 days. The morphology and functions of the cells were examined. The generated cells had the typical morphology of DCs. When the DCs were reinjected into the same patient, an augmentation of the cytotoxic T lymphocyte (CTL) activity was observed. Concomitantly, an increase in the natural killer (NK) cell activity was also detected in the patient. These results suggest that DCs-based cancer immunotherapy may become an important treatment option for cancer patients in the future. PMID 20221274

Presentation of tumour antigens by dendritic cells and challenges faced.
Mar 2010 | Robson, Neil C; Hoves, Sabine; Maraskovsky, Eugene; Schnurr, Max
The use of dendritic cells (DCs) for the generation of anti-tumour immunity has been the focus of a vast array of scientific and clinical studies. The ability of DCs to present protein tumour antigens (T-Ags) to CD4(+) and CD8(+) T cells is pivotal to the success of therapeutic cancer vaccines. DC's specialised capacity to cross-present exogenous Ags onto major histocompatibility (MHC) class I molecules for the generation of T-Ag-specific cytotoxic T lymphocytes (CTLs) has made these cells the focal point of vaccine-based immunotherapy of cancer. However, although DC-based strategies can induce T cell responses in cancer patients, recent reviews of clinical studies demonstrate that DC-based approaches have essentially failed to meet their clinical end points. These findings highlight the need to re-evaluate the DC-based vaccine strategies and incorporate recent advancements in DC biology and tumour immunology. The current review considers the issues related to how best to target the Ag-processing pathway of DCs, the role of adjuvants, the appropriate conditioning of the DCs and strategies to overcome tumour-mediated immune escape. PMID 20116984

Generation of tumor-specific T lymphocytes using dendritic cell/tumor fusions and anti-CD3/CD28.
Feb 2010 | Rosenblatt, Jacalyn; Wu, Zekui; Vasir, Baldev; Zarwan, Corrine; Stone, Richard; Mills, Heidi; Friedman, Thea; Konstantinopoulos, Panagiotis A; Spentzos, Dimitrios; Ghebremichael, Musie; Stevenson, Kristen; Neuberg, Donna; Levine, James D; Joyce, Robin; Tzachanis, Dimitrios; Boussiotis, Vassiliki; Kufe, Donald; Avigan, David
Adoptive immunotherapy with tumor-specific T cells represents a promising treatment strategy for patients with malignancy. However, the efficacy of T-cell therapy has been limited by the ability to expand tumor-reactive cells with an activated phenotype that effectively target malignant cells. We have developed an anticancer vaccine in which patient-derived tumor cells are fused with autologous dendritic cells (DCs), such that a wide array of tumor antigens are presented in the context of DC-mediated costimulation. In this study, we demonstrate that DC/tumor fusions induce T cells that react with tumor and are dramatically expanded by subsequent ligation of the CD3/CD28 costimulatory complex. These T cells exhibit a predominantly activated phenotype as manifested by an increase in the percentage of cells expressing CD69 and interferon gamma. In addition, the T cells upregulate granzyme B expression and are highly effective in lysing autologous tumor targets. Targeting of tumor-specific antigen was demonstrated by the expansion of T cells with specificity for the MUC1 tetramer. Stimulation with anti-CD3/CD28 followed by DC/tumor fusions or either agent alone failed to result in a similar expansion of tumor-reactive T cells. Consistent with these findings, spectratyping analysis demonstrates selective expansion of T-cell clones as manifested by considerable skewing of the Vbeta repertoire following sequential stimulation with DC/tumor fusions and anti-CD3/CD28. Gene expression analysis was notable for the upregulation of inflammatory pathways. These findings indicate that stimulation with DC/tumor fusions provides a unique platform for subsequent expansion with anti-CD3/CD28 in adoptive T-cell therapy of cancer. PMID 20145548

Tocotrienols are good adjuvants for developing cancer vaccines.
Feb 2010 | Hafid, Sitti Rahma Abdul; Radhakrishnan, Ammu Kutty; Nesaretnam, Kalanithi
Dendritic cells (DCs) have the potential for cancer immunotherapy due to their ability to process and present antigens to T-cells and also in stimulating immune responses. However, DC-based vaccines have only exhibited minimal effectiveness against established tumours in mice and humans. The use of appropriate adjuvant enhances the efficacy of DC based cancer vaccines in treating tumours. PMID 20051142

Adjuvant dendritic cell-based tumour vaccination for children with malignant brain tumours.
Feb 2010 | Ardon, Hilko; De Vleeschouwer, Steven; Van Calenbergh, Frank; Claes, Laurence; Kramm, Christof M; Rutkowski, Stefan; Wolff, Johannes E A; Van Gool, Stefaan W
A large experience with dendritic cell (DC)-based vaccination for malignant brain tumours has been gained in adults. Here we focus on the results obtained in children with relapsed malignant brain tumours. PMID 19852061

Enhanced T-cell activation by immature dendritic cells loaded with HSP70-expressing heat-killed melanoma cells.
Feb 2010 | Knudsen, Susanne; Schardt, Anke; Buhl, Timo; Boeckmann, Lars; Schön, Michael P; Neumann, Christine; Haenssle, Holger A
Vaccination protocols that utilize dendritic cells (DCs) to elicit therapeutic immunity against tumors are the subject of intense research. Given that the capacity of DCs to cross-present antigens is physiologically low, there is considerable interest to develop strategies that enhance that pathway. In order to best exploit the enhanced cross-presentation of antigens bound to heat shock protein 70 (HSP70), we analysed melanoma cell preparations for their HSP70 expression. Western blotting revealed strong upregulation of HSP70 after heat-killing in contrast to UV-B irradiation. When the uptake of heat-killed necrotic cells by DCs at various levels of maturation was assessed, 61 +/- 7% of immature DCs (iDCs) internalized fluorescence-labelled necrotic material. Apoptotic material from UV-B-irradiated cells was internalized by only 48 +/- 5% of iDCs. Maturation-inducing cytokines did not affect the uptake when added simultaneously with the tumor cell preparations. Loading DCs with heat-necrotic or apoptotic melanoma cells slightly reduced CD83 expression while leaving CD208 (DC-LAMP) expression unchanged. As determined by IFN-gamma-detecting enzyme-linked-immunospot assays, iDCs loaded with heat-killed melanoma cells activated autologous T cells most effectively when used without any further maturation, whereas DCs loaded with apoptotic material required maturation. In conclusion, HSP70-expressing melanoma cells could be generated by heat-killing. Loading iDCs with heat-killed melanoma cells resulted in a superior priming of autologous T cells in vitro. PMID 19758341

Partial T cell-depleted allogeneic stem cell transplantation following reduced-intensity conditioning creates a platform for immunotherapy with donor lymphocyte infusion and recipient dendritic cell vaccination in multiple myeloma.
Feb 2010 | Levenga, Henriëtte; Schaap, Nicolaas; Maas, Frans; Esendam, Bennie; Fredrix, Hanny; Greupink-Draaisma, Annelies; de Witte, Theo; Dolstra, Harry; Raymakers, Reinier
Allogeneic stem cell transplantation (SCT) in multiple myeloma (MM) may induce a curative graft-versus-myeloma (GVM) effect. Major drawback in unmanipulated reduced-intensity conditioning (RIC) SCT is the risk of severe and longstanding graft-versus-host-disease (GVHD). This study demonstrates that transplantation with a partial T cell-depleted graft creates a platform for boosting GVM immunity by preemptive donor lymphocyte infusion (DLI) and recipient dendritic cell (DC) vaccination, with limited GVHD. All 20MM patients engrafted successfully. Chimerism analysis in 19 patients evaluable at 3 months revealed that 7 patients were complete donor, whereas 12 patients were mixed chimeric. Grade II acute GVHD (aGVHD) occurred in 7 patients (35%) and only 4 patients (21%) developed chronic GVHD (cGVHD). Fourteen patients received posttransplantation immunotherapy, 8 preemptive DLI, 5 patients both DLI and DC vaccination, and 1 patient DC vaccination only. DC vaccination was associated with limited toxicity, and none of these patients developed GVHD. Importantly, overall treatment-related mortality (TRM) at 1 year was low (10%). Moreover, the overall survival (OS) is 84% with median follow-up of 27 months, and none of the patients died from progressive disease. These findings illustrate that this novel approach is associated with limited GVHD and mortality, thus creating an ideal platform for adjuvant immunotherapy. PMID 19835972

The evolving role of dendritic cells in cancer therapy.
Feb 2010 | Ilett, E J; Prestwich, R J D; Melcher, A A
Dendritic cells (DC) are a clear choice for use in cancer immunotherapy, and much research has focused on generating DC for clinical use. Although DC therapy has been successful in inducing specific anti-tumour immune responses, these have rarely translated into clinical efficacy. PMID 20132058

Therapeutic and tumor-specific immunity induced by combination of dendritic cells and oncolytic adenovirus expressing IL-12 and 4-1BBL.
Feb 2010 | Huang, Jing-Hua; Zhang, Song-Nan; Choi, Kyung-Ju; Choi, Il-Kyu; Kim, Joo-Hang; Lee, Min-Geol; Lee, Mingul; Kim, Hoguen; Yun, Chae-Ok
Recently, gene-based cytokine treatment has been actively pursued as a new promising approach in treating cancer. In an effort to augment the efficiency of antitumor effect by cytokine-mediated immunotherapy, we selected both interleukin (IL)-12 and 4-1BB ligand (4-1BBL) as suitable cytokines to fully activate the type-1 immune response. Coexpression of IL-12 and 4-1BBL mediated by oncolytic adenovirus (Ad) greatly enhanced the antitumor effect. Further, synergistic enhancement in interferon (IFN)-gamma levels were seen in mice treated with oncolytic Ad expressing both IL-12 and 4-1BBL. Next, to improve the overall antitumor immune response, we coadministered IL-12- and 4-1BBL-coexpressing oncolytic Ad with dendritic cells (DCs). Combination treatment of IL-12- and 4-1BBL-coexpressing oncolytic Ad and DCs elicited greater antitumor and antimetastatic effects than either treatment alone. Moreover, enhanced type-1 antitumor immune response and higher migratory abilities of DCs in tumors were also observed in the combination arms. The nature of the enhanced antitumor immune response seems to be mediated through the enhanced cytolytic activity of cytotoxic T lymphocytes (CTLs) and IFN-gamma-releasing immune cells. Taken together, these data highlight the potential therapeutic benefit of combining IL-12- and 4-1BBL-coexpressing oncolytic Ad with DCs and warrants further evaluation in the clinic. PMID 19738604

Dendritic cells for active anti-cancer immunotherapy: targeting activation pathways through genetic modification.
Dec 2009 | Breckpot, Karine; Escors, David
Tumour immunotherapy has become a treatment modality for cancer, harnessing the immune system to recognize and eradicate tumour cells specifically. It is based on the expression of tumour associated antigens (TAA) by the tumour cells and aims at the induction of TAA-specific effector T cell responses, whilst overruling various mechanisms that can hamper the anti-tumour immune response, e.g. regulatory T cells (Treg). (Re-) activation of effector T cells requires the completion of a carefully orchestrated series of specific steps. Particularly important is the provision of TAA presentation and strong stimulatory signals, delivered by co-stimulatory surface molecules and cytokines. These can only be delivered by professional antigen-presenting cells, in particular dendritic cells (DC). Therefore, DC need to be loaded with TAA and appropriately activated. It is not surprising that an extensive part of DC research has focused on the delivery of both TAA and activation signals to DC, developing a one step approach to obtain potent stimulatory DC. The simultaneous delivery of TAA and activation signals is therefore the topic of this review, emphasizing the role of DC in mediating T cell activation and how we can manipulate DC for the pill-pose of enhancing tumour immunotherapy. As we gain a better understanding of the molecular and cellular mechanisms that mediate induction of TAA-specific T cells, rational approaches for the activation of T cell responses can be developed for the treatment of cancer. PMID 19857199

Identification of a microRNA signature in dendritic cell vaccines for cancer immunotherapy.
Dec 2009 | Holmstrøm, Kim; Pedersen, Ayako Wakatsuki; Claesson, Mogens Helweg; Zocca, Mai-Britt; Jensen, Simon Skjøde
Dendritic cells (DCs) exposed to tumor antigens followed by treatment with T(h)1-polarizing differentiation signals have paved the way for the development of DC-based cancer vaccines. Critical parameters for assessment of the optimal functional state of DCs and prediction of the vaccine potency of activated DCs have in the past been based on measurements of differentiation surface markers like HLA-DR, CD80, CD83, CD86, and CCR7 and the level of secreted cytokines like interleukin-12p70. However, the level of these markers does not provide a complete picture of the DC phenotype and may be insufficient for prediction of clinical outcome for DC-based therapy. We therefore looked for additional biomarkers by investigating the differential expression of microRNAs (miRNAs) in mature DCs relative to immature DCs. A microarray-based screening revealed that 12 miRNAs were differentially expressed in the two DC phenotypes. Of these, four miRNAs, hsa-miR-155, hsa-miR-146a, hsa-miR-125a-5p, and hsa-miR-29a, were validated by real-time polymerase chain reaction and northern blotting. The matured DCs from 12 individual donors were divided into two groups of highly and less differentiated DCs, respectively. A pronounced difference at the level of miRNA induction between these two groups was observed, suggesting that quantitative evaluation of selected miRNAs potentially can predict the immunogenicity of DC vaccines. PMID 19819280

Clinical Benefit of Allogeneic Melanoma Cell Lysate-Pulsed Autologous Dendritic Cell Vaccine in MAGE-Positive Colorectal Cancer Patients.
Dec 2009 | Toh, Han Chong; Wang, Who-Whong; Chia, Whay Kuang; Kvistborg, Pia; Sun, Li; Teo, Kelly; Phoon, Yee Peng; Soe, Yatanar; Tan, Sze Huey; Hee, Siew Wan; Foo, Kian Fong; Ong, Simon; Koo, Wen Hsin; Zocca, Mai-Britt; Claesson, Mogens H
PURPOSE: We evaluated the clinical benefit of an allogeneic melanoma cell lysate (MCL)-pulsed autologous dendritic cell (DC) vaccine in advanced colorectal cancer patients expressing at least one of six MAGE-A antigens overexpressed by the cell line source of the lysate. EXPERIMENTAL DESIGN: DCs were cultured from peripheral blood mononuclear cells (PBMC), pulsed with the allogeneic MCL, and matured using cytokines that achieved high CD83- and CCR7-expressing DCs. Each patient received up to 10 intradermal vaccinations (3-5 x 10(6) cells per dose) at biweekly intervals. RESULTS: Twenty patients received a total of 161 vaccinations. Treatment was well tolerated and quality of life measurements did not vary much across time. One patient experienced partial response [5%; 95% confidence interval (CI), 1-24%] and seven achieved stable disease (35%; 95% CI, 18-57%), one of whom also achieved late tumor regression, yielding a clinical benefit response rate of 40% (95% CI, 22-61%). Although overall median progression-free survival was 2.4 months (95% CI, 1.9-4.1 months), five patients (25%) experienced prolonged progression-free survival (>6 months), two of whom (10%) remain progression-free for >27 and >37 months, respectively. This result is particularly meaningful as all patients had progressive disease before treatment. Overall, DC vaccination was associated with a serial decline in regulatory T cells. Using an antibody array, we characterized plasma protein profiles in responding patients that may correlate with vaccine activity and report a prevaccination protein signature distinguishing responders from nonresponders. CONCLUSION: This phase II vaccine study using mature, MCL-pulsed DCs has shown promising results and warrants further evaluation in a prospective randomized setting. (Clin Cancer Res 2009;15(24):7726-36). PMID 19996212

Comparison of monocyte-derived dendritic cells from colorectal cancer patients, non-small-cell-lung-cancer patients and healthy donors.
Dec 2009 | Kvistborg, P; Bechmann, C M; Pedersen, A W; Toh, H C; Claesson, M H; Zocca, M B
Dendritic cells (DCs) are bone marrow-derived professional antigen presenting cells. Due to their role as potent inducers of immune responses, these cells are widely used as adjuvant in experimental clinical settings for cancer immune therapy. We have developed a DC-based vaccine using autologous blood monocytes loaded with allogeneic tumor cell lysate rich in cancer/testis antigens. This vaccine has at present been tested for activity in three phase II clinical trials including two cohorts of patients with advanced colorectal cancer (CRC) and one cohort of patients with advanced non-small-cell-lung-cancer (NSCLC). In the present paper we retrospectively compare the maturation profile based on surface marker expression on DCs generated from the three patient cohorts and between cancer patient cohorts and a cohort of healthy donors. Vaccines were generated under cGMP conditions and phenotypic profiles of DC were analyzed by flow cytometry and the obtained data were used as a basis to set guideline values for our quality control of GMP produced DC vaccines. Each vaccine batch was analyzed for the expression of the surface maturation and differentiation molecules CD14, CD1a, CD83, CD86, MHC class II and CCR7, and the optimal expression pattern is considered as CD14(low), CD1a, CD83(high), CD86(high), MHC class II(high) and CCR7(high). In accordance with data from other studies including other types of cancer patients, especially breast cancer patients, we found that the maturation status of the DC batches depends on cancer type and correlates with clinical status of cancer patients included. PMID 19837091

Clinical applications of a peptide-based vaccine for glioblastoma.
Nov 2009 | Kanaly, Charles W; Ding, Dale; Heimberger, Amy B; Sampson, John H
Glioblastoma multiforme is a malignant, relentless brain cancer with no known cure, and standard therapies leave significant room for the development of better, more effective treatments. Immunotherapy is a promising approach to the treatment of solid tumors that directs the patient's own immune system to destroy tumor cells. The most successful immunologically based cancer therapy to date involves the passive administration of monoclonal antibodies, but significant antitumor responses have also been generated with active vaccination strategies and cell-transfer therapies. This article summarizes the important components of the immune system, discusses the specific difficulty of immunologic privilege in the central nervous system, and reviews treatment approaches that are being attempted, with an emphasis on active immunotherapy using peptide vaccines. PMID 19944970

Abrogation of local cancer recurrence after radiofrequency ablation by dendritic cell-based hyperthermic tumor vaccine.
Nov 2009 | Liu, Qiong; Zhai, Bo; Yang, Wen; Yu, Le-Xing; Dong, Wei; He, Ya-Qin; Chen, Lei; Tang, Liang; Lin, Yan; Huang, Dan-Dan; Wu, Hong-Ping; Wu, Meng-Chao; Yan, He-Xin; Wang, Hong-Yang
Local recurrence is a therapeutic challenge for radiofrequency ablation (RFA) in treatment of small solid focal malignancies. Here we show that RFA induced heat shock proteins (HSPs) expression and high mobility group box-1 (HMGB1) translocation in xenografted melanoma, which might create a proinflammatory microenvironment that favors tumor antigen presentation and activation of the effector T cells. On this basis, we investigate whether a prime-boost strategy combining a prime with heat-shocked tumor cell lysate-pulsed dendritic cell (HT-DC) followed by an in situ boost with radiofrequency thermal ablation can prevent local tumor recurrence. The combination treatment with HT-DC and RFA showed potent antitumor effects, with >or=90% of tumor recurrence abrogated following RFA treatment. By contrast, prevaccination with unheated tumor lysate-pulsed DC had little effect on tumor relapse. Analysis of the underlying mechanism revealed that splenocytes from mice treated with HT-DC plus RFA contained significantly more tumor-specific, IFN-gamma-secreting T cells compared with control groups. Moreover, adoptive transfer of splenocytes from successfully treated tumor-free mice protected naive animals from tumor recurrence following RFA, and this was mediated mainly by CD8(+) T cells. Therefore, the optimal priming for the DC vaccination before RFA is important for boosting antigen-specific T cell responses and prevention of cancer recurrence. PMID 19773743

Heat shock proteins in glioblastomas.
Nov 2009 | Yang, Isaac; Fang, Shanna; Parsa, Andrew T
Glioblastoma multiforme is the most common primary central nervous system tumor. The prognosis for these malignant brain tumors is poor, with a median survival of 14 months and a 5-year survival rate below 2%. Development of novel treatments is essential to improving survival and quality of life for these patients. Endogenous heat shock proteins have been implicated in mediation of both adaptive and innate immunity, and there is a rising interest in the use of this safe and multifaceted heat shock protein vaccine therapy as a promising treatment for human cancers, including glioblastoma multiforme. PMID 19944971

Dendritic cell vaccines for brain tumors.
Nov 2009 | Kim, Won; Liau, Linda M
Over the past decade, dendritic cell-based immunotherapy for central nervous system tumors has progressed from preclinical rodent models and safety assessments to phase I/II clinical trials in over 200 patients, which have produced measurable immunologic responses and some prolonged survival rates. Many questions regarding the methods and molecular mechanisms behind this new treatment option, however, remain unanswered. Results from currently ongoing and future studies will help to elucidate which dendritic cell preparations, treatment protocols, and adjuvant therapeutic regimens will optimize the efficacy of dendritic cell vaccination. As clinical studies continue to report results on dendritic cell-mediated immunotherapy, it will be critical to continue refining treatment methods and developing new ways to augment this promising form of glioma treatment. PMID 19944973

Towards a standardized protocol for the generation of monocyte-derived dendritic cell vaccines.
Nov 2009 | Erdmann, Michael; Schuler-Thurner, Beatrice
For more than one decade patients have been treated with dendritic cell (DC) immunotherapy against malignancies and infectious diseases. Proof of principle studies demonstrated immunogenicity and clinical responses were observed in a fraction of patients. Overlooking more than 200 publications one realizes, however, that it is almost impossible to compare many of these trials even in a given clinical setting or disease. This is primarily due to the fact that dendritic cell generation procedures are highly variable. There is a requirement for a standardized DC generation protocol which provides 'reference dendritic cells' to which other dendritic cells (e.g. differently matured ones) can be compared to in order to further optimize this promising vaccination approach. In this chapter, we describe in detail our standard DC generation protocols established during the last decade with over 200 melanoma patients treated and over 2,000 vaccinations applied in clinical studies at our hospital. We do not claim that these dendritic cells are the best ones, but the generation procedure is highly reliable and reproducible and provides a standardized reference DC vaccine. PMID 19941110

Immunizing against breast cancer: a new swing for an old sword.
Nov 2009 | Curigliano, Giuseppe; Locatelli, Marzia; Fumagalli, Luca; Goldhirsch, Aron
Therapeutic potential of vaccination has been explored in many clinical trials involving patients with breast cancer. A large variety of cancer immunogens have been tested. The majority of clinical vaccination studies have been carried out in patients with metastatic breast cancer, characterized by extremely aggressive malignant tumors, resistant to all standard cytotoxic treatments and with longest-lasting disease. With active specific immunotherapy, tumor-associated antigens coupled to appropriate adjuvant can elicit a powerful antitumor responses. The potential advantages of therapeutic cancer vaccines are that they can augment an established immunogenic response to the tumor (which is generally weak in breast cancer), they target specific tumor antigens (although there are few), they are potentially non-toxic, they can be combined with conventional therapies and/or other immunotherapies, and they elicit immunologic memory to prevent recurrence of the tumor. It is unclear whether therapeutic vaccines for cancer prolong survival. Data of clinical activity have been observed by using vaccines targeting HER-2/neu protein, human telomerase reverse transcriptase, carcinoembryonic antigen (CEA), and carbohydrate antigen given after stem cell rescue. A better understanding of the relation between innate and adaptive immune responses, and of the immune escape mechanisms employed by tumor cells, the discovery of mechanisms underlying immunological tolerance, and acknowledgment of the importance of both cell-mediated and humoral adaptive immunity for the control of tumour growth are necessary for leading to a more comprehensive immunotherapeutic approach in breast cancer. PMID 19914543

Heat-shock protein vaccines as active immunotherapy against human gliomas.
Nov 2009 | Yang, Isaac; Han, Seunggu; Parsa, Andrew T
Modern advances in cancer immunotherapy have led to the development of active immunotherapy that utilizes tumor-associated antigens to induce a specific immune response against the tumor. Current methods of immunotherapy implementation are based on the principle that tumor-associated antigens are capable of being processed by antigen-presenting cells and inducing an activated cytotoxic T-lymphocyte-specific immune response that targets the tumor cells. Antigen internalization and processing by antigen-presenting cells, such as dendritic cells, or macrophages results in their surface association with MHC class I molecules, which can be recognized by an antigen-specific cytotoxic T-lymphocyte adaptive immune response. With the aim of augmenting current immunotherapeutic modalities, much effort has been directed towards enhancing antigen-presenting cell activation and optimizing the processing of tumor-associated antigens and major histocompatibility molecules. The goal of these immunotherapy modifications is to ultimately improve the adaptive specific immune response in killing of tumor cells while sparing normal tissues. Immunotherapy has been actively studied and applied in glioblastomas. Preclinical animal models have shown the feasibility of an active immunotherapy approach through the utilization of tumor vaccines, and recently several clinical studies have also been initiated. Recently, endogenous heat-shock proteins have been implicated in the mediation of both the adaptive and innate immune responses. They are now being investigated as a potential modality and adjuvant to immunotherapy, and they represent a promising novel treatment for human glioblastomas. PMID 19895242

Dendritic cell-based cancer gene therapy.
Oct 2009 | Smits, Evelien L J M; Anguille, Sébastien; Cools, Nathalie; Berneman, Zwi N; Van Tendeloo, Viggo F I
In view of their potent antigen-presenting capacity and ability to induce effective immune responses, dendritic cells (DCs) have become an attractive target for therapeutic manipulation of the immune system. The application of tumor-associated antigen (TAA)-expressing DCs for cancer therapy has been the subject of intensive translational investigation. Previous clinical trials demonstrated tumor-specific immune responses without any significant toxicity. However, the clinical success has been modest, because only a limited number of immunized patients demonstrated cancer regression. Considerable progress has been made in the knowledge of DC biology, which opens new avenues for the development of optimized clinical protocols. One such promising approach that might carve its place in the future of DC-based therapy is the use of gene-modified DCs. DCs engineered to express TAAs allow multiepitope presentation by both major histocompatibility complex (MHC) class I and II molecules of full-length TAAs independent of the patient's HLA constitution, as opposed to peptide vaccination strategies. Besides transgene TAA expression, DCs can be genetically modified (1) to express a variety of immune-potentiating molecules (e.g., costimulatory molecules, cytokines, and chemokines) or (2) to downregulate negative modulators of DC functioning, all allowing an enhancement of their immunogenic potential. In the present review, gene delivery systems for DCs are discussed, as well as the various transgenes used for genetic modification of DCs. Moreover, a detailed review of the already published trials using gene-modified DCs is presented and future DC-based strategies targeting multiple layers of the complex cellular immune response are highlighted. PMID 19656053

Killer dendritic cells and their potential for cancer immunotherapy.
Oct 2009 | Larmonier, Nicolas; Fraszczak, Jennifer; Lakomy, Daniela; Bonnotte, Bernard; Katsanis, Emmanuel
Known for years as the principal messengers of the immune system, dendritic cells (DC) represent a heterogeneous population of antigen presenting cells critically located at the nexus between innate and adaptive immunity. DC play a central role in the initiation of tumor-specific immune responses as they are endowed with the unique ability to take up, process and present tumor antigens to naïve CD4(+) or CD8(+) effector T lymphocytes. By virtue of the cytokines they produce, DC also regulate the type, strength and duration of T cell immune responses. In addition, they can participate in anti-tumoral NK and NKT cell activation and in the orchestration of humoral immunity. More recent studies have documented that besides their primary role in the induction and regulation of adaptive anti-tumoral immune responses, DC are also endowed with the capacity to directly kill cancer cells. This dual role of DC as killers and messengers may have important implications for tumor immunotherapy. First, the direct killing of malignant cells by DC may foster the release and thereby the immediate availability of specific tumor antigens for presentation to cytotoxic or helper T lymphocytes. Second, DC may participate in the effector phase of the immune response, potentially augmenting the diversity of the killing mechanisms leading to tumor elimination. This review focuses on this non-conventional cytotoxic function of DC as it relates to the promotion of cancer immunity and discusses the potential application of killer DC (KDC) in tumor immunotherapy. PMID 19618185

Dendritic cell vaccination combined with CTLA4 blockade in patients with metastatic melanoma.
Oct 2009 | Ribas, Antoni; Comin-Anduix, Begoña; Chmielowski, Bartosz; Jalil, Jason; de la Rocha, Pilar; McCannel, Tara A; Ochoa, Maria Teresa; Seja, Elizabeth; Villanueva, Arturo; Oseguera, Denise K; Straatsma, Bradley R; Cochran, Alistair J; Glaspy, John A; Hui, Liu; Marincola, Francesco M; Wang, Ena; Economou, James S; Gomez-Navarro, Jesus
Tumor antigen-loaded dendritic cells (DC) are believed to activate antitumor immunity by stimulating T cells, and CTL-associated antigen 4 (CTLA4)-blocking antibodies should release a key negative regulatory pathway on T cells. The combination was tested in a phase I clinical trial in patients with advanced melanoma. PMID 19789309

Polarization of human monocyte-derived dendritic cells to DC1 by in vitro stimulation with Newcastle Disease Virus.
Sep 2009 | Fournier, P; Arnold, A; Schirrmacher, V
Dendritic cell (DC)-based tumor vaccines have been tested extensively to treat cancer patients. However, the results of several DC-based clinical trials have been disappointing. Amelioration of such a modality for cancer treatment seems warranted, i.e. by improving DC immunogenicity and polarization. The goal of our study was to evaluate the potential for immune activation of human DCs by incubating them in vitro with the Newcastle Disease Virus (NDV), a paramyxovirus with strong immunostimulatory properties. PMID 19785053

Dendritic cell-based cancer immunotherapies.
Sep 2009 | Fujii, Shin-ichiro; Takayama, Takuya; Asakura, Miki; Aki, Kaori; Fujimoto, Koji; Shimizu, Kanako
Because of their unique role in linking the innate and adaptive immune systems, dendritic cells (DCs) have been a logical focus for novel immunotherapies. However, strategies employing active immunization with ex vivo generated and antigen-pulsed DCs have shown limited efficacy in clinical trials. These past approaches did not take into account the complex interactions between cells of the innate immune system and DCs during DC maturation, antigen processing, and presentation to naïve T cells. By better understanding the natural sequence of events occurring in vivo during an effective immune response, we can tailor antitumor immunotherapeutic strategies to augment aspects of this response from the activation of innate immune cells to antigen uptake and DC maturation to priming of naïve T cells and, ultimately, to the establishment of antitumor immunity. Current DC vaccination strategies utilize a number of methods to recapitulate the cascade of events that culminate in a protective antitumor immune response. PMID 19479202

Harnessing dendritic cells to generate cancer vaccines.
Sep 2009 | Palucka, Karolina; Ueno, Hideki; Fay, Joseph; Banchereau, Jacques
Passive immunotherapy of cancer (i.e., transfer of T cells or antibodies) can lead to some objective clinical responses, thus demonstrating that the immune system can reject tumors. However, passive immunotherapy is not expected to yield memory T cells that might control tumor outgrowth. Active immunotherapy with dendritic cell (DC) vaccines has the potential to induce tumor-specific effector and memory T cells. Clinical trials testing first-generation DC vaccines pulsed with tumor antigens provided a proof-of-principle that therapeutic immunity can be elicited. Newer generation DC vaccines are built on the increased knowledge of the DC system, including the existence of distinct DC subsets and their plasticity all leading to the generation of distinct types of immunity. Rather than the quantity of IFN-gamma-secreting CD8(+) T cells, we should aim at generating high-quality, high-avidity, polyfunctional effector CD8(+) T cells able to reject tumors and long-lived memory CD8(+) T cells able to prevent relapse. PMID 19769741

Combining conventional therapies with intratumoral injection of autologous dendritic cells and activated T cells to treat patients with advanced cancers.
Sep 2009 | Mann, Dean L; Celluzzi, Christina M; Hankey, Kim G; Harris, Kristina M; Watanabe, Ryuko; Hasumi, Kenichiro
Dendritic cells (DCs) are potent antigen-presenting cells that have been used in cancer immunotherapy. To take advantage of the ability of DCs to acquire antigenic materials from their environment and generate primary as well as recall immune responses, 37 patients with advanced cancers were enrolled in a series of protocols based on direct intratumoral injection of immature DCs. To augment antigen uptake and antitumor immune response, DC injection was combined with radiotherapy or chemotherapy and/or injection of activated T cells. Treatments were well tolerated with no adverse reactions. Clinical responses were based on Response Evaluation Criteria in Solid Tumors, with the majority of patients showing stable disease. One of two patients who also received local radiation achieved a sustained complete response at injected and metastatic sites. The clinical responses observed in cancer patients with advanced disease suggest potential effectiveness of combination strategies and establish the basis for the current treatment protocol that is underway. PMID 19769735

Immunotherapy with dendritic cells pulsed by autologous dactinomycin-induced melanoma apoptotic bodies for patients with malignant melanoma.
Sep 2009 | Chang, John W C; Hsieh, Jia-Juan; Shen, Yung-Chi; Ho, E; Chuang, Cheng-Keng; Chen, Yu-Ray; Liao, Shuen-Kuei; Chen, Jen-Shi; Leong, Stanley P L; Hou, Ming-Mo; Chang, Nai-Jen; Wang, Cheng-Hsu
The primary goal of this study was to evaluate the efficacy of immunotherapy for patients with metastatic melanoma with autologous melanoma apoptotic bodies (MAB)-pulsed dendritic cells (DCs). Accessible tumors from eligible patients with refractory metastatic melanoma were surgically removed and processed for primary culture. The autologous tumor cells were treated with dactinomycin to obtain MAB. To generate DCs, adherent peripheral blood mononuclear cells were cultured in complete medium containing granulocyte macrophage-colony stimulating factor and interleukin-4. MAB-pulsed DCs were given either intradermally (i.d.) or intravenously. Patients were immunized at monthly intervals and boosted with keyhole limpet hemocyanin (KLH) and MAB 2 weeks post-vaccination, with a maximum of four cycles. Of the 10 patients enrolled in this trial, nine were treated with MAB-pulsed DCs; two were given intravenous vaccinations and the other seven were i.d. injected. Mild tenderness in the draining lymph nodes lasting for less than 48 h and enlargement of the draining lymph nodes were noted in all seven i.d. cases. Treatment-related grade 3-4 toxicity, neutropenia, skin ulceration, tumor growth at the injection site, and sepsis were not observed in any of the patients. Delayed-type hypersensitivity to KLH was observed in all patients, whereas no delayed-type hypersensitivity to autologous tumor antigens was observed. One patient achieved partial response with reduction in lung metastatic tumor mass, and a presence of vesicles in the post-vaccination KLH response. Two patients had stable disease for more than 24 months; one was still alive at the time of submission of this report, the other eventually developed multiple metastases. MAB-pulsed DC immunotherapy is well tolerated in patients with malignant melanoma; however, its efficacy is only modest. Combination with other modalities is required to enhance DC-based immunotherapy. PMID 19750589

Antigen-specific T-cell response from dendritic cell vaccination using cancer stem-like cell-associated antigens.
Sep 2009 | Xu, Qijin; Liu, Gentao; Yuan, Xiangpeng; Xu, Minlin; Wang, Hongqiang; Ji, Jianfei; Konda, Bindu; Black, Keith L; Yu, John S
Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor, with current treatment remaining palliative. Immunotherapies harness the body's own immune system to target cancers and could overcome the limitations of conventional treatments. One active immunotherapy strategy uses dendritic cell (DC)-based vaccination to initiate T-cell-mediated antitumor immunity. It has been proposed that cancer stem-like cells (CSCs) may play a key role in cancer initiation, progression, and resistance to current treatments. However, whether using human CSC antigens may improve the antitumor effect of DC vaccination against human cancer is unclear. In this study, we explored the suitability of CSCs as sources of antigens for DC vaccination again human GBM, with the aim of achieving CSC-targeting and enhanced antitumor immunity. We found that CSCs express high levels of tumor-associated antigens as well as major histocompatibility complex molecules. Furthermore, DC vaccination using CSC antigens elicited antigen-specific T-cell responses against CSCs. DC vaccination-induced interferon-gamma production is positively correlated with the number of antigen-specific T cells generated. Finally, using a 9L CSC brain tumor model, we demonstrate that vaccination with DCs loaded with 9L CSCs, but not daughter cells or conventionally cultured 9L cells, induced cytotoxic T lymphocytes (CTLs) against CSCs, and prolonged survival in animals bearing 9L CSC tumors. Understanding how immunization with CSCs generates superior antitumor immunity may accelerate development of CSC-specific immunotherapies and cancer vaccines. PMID 19536809

Dendritic cell-based immunotherapy induces transient clinical response in advanced rat fibrosarcoma - comparison with preventive anti-tumour vaccination.
Aug 2009 | Kucera, A; Pýcha, K; Pajer, P; Spísek, R; Skába, R
In this study we present the models of preventive and therapeutic vaccination of sarcoma-bearing rats with dendritic cells that present tumour antigens from killed tumour cells. We present the characteristics of dendritic cell-based vaccine and its capacity to induce anti-tumour immune response both in vitro and in vivo. We show that preventive vaccination efficiently prevents tumour growth. On the other hand, vaccination of rats with established tumours did not lead to eradication of the tumours. Despite the induction of a vigorous immune response after administration of dendritic cell-based vaccine and transient decrease in tumour progression, tumours eventually resumed their growth and animals vaccinated with dendritic cells succumbed to cancer. In both settings, preventive and therapeutic, dendritic cell-based vaccination induced a vigorous tumour-specific T-cell response. These results argue for the timing of cancer immunotherapy to the stages of low tumour load. Immunotherapy initiated at the stage of minimal residual disease, after reduction of tumour load by other modalities, will have much better chance to offer a clinical benefit to cancer patients than the immunotherapy at the stage of metastatic disease. PMID 19691918

Increases in serum TARC/CCL17 levels are associated with progression-free survival in advanced melanoma patients in response to dendritic cell-based immunotherapy.
Aug 2009 | Cornforth, Andrew N; Lee, Gregory J; Fowler, Abner W; Carbonell, Denysha J; Dillman, Robert O
Changes in the levels of serum cytokines and growth factors are associated with response to therapy. We examined cytokine, chemokine, and growth factor levels in serum collected from normal volunteers or metastatic melanoma patients receiving dendritic cell-based immunotherapy. PMID 19421847

Therapeutic potential of dendritic cell vaccines in sarcoma of the extremities.
Aug 2009 | Yu, Zhe; Ren, Pengcheng; Zhang, Xudong; Zhang, Ting; Ma, Bao'an
Sarcomas of the extremities are challenging to treat. They are divided into soft-tissue and bone sarcomas in general, which also have many subtypes, based on their different mesenchymal origins and anatomical locations, respectively. Each of these sarcomas present in different ways, exhibit different behaviors and prognoses, and present unique therapeutic challenges. Dendritic cells (DCs) are the best professional antigen-presenting cells that can induce both the generation and proliferation of specific cytotoxic T lymphocytes and helper T lymphocytes through antigen presentation by MHC class I and class II molecules, respectively. In this review, a series of recently conducted immunotherapy for extremital sarcomas based on DCs are summarized and the potential for therapeutic DC vaccination targeted against these tumors is assessed. PMID 19671026

Massive expansion of regulatory T-cells following interleukin 2 treatment during a phase I-II dendritic cell-based immunotherapy of metastatic renal cancer.
Jul 2009 | Lemoine, François M; Cherai, Mustapha; Giverne, Camille; Dimitri, Dalia; Rosenzwajg, Michelle; Trebeden-Negre, Helene; Chaput, Nathalie; Barrou, Benoit; Thioun, Nicolas; Gattegnio, Bernard; Selles, Frederic; Six, Alain; Azar, Nabih; Lotz, Jean Pierre; Buzyn, Agnes; Sibony, Mathilde; Delcourt, Annick; Boyer, Olivier; Herson, Serge; Klatzmann, David; Lacave, Roger
Cytotoxic chemotherapy is ineffective in metastatic renal cancer. However, systemic administration of interleukin 2 (IL-2) or infusion of dendritic cells (DCs) loaded with tumor extracts can lead to some response rates with concomitant survival improvements. We report the results of a phase I-II pilot study combining DCs and IL-2 where six patients were included. DCs were derived from bone marrow CD34+ cells and loaded with autologous tumor extracts. CD34-DC vaccines were infused subcutaneously at day 45, 52, 59, 90 and 120 following surgery in combination with IL-2, that was subsequently administrated after the 3rd and 4th DC vaccinations. Preparation of tumor extracts and CD34-DCs were satisfactory in all patients but one. Due to rapid tumor progression, one patient was excluded before vaccination. In the 4 remaining patients, two received 3 vaccinations, while the 2 others received 5 vaccinations and the full IL-2 treatment. No adverse effect due to the vaccinations was observed. A specific immune response against autologous tumor cells was observed in the 2 patients who completed the treatment. Interestingly, these 2 patients had a more prolonged survival than the patients receiving 3 vaccinations. Importantly, a transient and massive increase of circulating natural regulatory T-cells (nTregs) was evidenced in 3 patients following IL-2 administration. Overall, the use of CD34-DC vaccines is feasible, safe and non-toxic. A specific anti-tumor immune response can be detected. However, our data highlights that IL-2 is a potent inducer of nTregs in vivo and as such may have a negative impact on cancer immunotherapy. PMID 19639177

On immunotherapies and cancer vaccination protocols: a mathematical modelling approach.
Jul 2009 | Joshi, Badal; Wang, Xueying; Banerjee, Sayanti; Tian, Haiyan; Matzavinos, Anastasios; Chaplain, Mark A J
In this paper we develop a new mathematical model of immunotherapy and cancer vaccination, focusing on the role of antigen presentation and co-stimulatory signaling pathways in cancer immunology. We investigate the effect of different cancer vaccination protocols on the well-documented phenomena of cancer dormancy and recurrence, and we provide a possible explanation of why adoptive (i.e. passive) immunotherapy protocols can sometimes actually promote tumour growth instead of inhibiting it (a phenomenon called immunostimulation), as opposed to active vaccination protocols based on tumour-antigen pulsed dendritic cells. Significantly, the results of our computational simulations suggest that elevated numbers of professional antigen presenting cells correlate well with prolonged time periods of cancer dormancy. PMID 19446568

Vaccination with multiple peptides derived from novel cancer-testis antigens can induce specific T-cell responses and clinical responses in advanced esophageal cancer.
Jul 2009 | Kono, Koji; Mizukami, Yoshiki; Daigo, Yataro; Takano, Atsushi; Masuda, Ken; Yoshida, Koji; Tsunoda, Takuya; Kawaguchi, Yoshihiko; Nakamura, Yusuke; Fujii, Hideki
We previously identified three novel HLA-A24-restricted epitope peptides, which were derived from three cancer-testis antigens, TTK protein kinase (TTK), lymphocyte antigen 6 complex locus K (LY6K), and insulin-like growth factor (IGF)-II mRNA binding protein 3 (IMP-3), as targets for cancer vaccination against esophageal squamous cell carcinoma (ESCC). To examine the safety, immunogenicity, and antitumor effect of vaccine treatment using a combination of these three peptides, 10 HLA-A2402-positive advanced ESCC patients who failed to standard therapy were enrolled in a phase I clinical trial. Each of the three peptides (1 mg each) was intradermally administered with 1 mL of incomplete Freund's adjuvant to the neck in three separate regions weekly for 5 weeks. The cancer vaccination therapy was well tolerated without any treatment-associated adverse events of grade 3 or 4. The TTK-, LY6K-, and/or IMP-3-specific T-cell immune responses were observed by enzyme-linked immunospot assay in peripheral blood lymphocytes obtained from nine of the 10 ESCC patients after their vaccination. The median survival time after the vaccination was 6.6 months. The vaccination could induce good clinical responses in 50% of the 10 patients. One patient experienced a complete response in hepatic metastasis lasting 7 months, one showed objective responses in all lung metastasis lesions, and three patients revealed a stable disease condition for at least 2.5 months. The cancer vaccine therapy using these three peptides demonstrated satisfactory safety and good immunogenicity as well as promising disease control rate, and therefore warrants further clinical studies. PMID 19459850

Targeted delivery of tumor antigens to activated dendritic cells via CD11c molecules induces potent antitumor immunity in mice.
Jul 2009 | Wei, Huafeng; Wang, Suhui; Zhang, Dapeng; Hou, Sheng; Qian, Weizhu; Li, Bohua; Guo, Huaizu; Kou, Geng; He, Jinqiu; Wang, Hao; Guo, Yajun
CD11c is an antigen receptor predominantly expressed on dendritic cells (DC), to which antigen targeting has been shown to induce robust antigen-specific immune responses. To facilitate targeted delivery of tumor antigens to DCs, we generated fusion proteins consisting of the extracellular domain of human HER or its rat homologue neu, fused to the single-chain fragment variable specific for CD11c (scFv(CD11c)-HER2/neu). PMID 19584156

[Dendritic cell-based immunotherapy for multiple myeloma -- review].
Jun 2009 | Zhu, Xue-Jun; He, Long; Sun, Xue-Mei
Patients with multiple myeloma (MM) have increased constantly in recent years, but treatment for patients with MM is currently unsatisfactory and it is necessary to develop new complementary therapies. Dendritic cells (DCs) are specialized antigen-presenting cells capable of initiating and regulating immune responses. Vaccination with tumor antigen-pulsed DCs has shown to be safe and possesses therapeutic effect against many tumors. In this review, the various types of MM-associated antigens and clinical trials on DC-based immunotherapy in MM are summarized, the development of DC immunotherapy for MM patients in future trials is discussed. PMID 19549416

Cryopreservation of monocytes is superior to cryopreservation of immature or semi-mature dendritic cells for dendritic cell-based immunotherapy.
Jun 2009 | Hayden, Hubert; Friedl, Josef; Dettke, Markus; Sachet, Monika; Hassler, Michaela; Dubsky, Peter; Bachleitner-Hofmann, Thomas; Gnant, Michael; Stift, Anton
Cryopreservation of immature or mature dendritic cells (DC) has been proposed as a suitable method to gain large numbers of DC for immunotherapeutic trials against cancer. However, clinical studies using cryopreserved DC have demonstrated only limited success so far. The aim of this study was to investigate whether cryopreservation of monocytes elicits more potent DC and whether these DC are comparable to freshly generated DC preparations. Monocytes, either separated immunomagnetically or by means of leukapheresis and elutriation, were differentiated into DC and cryopreserved at various developmental stages. DC preparations were analyzed regarding recovery, viability, phenotype, and functional properties. In contrast to DC frozen at their immature or semi-mature state, generation of DC from cryopreserved monocytes elicited viability values comparable with freshly generated DC. Furthermore, using frozen monocytes for DC differentiation revealed improved expression of DC surface markers and interleukin-12p70 secretion as compared with DC generated from frozen immature or frozen semi-mature DC. Impaired phenotypical appearance of the latter DC variants was further substantiated by functional analysis. T-cells cocultured with these DC showed decreased expression of interferon-gamma and granzyme B, and lowered proliferation when compared with T-cells cocultured with DC generated from frozen monocytes or DC generated from freshly isolated monocytes. Induction of regulatory T-cell populations was negligible among all investigated DC preparations. These findings may further improve DC-based immunotherapeutical protocols. Cryopreservation of unchallenged monocytes enables targeted therapy by loading DC with varying antigenic compositions in case of tumor escape during treatment. PMID 19483645

Beyond RET: potential therapeutic approaches for advanced and metastatic medullary thyroid carcinoma.
Jun 2009 | Santarpia, L; Ye, L; Gagel, R F
Medullary thyroid carcinoma (MTC) is a rare calcitonin-producing neuroendocrine tumour that originates from the parafollicular C-cells of the thyroid gland. The RET proto-oncogene encodes the RET receptor tyrosine kinase, which has essential roles in cell survival, differentiation and proliferation. Activating mutations of RET are associated with the pathogenesis of MTC and have been demonstrated in nearly all hereditary and in 30-50% of sporadic MTC cases, making this receptor an excellent target for small-molecule inhibitors for this tumour. Clinical trials of small organic inhibitors of tyrosine kinase receptors (TKIs) targeting the RET receptor have shown efficacy for treatment of metastatic MTC with 30-50% of patients responding to these agents. Despite the importance of the RET receptor in MTC, it is clear that other signal transduction pathways, tyrosine kinase receptors, and tumour suppressor genes are involved in MTC tumourigenesis and progression. A better understanding of molecular cross-talk between these signal pathways and the RET receptor may lead to combinatorial therapy that will improve outcomes beyond what is currently possible with RET-directed TKIs. Finally, there is evidence that immunological-based therapy using dendritic cell vaccination strategies have been effective for reducing tumour mass in a small number of patients. The identification of additional MTC-specific tumour antigens and a better understanding of specific epitopes in these tumour antigens may lead to improvement of response rates. PMID 19522829

[The preparation of anticancer vaccine for patients with multiple myeloma on the base of monoclonal immunoglobulin loaded dendritic cells].
Jun 2009 | Ocadlíková, D; Zahradová, L; Kovárová, L; Smejkalová, J; Pour, L; Vidláková, P; Kyjovská, D; Moravcová, J; Rycová, M; Novotná, H; Jelínková, I; Penka, M; Michálek, J; Hájek, R
On June 2006, phase II clinical trial focused on anticancer vaccination of multiple myeloma patients, was started. On September 2007, the immune and clinical response evaluation of first four patients was finished.The anticancer vaccine contained dendritic cells loaded with monoclonal immunoglobulin produced by myeloma cells. PMID 19522376

Costimulatory ligand CD70 allows induction of CD8+ T-cell immunity by immature dendritic cells in a vaccination setting.
May 2009 | Keller, Anna M; Xiao, Yanling; Peperzak, Victor; Naik, Shalin H; Borst, Jannie
The use of dendritic cells (DCs) as anticancer vaccines holds promise for therapy but requires optimization. We have explored the potential of costimulatory ligand CD70 to boost the capacity of DCs to evoke effective CD8(+) T-cell immunity. We show that immature conventional DCs, when endowed with CD70 expression by transgenesis, are converted from a tolerogenic state into an immunogenic state. Adoptively transferred CD70-expressing immature DCs could prime CD8(+) T cells, by CD27, to become tumor-eradicating cytolytic effectors and memory cells with a capacity for robust secondary expansion. The CD8(+) T-cell response, including memory programming, was independent of CD4(+) T-cell help, because the transferred immature DCs were loaded with major histocompatibility complex class I-restricted peptide only. Without CD70 expression, the DCs generated abortive clonal expansion, dysfunctional antitumor responses, and no CD8(+) T-cell memory. CD70-expressing CD8(+) DCs were the primary subset responsible for CD8(+) T-cell priming and performed comparably to fully matured DCs. These data highlight the importance of CD27/CD70 interactions at the T-cell/DC interface and indicate that CD70 should be considered in the design of DC vaccination strategies. PMID 19279334

Antigen loading of DCs with irradiated apoptotic tumor cells induces improved anti-tumor immunity compared to other approaches.
May 2009 | Fry, Terry J; Shand, Jessica L; Milliron, Matthew; Tasian, Sarah K; Mackall, Crystal L
Dendritic cells (DCs) serve as central regulators of adaptive immunity by presenting antigens and providing necessary co-signals. Environmental information received by the DCs determines the co-signals delivered to the responding adaptive cells and, ultimately, the outcome of the interaction. DCs loaded with relevant antigens have been used as therapeutic cellular vaccines, but the optimal antigen loading method has not been determined. We compared different methods to load class I and class II epitopes from the male antigenic complex, HY, onto DCs for the potency of the immune response induced in vivo. Co-incubation of female DCs with HY peptides, RNA or cell lysate from HY expressing tumor induced immune responses equivalent to male DCs. In contrast, female DCs incubated with irradiated, apoptotic HY expressing tumor cells (or male B cells) generated a stronger immune response than male DCs or female DCs loaded using any of the other methods. DC loading with apoptotic tumor resulted in complete protection against high dose HY-expressing tumor challenge whereas 100% lethality was observed in groups receiving DCs that were loaded with peptides, RNA, or lysate. We conclude that signals provided to the DCs by apoptotic cells substantially augment the potency of DC vaccines. PMID 19139888

Vaccination with recombinant adenoviruses and dendritic cells expressing prostate-specific antigens is effective in eliciting CTL and suppresses tumor growth in the experimental prostate cancer.
May 2009 | Kim, Sol; Lee, Jee-Boong; Lee, Geon Kook; Chang, Jun
Prostate cancer is currently the most commonly diagnosed cancer in men and the second leading cause of cancer-related death in men in the US. Immunological approaches may provide an alternative option for prevention and treatment of prostate cancer. PMID 19267351

Ampligen: a potential toll-like 3 receptor adjuvant for immunotherapy of cancer.
May 2009 | Jasani, B; Navabi, H; Adams, M
Therapeutic vaccination against cancer-associated antigens represents an attractive option for cancer therapy in view of its potential efficacy, the possibility of long-lasting immunity against the cancer, and safety profile. Cancer patients are however usually immunosuppressed and most cancer-associated antigens are 'self-antigens', making it a significant challenge to vaccinate patients against a cancer-associated antigen. Various immunostimulant adjuvants are therefore under investigation in an effort to boost the immune system to overcome the tolerance to tumour associated self-antigens and the ambient immunosuppressory influence of cytokines and regulatory T-cells (Tregs). Many adjuvants appear to be specific ligands for toll-like receptors (TLR) which are potent activators of innate immune responses [Kwissa M, Kasturi SP, Pulendran B. Expert Rev Vaccines. The Science of Adjuvants 2007 6(October(5)):673-84] [1], activating dendritic cell (DC) maturation and inflammatory cytokine secretion, inducing an increase in the cross talk between the innate and adaptive immune systems, and thereby driving the expansion of CTLs that can destroy cancer cells. However, recently some TLR agonists such as CpG have been shown to generate parallel immunosuppressive and inflammatory responses in innate immune cells capable of induction and expansion of Tregs [Conroy H, Marshall NA, Mills KH. TLR ligand suppression or enhancement of Treg cells? A double-edged sword in immunity to tumours. Oncogene 2008 27(January 7(2)):168-80 [2]; Huang B, Zhao J, Unkeless JC, Feng ZH, Xiong H TLR signaling by tumor and immune cells: a double-edged sword. Oncogene 2008;27(2):218-24] [3]. In this context it is noteworthy that poly(I:C), a synthetic double-stranded RNA polymer and a TLR3 agonist, has been shown in mouse models to be capable of enhancing the T cell response to nonimmunogenic self-antigen linked dendritic cell based vaccine strategy, and stimulating diabetic insulitis in the presence of Tregs [Hornum L, Lundsgaard D, Markholst H. PolyI:C induction of diabetes is controlled by Iddm4 in rats with a full regulatory T cell pool. Ann N Y Acad Sci 2007;1110:65-72] [4]. Ampligen poly(I:C(12)U) is a GMP-grade synthetic analogue of poly(I:C) and therefore suitable for human use. Its effects in a preclinical setting have been recently tested to be similar to poly(I:C) [Hornum L, Lundsgaard D, Markholst H. PolyI:C induction of diabetes is controlled by Iddm4 in rats with a full regulatory T cell pool. Ann N Y Acad Sci 2007;1110:65-72]. In particular, it potently induces in vitro maturation of human monocyte derived DC with sustained bioactive IL12 production. In addition human monocyte derived DC primed with tumour lysate and matured with Ampligen are capable of generating Th1 specific anti-cancer responses in peripheral blood T-cells derived from cancer patients in the presence of ascites medium containing immunosuppressory cytokines. In this review the key findings are summarised and discussed with a view to offering a rationale for the use of Ampligen as a potentially safe adjuvant capable of overcoming the tumour-related immune tolerance mechanisms in a clinical setting. PMID 19200817

Cellular immunotherapy for ovarian cancer.
May 2009 | Cannon, Martin J; O'Brien, Timothy J
Ovarian cancer is frequently diagnosed at an advanced stage, and although initially responsive to surgery and chemotherapy, has a high rate of recurrence and mortality. Cellular immunotherapy may offer the prospect of treatment to prevent or delay recurrent metastatic disease. PMID 19456205

Monocyte-derived dendritic cells from HIV type 1-infected individuals show reduced ability to stimulate T cells and have altered production of interleukin (IL)-12 and IL-10.
May 2009 | Buisson, Sandrine; Benlahrech, Adel; Gazzard, Brian; Gotch, Frances; Kelleher, Peter; Patterson, Steven
Monocyte-derived dendritic cells (MDDCs) have been used in therapeutic vaccination for cancer. A small number of studies have employed a similar approach to vaccinate human immunodeficiency virus (HIV)-infected individuals. We have thus analyzed the functional properties of MDDCs generated from HIV-infected individuals who either are receiving highly active antiretroviral therapy or are therapy naive. There was no difference in the MDDC phenotype or efficiency of MDDC generation between HIV-infected individuals and healthy control subjects. Despite this, the MDDCs derived from both groups of infected individuals were severely impaired in their ability to stimulate the proliferation of allogeneic T cells. Furthermore, production of interferon-gamma was reduced in T cells stimulated by MDDCs. These functional changes may be at least partly explained by reduced interleukin-12 and increased interleukin-10 secretion on stimulation with lipopolysaccharide and CD40 ligand. Our findings suggest that MDDCs used in therapeutic vaccination of HIV-infected individuals may show reduced potency. PMID 19419334

Single-step antigen loading and activation of dendritic cells by mRNA electroporation for the purpose of therapeutic vaccination in melanoma patients.
May 2009 | Bonehill, Aude; Van Nuffel, An M T; Corthals, Jurgen; Tuyaerts, Sandra; Heirman, Carlo; François, Violaine; Colau, Didier; van der Bruggen, Pierre; Neyns, Bart; Thielemans, Kris
A critical factor determining the effectiveness of currently used dendritic cell (DC)-based vaccines is the DC activation or maturation status. We have recently shown that the T-cell stimulatory capacity of DCs pulsed with tumor-antigen-derived peptides can be considerably increased by activating the DCs through electroporation with mRNA encoding CD40 ligand, CD70, and a constitutively active Toll-like receptor 4 (TriMix DCs). Here, we investigate whether TriMix DCs can be coelectroporated with whole tumor-antigen-encoding mRNA. PMID 19417017

The efficient generation of immunocompetent dendritic cells from leukemic blasts in acute myeloid leukemia: a local experience.
May 2009 | Bagheri, Kambiz; Alimoghadam, Kamran; Pourfathollah, Ali Akbar; Hassan, Zuhair Muhammad; Hajati, Jamshid; Moazzeni, Seyyed Mohammad
Dendritic cells (DCs) are the most important antigen presenting cells with potentially useful applications in cancer immunotherapy. Leukemic cells of patients with acute myeloid leukemia (AML) could be differentiated to DC-like cells possessing the ability of stimulating anti-leukemic immune response. Despite obvious progress in DC-based immunotherapy, some discrepancies were reported in differentiation potential of AML blasts from all patients toward DC like cells. The present study, as a local experience, was set up to generate DCs from AML blasts of various subtypes. Leukemic Blasts from 16 Iranian AML patients were differentiated into functional DCs by culturing in the presence of rhGM-CSF, rhIL-4 and TNF-alpha for 8 days. The morphology, expression of key surface molecules and allostimulatory activity of resultant DCs were compared with primary blasts and cultured but cytokine untreated control groups. The pattern of angiotensin-converting enzyme (ACE) expression was used to approve the leukemic origin of generated DCs. Neo-expression or upregulation of DC-associated markers were occurred during culturing period in cytokine treated cells compared with primary blasts and cultured but cytokine untreated control groups: CD1a (63.22% vs. 3.22% and 11.79%), CD83 (41.27% vs. 0.11% and 0.70%), CD40 (15.17% vs. 0.00% and 0.04%), CD80 (49.96 vs. 0.02% and 0.32%), CD86 (56.49% vs. 0.50% and 5.71%) and HLA-DR (52.52% vs. 14.32% and 2.49%) respectively. The potency of generated DCs to induce allogeneic T cell proliferation increased significantly compared to pre and post culture control groups (27,533.4 +/- 2,548.3, 8,820.4 +/- 1,639.4 and 3,200.35 +/- 976 respectively). The expression pattern of ACE in AML-DCs, blast cells and DCs derived from normal monocytes (7.93%, 1.28% and 74.97% respectively) confirmed the leukemic origin of DCs. Our data confirmed the generation of sufficient AML-derived cells with the properties of DCs in all cases. This potency of AML blasts, offers a useful route for active immunotherapy of AML patients. PMID 18807213

Generation of a dendritic cell-based vaccine in chronic lymphocytic leukaemia using CliniMACS platform for large-scale production.
May 2009 | Adamson, L; Palma, M; Choudhury, A; Eriksson, I; Näsman-Glaser, B; Hansson, M; Hansson, L; Kokhaei, P; Osterborg, A; Mellstedt, H
We previously demonstrated that dendritic cells (DC) that have endocytosed apoptotic bodies of autologous leukemic cells (Apo-DC) can boost antileukemic T-cell responses. In this study, we report a description of the production procedure and product specification of the Apo-DC vaccine preparations for clinical use. Enriched populations of CD14+ monocytic precursors and CD19+ leukaemic cells were obtained using CliniMACS technology from a single leukapheresis product. Apoptotic bodies were obtained by irradiating (5 Gy) CD19+ selected B cells. DC were generated ex vivo by culturing monocytes with granulocyte macrophage colony-stimulating factor and interleukin-4. Following coculture with apoptotic bodies, DCs were matured with tumour necrosis factor-alpha. The mean percentage of CD14+ cells in the peripheral blood as well as in the leukapheresis product of the patients (n = 10) was approximately 2% (range, 0.8-3.3). Immunomagnetic selection using the CD14 reagent yielded a CD14+ population that was 91 +/- 2.2% (mean +/- SEM) pure. Immunomagnetic selection of CD19 expressing cells yielded a population that was 100 +/- 0.03% pure. Cell viability immediately after selection was 97% and 98% after 7 days of culture. The Apo-DC cellular vaccine product showed a mature phenotype, with a high rate of endocytosis (84%) of apoptotic leukemic B-cells. In conclusion, despite significant variability in the circulating monocyte frequency of the chronic lymphocytic leukaemia patients, our method permitted the production of a DC vaccine with high reproducibility and conforming with recommended quality standards. PMID 19439014

Antitumor vaccines, immunotherapy and the immunological constant of rejection.
May 2009 | Wang, Ena; Monaco, Alessandro; Monsurró, Vladia; Sabatino, Marianna; Pos, Zoltan; Uccellini, Lorenzo; Wang, Jeanne; Worschech, Andrea; Stroncek, David F; Marincola, Francesco M
Anticancer vaccines have not matched the clinical expectations projected from their ability to induce consistently systemic anticancer T-cell responses. Thus, a dichotomy is observed between the immunological and clinical endpoints of anticancer immunization. Anticancer vaccines have clearly demonstrated that highly specific T-cell responses can be induced that can recognize autologous cancer antigens in patients with cancer. This ability is an outstanding achievement of modern biotechnology, yielding one of the most specific types of potential anticancer reagents. However, systemic, vaccine-induced anticancer responses exemplify a broader immunological paradox: cytotoxic T-cells can coexist within the same organism with their target cells not only in the context of cancer, but also in the context of chronic infections, well-controlled allo-transplant reactions and autoimmunity. According to this view, anticancer immune responses are a facet of a tissue-specific autoimmune phenomenon specific for cancer tissue that may or may not result in the successful immune-destruction of target cells, depending on an assortment of genetic factors related to the background of the host or evolving phenotypes of a heterogeneous cancer environment. This feature article summarizes the current understanding of the mechanisms leading to tumor rejection in humans as well as in experimental models, in the context of the broader immunological phenomenon leading to tissue-specific destruction. Anticancer vaccines that may not induce clinically significant anticancer responses independently could function as a unique tool to enhance the specificity of the response of the host against cancer, provided that strategies are implemented to amplify the immune reaction initiated by vaccine-induced antibodies and/or T-cells. PMID 19431094

Pilot trial of autologous dendritic cells loaded with tumor lysate(s) from allogeneic tumor cell lines in patients with metastatic medullary thyroid carcinoma.
May 2009 | Bachleitner-Hofmann, Thomas; Friedl, Josef; Hassler, Michaela; Hayden, Hubert; Dubsky, Peter; Sachet, Monika; Rieder, Erwin; Pfragner, Roswitha; Brostjan, Christine; Riss, Stefan; Niederle, Bruno; Gnant, Michael; Stift, Anton
Immunotherapy with autologous dendritic cells (DCs) loaded with tumor lysate(s) from allogeneic tumor cell lines is a novel strategy to induce immune responses in cancer patients. We report on a pilot trial of autologous DCs pulsed with tumor cell lysate derived from allogeneic medullary thyroid carcinoma (MTC) cell lines in patients with metastatic MTC. The purpose of this study was to assess the safety, resulting immune responses and clinical activity of the DCs. DCs were injected into a groin lymph node at 3-week intervals. Monitoring included serial calcitonin tumor marker measurements, radiological imaging and immunological in vitro tests (T-cell interferon-gamma detection assay, T-cell cytotoxicity assay). Ten patients (median age 47 years, range 29-77) were enrolled. DC vaccinations were well-tolerated and safe. After a median follow-up of 11 months, (range 7-26), 3 (30%) of 10 patients had stable disease, while 7 (70%) of the patients progressed during treatment. In 2 patients with stable disease, calcitonin decreased below treatment levels, paralleled by a T-cell-mediated immune response. Notably, treatment with DCs pulsed with a combination of different tumor cell lysates was followed by a calcitonin decrease in 4 patients who had previously experienced a calcitonin increase during monotherapy with DCs pulsed with a single lysate. Allogeneic tumor cell lysate-based DC immunotherapy is well-tolerated and safe. Combined treatment with different tumor cell lysate-pulsed DCs increases the likelihood of a calcitonin tumor marker response and should therefore be preferred over monotherapy with DCs pulsed with a single lysate. PMID 19424640

Impact of surgery and chemotherapy on cellular immunity in pancreatic carcinoma patients in view of an integration of standard cancer treatment with immunotherapy.
May 2009 | Bellone, Graziella; Novarino, Anna; Vizio, Barbara; Brondino, Gabriele; Addeo, Alfredo; Prati, Adriana; Giacobino, Alice; Campra, Donata; Fronda, Gian Ruggero; Ciuffreda, Libero
As surgery and chemotherapy may act as adjuvants providing antitumor immunity benefits, we ran phenotypical and functional immunomonitoring in patients with resectable pancreatic adenocarcinoma and advanced metastatic disease receiving combined treatment (cisplatin, gemcitabine, 5-FU). Blood was taken before/one month after resection; before/during chemotherapy. Controls were age- and gender-matched. Circulating lymphocyte, myeloid and plasmacytoid dendritic cell (MDC and PDC) subsets were examined by flow cytometry; functional activity by mixed lymphocyte reaction (MLR) for DC allostimulation, through 4-h 51Cr-release assay for Natural Killer (NK) and lymphokine-activated-killer (LAK) cell cytotoxicity; ELISA for spontaneous/activated cytokine release by PBMC and T cells. Significant differences occurred in several parameters between pretreatment patient and control values: fewer CD8+ cells and increased apoptosis-prone CD3+/CD95+ lymphocytes, higher frequency of MDC, reduced allostimulatory activity by ex vivo-generated DC, depressed LAK activity, elevated IL-10 and IL-12p40 production; impaired IL-12p70 and IFN-gamma production by stimulated PBMC and T cells. Only IL-12p70 level was correlated with survival. One month after radical, but not palliative surgery, the percentage of T-lymphocytes coexpressing CD3/CD95 decreased significantly, the stimulatory capacity of DC increased, and LPS-induced IL-12p70 release by PBMC rose concomitantly with the anti-CD3 stimulated-IFN-gamma production by T cells. In patients with locally advanced or metastatic disease, one and/or two combined drug cycles increased percentage of CD4+ cells and LAK cell cytotoxicity and decreased PDC frequency and spontaneous/LPS-stimulated IL-10 by PBMC. Results suggest immunological changes induced by surgical resection/combined chemotherapy indicate specific precisely-timed windows of opportunity for introducing immunotherapy in pancreatic cancer, possibly improving survival in this highly lethal disease. PMID 19424589

Th-1 polarization is regulated by dendritic-cell comparison of MHC class I and class II antigens.
May 2009 | Decker, William K; Xing, Dongxia; Li, Sufang; Robinson, Simon N; Yang, Hong; Steiner, David; Komanduri, Krishna V; Shpall, Elizabeth J
In the control of T-helper type I (Th-1) polarization, dendritic cells (DCs) must interpret a complex array of stimuli, many of which are poorly understood. Here we demonstrate that Th-1 polarization is heavily influenced by DC-autonomous phenomena triggered by the loading of DCs with antigenically matched major histocompatibility complex (MHC) class I and class II determinants, that is, class I and II peptide epitopes exhibiting significant amino acid sequence overlap (such as would be physiologically present during infectious processes requiring Th-1 immunity for clearance). Data were derived from 13 independent antigenic models including whole-cell systems, single-protein systems, and 3 different pairs of overlapping class I and II binding epitopes. Once loaded with matched class I and II antigens, these "Th-1 DCs" exhibited differential cytokine secretion and surface marker expression, a distinct transcriptional signature, and acquired the ability to enhance generation of CD8(+) T lymphocytes. Mechanistically, tRNA-synthetases were implicated as components of a putative sensor complex involved in the comparison of class I and II epitopes. These data provide rigorous conceptual explanations for the process of Th-1 polarization and the antigenic specificity of cognate T-cell help, enhance the understanding of Th-1 responses, and should contribute to the formulation of more effective vaccination strategies. PMID 19171878

Conditioning vaccination site with irradiated MIP-3alpha-transfected tumor cells enhances efficacy of dendritic cell-based cancer vaccine.
Apr 2009 | Shih, Neng-Yao; Yang, Hui-Yu; Cheng, Hui-Ting; Hung, Yi-Mei; Yao, Yi-Chuan; Zhu, Yun-Han; Wu, Yu-Chen; Liu, Ko-Jiunn
Macrophage inflammation protein-3alpha (MIP-3alpha) is a chemokine expressed in inflamed tissue and capable of inducing migration of immature dendritic cells (DCs) or Langerhans cells. We postulated that conditioning vaccination sites with MIP-3alpha might enhance the efficacy of subsequently administered DC-based cancer vaccines. Our results demonstrate that subcutaneously injection of irradiated tumor cells expressing MIP-3alpha induces substantial cell infiltration to the injection site. Vaccination of irradiated tumor cells expressing MIP-3alpha followed by DCs pulsed with irradiated tumor cells can effectively suppress tumor growth in animals, which is significantly better than vaccination with irradiated MIP-3alpha-producing tumor cells or DCs pulsed with tumor cells alone. The protective effect was most evident when the MIP-3alpha-producing tumor cells and DC-based vaccines were injected at the same site. These results support the notion that this combination vaccination strategy might generate a more effective immune response to suppress the growth of tumor cells in animals. PMID 19342969

Synergistic effect of dendritic cell vaccination and anti-CD20 antibody treatment in the therapy of murine lymphoma.
Apr 2009 | Gadri, Zohar; Kukulansky, Tova; Bar-Or, Eyal; Haimovich, Joseph; Hollander, Nurit
Indolent B-cell lymphomas are characterized by repeated remissions and relapses with most patients eventually dying of the disease. Although combination treatments with chemotherapy and the anti-CD20 antibody rituximab improved duration of remissions and overall survival, the disease is essentially incurable. Thus, novel therapeutic approaches are needed. One such approach is active immunization with dendritic cells (DCs). Given that rituximab depletes patients of normal B cells, optimal vaccination strategies for rituximab-treated patients require induction of effector T cells. We have previously demonstrated in a murine model that idiotype (Id)-keyhole limpet hemocyanin-pulsed DCs induced Id-reactive CD8 T cells and protection against tumor challenge in the absence of anti-Id antibodies. On the basis of these results, we investigated vaccination in a therapeutic model, in which mice carrying advanced tumors of the highly aggressive 38C-13 lymphoma were treated with chemotherapy and anti-CD20 antibodies combined with a DC-based vaccine. As a rule, cytoreduction by cyclophosphamide was required in each regimen of combination treatment, and vaccination with tumor cell-loaded DCs was more effective than vaccination with Id-keyhole limpet hemocyanin-loaded DCs. We demonstrated that under conditions of large primary tumors that had already spread to lymph nodes, when anti-CD20 antibody treatment showed minimal effect and DC vaccination had no effect, synergism between anti-CD20 antibodies and DC vaccines resulted in significant long-term survival that did not involve active antitumor antibody production. Combination treatments including tumor cell-loaded DC vaccines may therefore provide a strategy for enhancing the potency of therapy in rituximab-treated patients. PMID 19342972

Autologous dendritic cells loaded with apoptotic tumor cells induce T cell-mediated immune responses against breast cancer in vitro.
Apr 2009 | Delirezh, Nowruz; Moazzeni, Seyed Mohammad; Shokri, Fazel; Shokrgozar, Mohammad Ali; Atri, Morteza; Kokhaei, Parviz
Dendritic cell (DCs) based immunotherapy has received increased interest in the treatment of specific malignancies including breast cancer. In this in vitro study, T cell responses, which are induced by monocyte-derived DCs pulsed with apoptotic breast tumor cells (ApTC), were analyzed in terms of proliferation, specific cytotoxicity, and cytokine release. Nylon wool-enriched T lymphocytes from five patients with breast cancer stimulated with monocyte-derived DCs pulsed with apoptotic tumor cells in vitro and their proliferation response were analyzed by [(3)H] thymidine uptake and specific cytotoxic activity of tumor antigen-primed T cells after three rounds of weekly stimulation by flow cytometry. Interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) cytokine release assay was carried out 24h after the last stimulation. The supernatant from primed T cells was collected and analyzed using commercially available ELISA kits. T cell proliferation assays revealed that DCs pulsed with apoptotic tumor cell could stimulate an autologous T cell proliferation response with stimulation indices of 5-21. The T cell-mediated cytotoxicity assay demonstrated that tumor antigen-primed T cells could kill significantly more autologous tumor cells than normal cells (P<0.05). These cells had variable amounts of cytotoxic activity against K562 cells. Primed T cells released both IFN-gamma and IL-4 in response to re-stimulation by antigen-pulsed DCs, but were dominated by IFN-gamma production in two out of five patients and IL-4 production in three out of five patients. In conclusion, our results suggested that DCs pulsed with apoptotic breast tumor cells could elicit effective specific antitumor T cell responses in vitro. Therefore, vaccination with DCs pulsed with apoptotic tumor cells may be considered as a novel strategy for immunotherapy of patients with breast cancer refractory to standard modalities. PMID 19306994

Novel strategies for improved cancer vaccines.
Apr 2009 | Chen, Xiaochuan; Chang, Chien-Hsing; Goldenberg, David M
Therapeutic vaccination against cancer is an important modality complementing current standard therapies and may lead to long-term control of cancer. Numerous strategies are in development in an attempt to achieve better effectiveness but, except for the recent advent of vaccines against human papillomavirus, the long effort to produce a cancer vaccine has not succeeded. Nevertheless, a number of novel approaches can be pursued that, in our view, include optimized antigen design, in vivo-targeted dendritic cell vaccination and cancer vaccines used in combination with chemotherapy, monoclonal antibodies, adoptive T-cell transfer or stem cell transplantation. This article summarizes the rationale and development of these approaches for improved cancer vaccines. PMID 19397414

Vaccination strategies in patients with renal cell carcinoma.
Apr 2009 | Asemissen, Anne Marie; Brossart, Peter
Although new treatment options for patients with advanced renal cell cancer (RCC) have been developed within recent years, vaccination is still a promising emerging treatment option. An increasing number of tumor-associated antigens (TAA) available for RCC are currently used and analyzed for their efficacy for antigen-specific vaccine strategies. Recently, antigen-specific vaccination with dendritic cells in patients with metastatic RCC was shown to induce cytotoxic T cell response associated with objective clinical responses in some of the patients. Furthermore, current studies focus on the development of more effective vaccine regimes, such as the application of polyvalent, HLA-independent RNA coding for multiple TAA and adjuvants. First results demonstrate promising clinical and immunological efficacy. The efficacy of antigen-specific vaccination might be improved by a combination of tyrosine kinase inhibitors, since sunitinib was shown to promote T cell induction following vaccination in a mouse model and elimination of regulatory T cells. PMID 19360405

Dendritic cells: therapy and imaging.
Apr 2009 | Pham, Wellington; Kobukai, Saho; Hotta, Chie; Gore, John C
Dendritic cells (DCs) play a major role in cell-mediated immunotherapy. In this approach, DCs are isolated from cancer patients and pulsed with exogenous and specific tumor antigens in vitro, and the antigen-loaded DCs are then transferred to the hosts to enhance the immune response against tumor targets. Clinical observations and animal studies have shown that tumors can elicit immune responses caused by tumor infiltration of T-lymphocytes. Several pilot clinical trials have been recently conducted using this strategy for treating several types of cancers. PMID 19392575

Limited amounts of dendritic cells migrate into the T-cell area of lymph nodes but have high immune activating potential in melanoma patients.
Apr 2009 | Verdijk, Pauline; Aarntzen, Erik H J G; Lesterhuis, W Joost; Boullart, A C Inge; Kok, Ellemieke; van Rossum, Michelle M; Strijk, Simon; Eijckeler, Femke; Bonenkamp, Johannes J; Jacobs, Joannes F M; Blokx, Willeke; Vankrieken, J Han J M; Joosten, Irma; Boerman, Otto C; Oyen, Wim J G; Adema, Gosse; Punt, Cornelis J A; Figdor, Carl G; de Vries, I Jolanda M
The success of immunotherapy with dendritic cells (DC) to treat cancer is dependent on effective migration to the lymph nodes and subsequent activation of antigen-specific T cells. In this study, we investigated the fate of DC after intradermal (i.d.) or intranodal (i.n.) administration and the consequences for the immune activating potential of DC vaccines in melanoma patients. PMID 19318472

Short-term activation induces multifunctional dendritic cells that generate potent antitumor T-cell responses in vivo.
Apr 2009 | Wurzenberger, Cornelia; Koelzer, Viktor H; Schreiber, Susanne; Anz, David; Vollmar, Angelika M; Schnurr, Max; Endres, Stefan; Bourquin, Carole
Dendritic cell (DC) vaccines have emerged as a promising strategy to induce antitumoral cytotoxic T cells for the immunotherapy of cancer. The maturation state of DC is of critical importance for the success of vaccination, but the most effective mode of maturation is still a matter of debate. Whereas immature DC carry the risk of inducing tolerance, extensive stimulation of DC may lead to DC unresponsiveness and exhaustion. In this study, we investigated how short-term versus long-term DC activation with a Toll-like receptor 9 agonist influences DC phenotype and function. Murine DC were generated in the presence of the hematopoietic factor Flt3L (FL-DC) to obtain both myeloid and plasmacytoid DC subsets. Short activation of FL-DC for as little as 4 h induced fully functional DC that rapidly secreted IL-12p70 and IFN-alpha, expressed high levels of costimulatory and MHC molecules and efficiently presented antigen to CD4 and CD8 T cells. Furthermore, short-term activated FL-DC overcame immune suppression by regulatory T cells and acquired high migratory potential toward the chemokine CCL21 necessary for DC recruitment to lymph nodes. In addition, vaccination with short-term activated DC induced a strong cytotoxic T-cell response in vivo and led to the eradication of tumors. Thus, short-term activation of DC generates fully functional DC for tumor immunotherapy. These results may guide the design of new protocols for DC generation in order to develop more efficient DC-based tumor vaccines. PMID 18953536

Treatment of advanced metastasized breast cancer with bone marrow-derived tumour-reactive memory T cells: a pilot clinical study.
Apr 2009 | Schuetz, Florian; Ehlert, Katrin; Ge, Yingzi; Schneeweiss, Andreas; Rom, Joachim; Inzkirweli, Natalija; Sohn, Christoph; Schirrmacher, Volker; Beckhove, Philipp
Breast cancer patients frequently harbour tumour-reactive memory T cells in their bone marrow (BM) but not in the blood. After reactivation ex-vivo these cells rejected autologous breast tumours in xenotransplanted mice demonstrating therapeutic potential upon reactivation and mobilization into the blood. We conducted a clinical pilot study on metastasized breast cancer patients to investigate if ex-vivo reactivation of tumour-reactive BM memory T cells and their adoptive transfer is feasible and increases the frequencies of tumour-reactive T cells in the blood. PMID 18998129

DCVax-Brain and DC vaccines in the treatment of GBM.
Apr 2009 | Wheeler, Christopher J; Black, Keith L
DCVax-Brain (Northwest Biotherapeutics, Inc., Bethesda, MD, USA) is a personalized treatment for brain tumors. Its approach of administering autologous tumor antigen-bearing dendritic cells (DCs) has garnered hope for more effective and less toxic therapy for patients with malignant brain tumors including glioblastoma multiforme (GBM). DCVax-Brain composition and efficacy are not fully disclosed, although sponsors claim it is poised to critically test clinical DC vaccine efficacy in GBM patients. PMID 19335279

Prolonged survival of dendritic cell-vaccinated melanoma patients correlates with tumor-specific delayed type IV hypersensitivity response and reduction of tumor growth factor beta-expressing T cells.
Mar 2009 | López, Mercedes N; Pereda, Cristian; Segal, Gabriela; Muñoz, Leonel; Aguilera, Raquel; González, Fermín E; Escobar, Alejandro; Ginesta, Alexandra; Reyes, Diego; González, Rodrigo; Mendoza-Naranjo, Ariadna; Larrondo, Milton; Compán, Alvaro; Ferrada, Carlos; Salazar-Onfray, Flavio
The aim of this work was to assess immunologic response, disease progression, and post-treatment survival of melanoma patients vaccinated with autologous dendritic cells (DCs) pulsed with a novel allogeneic cell lysate (TRIMEL) derived from three melanoma cell lines. PMID 19139436

Androgen ablation augments prostate cancer vaccine immunogenicity only when applied after immunization.
Mar 2009 | Koh, Yi T; Gray, Andrew; Higgins, Sean A; Hubby, Bolyn; Kast, W Martin
Androgen ablation (AA) causes apoptosis of normal and neoplastic prostate cells. It is a standard treatment for advanced prostate cancer. Androgen ablation-mediated immunological effects include bone marrow hyperplasia, thymic regeneration, T and B cell lymphopoeisis and restoration of age-related peripheral T cell dysfunction. Androgens also regulate the transcription of several cytokines. Dendritic cells (DC) are the most potent antigen presenting cells that can activate antigen-specific naïve T cells. Despite myriad clinical trials involving DC-based prostate cancer immunotherapies, the effects of AA on DC function remain largely uncharacterized. Therefore, we investigated the effects of AA on DC and whether it could improve the efficacy of prostate cancer immunotherapy. PMID 19143030

A combination therapy of gemcitabine with immunotherapy for patients with inoperable locally advanced pancreatic cancer.
Mar 2009 | Hirooka, Yoshiki; Itoh, Akihiro; Kawashima, Hiroki; Hara, Kazuo; Nonogaki, Koji; Kasugai, Toshifumi; Ohno, Eizaburo; Ishikawa, Takuya; Matsubara, Hiroshi; Ishigami, Masatoshi; Katano, Yoshiaki; Ohmiya, Naoki; Niwa, Yasumasa; Yamamoto, Koji; Kaneko, Toru; Nieda, Mie; Yokokawa, Kiyoshi; Goto, Hidemi
Dendritic cell (DC) therapy frequently induces a measurable immune response. However clinical responses are seen in a minority of patients, presumably due to insufficient expansion of antigen-specific cytotoxic T lymphocytes (CTLs) capable of eradicating tumor cells. To increase therapeutic efficacy of DC-based vaccination, we have undertaken the first clinical trial involving a combination therapy of gemcitabine (GEM) with immunotherapy for patients with inoperable locally advanced pancreatic cancer. PMID 19276867

Tumour vaccine approaches for CNS malignancies: progress to date.
Mar 2009 | Ebben, Johnathan D; Rocque, Brandon G; Kuo, John S
Despite the many overall advances in understanding cancer biology and therapeutic development in the last 50 years, most CNS malignancies are still clinically difficult, incurable diseases. Current combinations of aggressive surgical resection, radiation therapy and chemotherapy regimens do not significantly improve long-term patient survival for these cancers. Cancer immunotherapy is a potentially promising new therapeutic strategy that primes a patient's immune system to attack neoplastic cells. We review the preclinical and clinical progress in developing vaccination-based therapy for CNS malignancies to date, including peptide-based vaccinations, dendritic cell-based vaccinations and other potential modalities. Some of the challenges for developing an effective vaccination strategy, such as abnormal immune molecules on glioma cells and abnormal lymphocyte populations within a glioma, are also discussed. PMID 19275269

Immunoregulatory T cells in the peripheral blood of melanoma patients treated with melanoma antigen-pulsed mature monocyte-derived dendritic cell vaccination.
Mar 2009 | Nakai, Noriaki; Katoh, Norito; Kitagawa, Tomoko; Ueda, Eiichiro; Takenaka, Hideya; Kishimoto, Saburo
Regulatory T cells (Treg) may inhibit monocyte-derived melanoma antigen-pulsed dendritic cells (DC) vaccination in treatment of melanoma. However, the Treg level in peripheral blood mononuclear cells (PBMCs) following DC vaccination has not been examined in melanoma patients in Japan. PMID 19157789

Antitumoral immune response by recruitment and expansion of dendritic cells in tumors infected with telomerase-dependent oncolytic viruses.
Feb 2009 | Edukulla, Ramakrishna; Ramakrishna, Edukulla; Woller, Norman; Mundt, Bettina; Knocke, Sarah; Gürlevik, Engin; Saborowski, Michael; Malek, Nisar; Manns, Michael P; Wirth, Thomas; Kühnel, Florian; Kubicka, Stefan
Virotherapy can potentially be used to induce tumor-specific immune responses and to overcome tumor-mediated tolerance mechanisms because apoptotic tumor cells are exposed together with viral danger signals during oncolysis. However, insufficient numbers of dendritic cells (DC) present at the site of oncolysis can limit a tumor-specific immune response and the resulting therapeutic benefit. We investigated MHC class I peptide-specific immune responses against model antigens ovalbumin (OVA) and hemagglutinin (HA) in mouse tumor models that support efficient replication of the oncolytic adenovirus hTert-Ad. Virotherapy resulted in peptide-specific cytotoxic T-cell responses against intracellular tumor antigens. Triggering of DC and T-cell infiltration to the oncolytic tumors by macrophage inflammatory protein 1alpha (MIP-1alpha, CCL3) and Fms-like tyrosine kinase-3 ligand (Flt3L) enhanced both antitumoral and antiviral immune responses. Although immune-mediated clearance of the virus can restrict therapeutic efficacy of virotherapy, MIP-1alpha/FLT3L-augmented hTert-Ad virotherapy inhibited local tumor growth more effectively than virotherapy alone. In agreement with the hypothesis that immune-mediated mechanisms account for improved outcome in MIP-1alpha/FLT3L virotherapy, we observed systemic antitumoral effects by MIP-1alpha/FLT3L virotherapy on uninfected lung metastasis in immunocompetent mice but not in nude mice. Furthermore, MIP-1alpha/FLT3L virotherapy of primary tumors was strongly synergistic with tumor DC vaccination in inhibition of established lung metastasis. Combined viroimmunotherapy resulted in long-term survival of 50% of treated animals. In summary, improvement of cross-presentation of tumor antigens by triggering of DC and T-cell infiltration during virotherapy enhances antitumoral immune response that facilitates an effective viroimmunotherapy of primary tumors and established metastases. PMID 19190348

Enhancement of dendritic cell-based vaccine potency by anti-apoptotic siRNAs targeting key pro-apoptotic proteins in cytotoxic CD8(+) T cell-mediated cell death.
Feb 2009 | Kim, Jin Hee; Kang, Tae Heung; Noh, Kyung Hee; Bae, Hyun Cheol; Kim, Seok-Ho; Yoo, Young Do; Seong, Seung-Yong; Kim, Tae Woo
Dendritic cells (DCs) have become an important measure for the treatment of malignancies. Current DC preparations, however, generate short-lived DCs because they are subject to cell death from various apoptotic pressures. Antigen-specific CD8(+) cytotoxic T lymphocytes (CTLs) is one of the main obstacles to limit the DC-mediated immune priming since CTLs can recognize the target antigen expressing DCs as target cells and kill the DCs. CTLs secret perforin and serine protease granzymes during CTL killing. Perforin and serine protease granzymes induce the release of a number of mitochondrial pro-apoptotic factors, which are controlled by members of the BCL-2 family, such as BAK, BAX and BIM. FasL linking to Fas on DCs triggers the activation of caspase-8, which eventually leads to mitochondria-mediated apoptosis via truncation of BID. In this study, we tried to enhance the DC priming capacity by prolonging DC survival using anti-apoptotic siRNA targeting these key pro-apoptotic molecules in CTL killing. Human papillomavirus (HPV)-16 E7 antigen presenting DCs that were transfected with these anti-apoptotic siRNAs showed increased resistance to T cell-mediated death, leading to enhanced E7-specific CD8(+) T cell activation in vitro and in vivo. Among them, siRNA targeting BIM (siBIM) generated strongest E7-specific E7-specific CD8(+) T cell immunity. More importantly, vaccination with E7 presenting DCs transfected with siBIM was capable of generating a marked therapeutic effect in vaccinated mice. Our data indicate that ex vivo manipulation of DCs with siBIM may represent a plausible strategy for enhancing dendritic cell-based vaccine potency. PMID 19135479

Targeting the immune system in cancer.
Feb 2009 | Chaudhuri, Devyani; Suriano, Robert; Mittelman, Abraham; Tiwari, Raj K
The concept of cancer immunotherapy provides a fresh perspective as it is not associated with many of the drawbacks of conventional therapies such as chemotherapy, radiotherapy and surgery. When fully activated the immune system has immense potential as is evident from mis-matched transplanted organs undergoing rapid immunological attack and rejection. However, the development of immune strategies for cancer therapy has been associated with challenges of their own. Early attempts at cancer vaccination were carried out in an empirical manner that did not always lead to reproducibility. This led to a search of tumor associated antigens with the belief that specific targeting of these antigens would lead to successful tumor elimination. Active vaccination with TAA peptides or passive vaccination with specific lymphocytes against these TAAs did not however demonstrate encouraging results in clinical trials. This was mainly because of the lack of an activating immune response which is required for continuous stimulation of lymphocytes and also because of the selection of tumor escape variants that did not express the particular TAA. On the positive side, attempts at characterizing TAAs illuminated the molecular changes that attribute a malignant phenotype to cancer cells. Attempts at cytokine therapy were also met with challenges of high systemic toxicity and a lack of specific lymphocyte activation. It was therefore realized that an ideal vaccinating agent should be able to combine the effects of both these therapeutic strategies, i.e., it should be able to induce an innate immune response which can be tailored to a tumor specific adaptive immune response. By this, the immunosuppressive tumor environment can be altered to become immune activating, thus facilitating the infiltration of myeloid and lymphoid cells that can act in concert leading to tumor regression. In this regard, immunotherapeutic approaches such as DNA vaccines, dendritic cell based vaccines, HSP based vaccines and gene transfer technology, are being developed and further refined to overcome their inherent limitations. Animal experiments with these therapeutic modalities have demonstrated exciting results, although their evaluation in clinical trials has not indicated exceptional tumor protection in a large percentage of the patients. These observations only further underscore the multivariate and dynamic nature of the immune system and the many ways in which tumor cells modulate themselves and their surroundings to escape immune surveillance. Assessment of successful therapeutic intervention will require periodic evaluations of the suppressive nature of the tumor microenvironment accompanied by qualitative and quantitative measurements of lymphocyte responses in patients. With the development of advanced genetic technologies and continuous identification of tumor antigens, the field of cancer immunotherapy is progressing at an exciting pace giving us hope for the advent of effective treatment modalities that will prolong tumor free survival and enhance the quality of life in patients with malignant disease. PMID 19199949

Physiological role of plasmacytoid dendritic cells and their potential use in cancer immunity.
Feb 2009 | Schettini, Jorge; Mukherjee, Pinku
Dendritic cells (DCs) play a pivotal role in the control of innate and adaptive immune responses. They are a heterogeneous cell population, where plasmacytoid dendritic cells (pDCs) are a unique subset capable of secreting high levels of type I IFNs. It has been demonstrated that pDCs can coordinate events during the course of viral infection, atopy, autoimmune diseases, and cancer. Therefore, pDC, as a main source of type I IFN, is an attractive target for therapeutic manipulations of the immune system to elicit a powerful immune response against tumor antigens in combination with other therapies. The therapeutic vaccination with antigen-pulsed DCs has shown a limited efficacy to generate an effective long-lasting immune response against tumor cells. A rational manipulation and design of vaccines which could include DC subsets outside "Langerhans cell paradigm" might allow us to improve the therapeutic approaches for cancer patients. PMID 19190769

Heat shock protein 70, released from heat-stressed tumor cells, initiates antitumor immunity by inducing tumor cell chemokine production and activating dendritic cells via TLR4 pathway.
Jan 2009 | Chen, Taoyong; Guo, Jun; Han, Chaofeng; Yang, Mingjin; Cao, Xuetao
Extracellular heat shock proteins (HSP) can activate dendritic cells (DC) and monocytes/macrophages, and HSP derived from tumor cells have been regarded as potent adjuvant facilitating presentation of tumor Ags and induction of antitumor immunity. However, the roles and the underlying mechanisms of releasable HSP in the induction of antitumor immunity have not been fully elucidated. In this study, we report that heat stress can induce the release of various HSP from tumor cells, which, in turn, activate tumor cells to produce chemokines for chemoattraction of DC and T cells via TLR4 signaling pathway. In vivo, we find that the infiltration and function of DC and T cells within tumor after local hyperthermia are increased significantly. We also provide evidence that HSP70 proteins released by tumor cells and TLR4 expressed by tumor cells/DC are essential for the chemoattraction of DC/T cells and for the subsequent induction of tumor-specific antitumor immunity. Therefore, our study suggests that heat stress-induced releasable HSP70 proteins from tumor cells play important roles in the initiation of antitumor immunity by inducing tumor cell production of chemokines and by activating the chemoattracted DC via TLR4 pathway. PMID 19155492

Recent advances in cancer vaccines: an overview.
Jan 2009 | Itoh, Kyogo; Yamada, Akira; Mine, Takashi; Noguchi, Masanori
The field of cancer vaccines is currently in an active state of clinical investigations. Human papilloma virus vaccine has been approved as a prophylactic cancer vaccine, while Oncophage (heat shock protein-peptide complex) was recently approved in Russia for a certain stage of kidney cancer, although to date none has been approved in Japan or the USA. We reviewed recent clinical trials of several different types of cancer vaccines, mainly by using PubMed from 2005 to 2008. There have been slow but substantial advances in peptide vaccines and dendritic cell-based vaccines with regard to both clinical responses and immunological markers. A personalized approach to boost immune responses, addition of chemotherapy to overcome robust cancers and changing of endpoints from tumor reduction to overall survival seem to be the three key elements for the development of therapeutic cancer vaccines. PMID 19015149

Dendritic cell-based therapeutic vaccination against myeloma: vaccine formulation determines efficacy against light chain myeloma.
Jan 2009 | Cohen, Sharon; Haimovich, Joseph; Hollander, Nurit
Multiple myeloma is an incurable plasma cell malignancy. Immunotherapy in myeloma patients had limited success to date. We have previously demonstrated that dendritic cells (DCs) pulsed with autologous Ig Id induced Id-reactive CD8(+) T cells and protection against a myeloma tumor challenge. In this work, we studied the therapeutic efficacy of chemotherapy combined with different formulations of DC-based vaccines in mice bearing large plasma cell tumors. The comparative study demonstrated that s.c. injection of DCs loaded with Id coupled to keyhole limpet hemocyanin, s.c. injection of DCs loaded with irradiated tumor cells, and intratumoral injection of naive DCs were similarly effective in mediating tumor regression and long-term survival. However, whereas the Id-keyhole limpet hemocyanin-DC vaccine was inefficient against myeloma cells that lost expression of the Ig H chain, intratumoral injection of naive DCs and s.c. injection of DCs loaded with irradiated tumor cells were highly effective against cells producing L chains only. This may be of particular importance for patients with L chain myeloma. Given that T cells respond primarily to peptides derived from H chain CDRs, attempts to treat L chain disease with myeloma protein-pulsed DCs may be futile. Vaccination with tumor cell-loaded DCs may, however, induce an effective antitumor response. PMID 19155516

Randomized clinical studies of anti-tumor vaccination: state of the art in 2008.
Dec 2008 | Fournier, Philippe; Schirrmacher, Volker
This review elucidates state-of-the-art clinical studies on active specific immunotherapy with tumor vaccines. It refers solely to randomized studies and has a special focus on patient's survival, the most important parameter for any therapy. Of special interest, from a tumor immunological point of view, is a comparison between the results obtained with allogeneic tumor cell-derived vaccines and those obtained with autologous tumor cell-derived vaccines. Overall, autologous vaccines have given better results than allogeneic vaccines. Random mutations in cancer generate unique antigens in each individual case. The superiority of autologous vaccines suggests that unique tumor-associated antigens are particularly important in generating responsive T cells for a therapeutic effect. PMID 19093773

Novel therapeutic strategies for treating esophageal adenocarcinoma: the potential of dendritic cell immunotherapy and combinatorial regimens.
Oct 2008 | Milano, Francesca; Krishnadath, Kausilia K
Esophageal adenocarcinoma (EAC) is an extremely aggressive disease with an overall 5 years survival rate of less than 20%. Current treatments, such as surgery, or chemo- and radiotherapy have only little effect on survival. Attempts to combine these treatment modalities were only limited successful with marginal improvement of prognosis. Therefore, novel treatment strategies are urgently needed. In a previous study we demonstrated that dendritic cell (DC) immunotherapy may be an attractive and promising approach to treat EAC. Although potent immune responses can be raised by DC therapy, there are several concerns about the immunosuppressive microenvironment that characterizes these cancers, which may inhibit an effective immune response. Here a general overview is given of the current management of EAC and immunotherapies. More specific focus is on the EAC tumor microenvironment, and several potential combinatorial strategies that can be explored for improving treatment of EAC. PMID 18703104

Dendritic cell vaccines in metastasized malignant melanoma.
Oct 2008 | Erdmann, M; Schuler-Thurner, B
Dendritic cells as immunotherapeutic agents against malignancies have been applied for over ten years. Proof of principle studies demonstrated immunogenicity of dendritic cells even in patients suffering from advanced malignancies. Clinicians and immunologists early focused on this innovative immunotherapeutic approach in metastasized malignant melanoma--a malignancy so far resisting most traditional oncologic treatment modalities. In this review we summarize the experience obtained of dendritic cell therapy in patients with malignant melanoma and state past, present and future obstacles. So far over 850 melanoma patients in 51 trials have been reported since 1998. Within these trials there exists a vast heterogeneity concerning type of dendritic cell applied, differentiation and maturation of dendritic cells, type of antigen target and nature, application mode, number of cells applied, vaccination intervals in addition to patients treated at various stages of melanoma. A minority of patients developed anticipated autoimmune adverse events in addition to expected immune system activation symptoms such as fever and local site reaction. As only solitary World Health Organization (WHO) grade III or IV adverse events were reported one can state that dendritic cell therapy is safe. Objective clinical responses have repeatedly been observed in a minority of heavily pretreated and far advanced melanoma patients. Future challenges include optimization and standardization of dendritic cell generation and application, addition of synergistic immunomodulatory agents to enhance immunogenicity and block tumor escape and treatment of patients at earlier stages of disease who will benefit from this innovative therapy. PMID 18833080

Cancer immunotherapy by dendritic cells.
Sep 2008 | Melief, Cornelis J M
Cancerous lesions promote tumor growth, motility, invasion, and angiogenesis via oncogene-driven immunosuppressive leukocyte infiltrates, mainly myeloid-derived suppressor cells, tumor-associated macrophages, and immature dendritic cells (DCs). In addition, many tumors express or induce immunosuppressive cytokines such as TGF-beta and IL-10. As a result, tumor-antigen crosspresentation by DCs induces T cell anergy or deletion and regulatory T cells instead of antitumor immunity. Tumoricidal effector cells can be generated after vigorous DC activation by Toll-like receptor ligands or CD40 agonists. However, no single immunotherapeutic modality is effective in established cancer. Rather, chemotherapies, causing DC activation, enhanced crosspresentation, lymphodepletion, and reduction of immunosuppressive leukocytes, act synergistically with vaccines or adoptive T cell transfer. Here, I discuss the considerations for generating promising therapeutic antitumor vaccines that use DCs. PMID 18799145

Alterations in p53-specific T cells and other lymphocyte subsets in breast cancer patients during vaccination with p53-peptide loaded dendritic cells and low-dose interleukin-2.
Aug 2008 | Svane, Inge Marie; Pedersen, Anders E; Nikolajsen, Kirsten; Zocca, Mai-Britt
We have previously established a cancer vaccine using autologous DCs, generated by in vitro stimulation with IL-4 and GM-CSF, and pulsed with six HLA-A*0201 binding wild-type p53 derived peptides. This vaccine was used in combination with low-dose interleukin-2 in a recently published clinical Phase II trial where 26 HLA-A2+ patients with progressive late-stage metastatic breast cancer (BC) were included. Almost 1/3rd of the patients obtained stable disease or minor regression during treatment with a positive correlation to tumour over-expression of p53. In the present study, we performed a comprehensive analysis of the effector stage of the p53-specific CD8+ T cells by the use of Dextramer Technology and multicolour FACS. Pre- and post-treatment blood samples from eight BC patients were analysed. Independent of clinical outcome p53-specific T cells were phenotypic distinctly antigen experienced (CD44high, CCR-7low and CD62Llow). Furthermore, fresh blood from 18 cancer patients included in the vaccination trial were prospectively examined for more general treatment associated quantitative and qualitative changes in T cell subpopulations. We found that the frequency of CD4+ CD25high regulatory T cells was almost doubled after only 4 weeks of weekly vaccination and low-dose IL-2. In addition, a decrease in the percentage of CD27highCCR-7high CD4/CD8 naïve T cells was measured particularly in patients with progressive disease during vaccination. Finally, prior to immunotherapy a higher percentage of both CD28 and CD27 positive CD8naïve/early effector memory T cells were present in chemotherapy-treated patients. PMID 18616968

Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients.
Jul 2008 | Wheeler, Christopher J; Black, Keith L; Liu, Gentao; Mazer, Mia; Zhang, Xiao-xue; Pepkowitz, Samuel; Goldfinger, Dennis; Ng, Hiushan; Irvin, Dwain; Yu, John S
Cancer vaccine trials have failed to yield robust immune-correlated clinical improvements as observed in animal models, fueling controversy over the utility of human cancer vaccines. Therapeutic vaccination represents an intriguing additional therapy for glioblastoma multiforme (GBM; grade 4 glioma), which has a dismal prognosis and treatment response, but only early phase I vaccine trial results have been reported. Immune and clinical responses from a phase II GBM vaccine trial are reported here. IFN-gamma responsiveness was quantified in peripheral blood of 32 GBM patients given therapeutic dendritic cell vaccines. Posttreatment times to tumor progression (TTP) and survival (TTS) were compared in vaccine responders and nonresponders and were correlated with immune response magnitudes. GBM patients (53%) exhibited >or=1.5-fold vaccine-enhanced cytokine responses. Endogenous antitumor responses of similar magnitude occurred in 22% of GBM patients before vaccination. Vaccine responders exhibited significantly longer TTS and TTP relative to nonresponders. Immune enhancement in vaccine responders correlated logarithmically with TTS and TTP spanning postvaccine chemotherapy, but not with initial TTP spanning vaccination alone. This is the first report of a progressive correlation between cancer clinical outcome and T-cell responsiveness after therapeutic vaccination in humans and the first tracing of such correlation to therapeutically exploitable tumor alteration. As such, our findings offer unique opportunities to identify cellular and molecular components of clinically meaningful antitumor immunity in humans. PMID 18632651

Ex vivo recovery and activation of dysfunctional, anergic, monocyte-derived dendritic cells from patients with operable breast cancer: critical role of IFN-alpha.
Jul 2008 | Satthaporn, Sukchai; Aloysius, Mark M; Robins, Richard A; Verma, Chandan; Chuthapisith, Suebwong; McKechnie, Alasdair J; El-Sheemy, Mohamad; Vassanasiri, Wichai; Valerio, David; Clark, David; Jibril, Jibril A; Eremin, Oleg
Dendritic cells (DCs) play a crucial role in initiating effective cell-mediated immune responses, but are dysfunctional and anergic in breast cancer. Reversal of this dysfunction and establishment of optimal DC function is a key prerequisite for the induction of effective anti-cancer immune responses. PMID 18588665

Dendritic cell vaccination with xenogenic polypeptide hormone induces tumor rejection in neuroendocrine cancer.
Jul 2008 | Papewalis, Claudia; Wuttke, Margret; Seissler, Jochen; Meyer, Yvonne; Kessler, Caroline; Jacobs, Benedikt; Ullrich, Evelyn; Willenberg, Holger S; Schinner, Sven; Baehring, Thomas; Scherbaum, Werner A; Schott, Matthias
No relevant breakthrough has yet been achieved in the identification of tumor antigens in many neuroendocrine cancer types that exist, such as malignant gastrinoma, insulinoma, or medullary thyroid carcinoma. The aim of this study was to proof the concept of dendritic cell immunization with a tumor cell-specific polypeptide hormone as a target molecule in a transgenic mouse model for medullary thyroid carcinoma (Ret/Cal mice). PMID 18594013

Maximizing dendritic cell migration in cancer immunotherapy.
Jun 2008 | Verdijk, Pauline; Aarntzen, Erik H J G; Punt, Cornelis J A; de Vries, I Jolanda M; Figdor, Carl G
The success of dendritic cell (DC)-based immunotherapy in inducing cellular immunity against tumors is highly dependent on accurate delivery and trafficking of the DC to T-cell-rich areas of secondary lymphoid tissues. PMID 18549318

Therapeutic vaccination with dendritic cells pulsed with tumor-derived Hsp70 and a COX-2 inhibitor induces protective immunity against B16 melanoma.
Jun 2008 | Toomey, Deirdre; Conroy, Helen; Jarnicki, Andrew G; Higgins, Sarah C; Sutton, Caroline; Mills, Kingston H G
Prophylactic immunization of mice with autologous tumor-derived heat shock proteins (Hsp) generates effective anti-tumor immunity. However, this approach is ineffective when used therapeutically, partly due to the immunosuppressive effects of the growing tumor. Here we sought to overcome this problem by therapeutic vaccination with dendritic cells (DC) pulsed with Hsp70 and a COX-2 inhibitor. We found that Hsp70 induces IL-6 and IL-10 production and suppressed expression of CD40 on DC. Incubation of DC with tumor-conditioned medium attenuated Hsp70-induced expression of CD80 and induced expression of COX-2. Inhibition of COX-2 partially reversed the stimulatory effect of Hsp70 on DC IL-6 and IL-10 production and enhanced expression of CD80 and MHC classes I and II. Therapeutic administration of DC pulsed in vitro with Hsp70 in the presence of a COX-2 inhibitor significantly reduced progression of B16 tumors in mice and significantly enhanced survival. This was associated with a reduction in the frequency of IL-10-producing CD4(+) T cells and enhancement of IFN-gamma-producing CD8(+) T cells. Our findings provide a novel immunotherapeutic approach against cancer based on attenuation of COX-2-mediated immunosuppression using in vitro modulated DC. PMID 18479787

Postoperative adjuvant dendritic cell-based immunotherapy in patients with relapsed glioblastoma multiforme.
May 2008 | De Vleeschouwer, Steven; Fieuws, Steffen; Rutkowski, Stefan; Van Calenbergh, Frank; Van Loon, Johannes; Goffin, Jan; Sciot, Raf; Wilms, Guido; Demaerel, Philippe; Warmuth-Metz, Monika; Soerensen, Niels; Wolff, Johannes E A; Wagner, Sabine; Kaempgen, Eckhart; Van Gool, Stefaan W
To investigate the therapeutic role of adjuvant vaccination with autologous mature dendritic cells (DC) loaded with tumor lysates derived from autologous, resected glioblastoma multiforme (GBM) at time of relapse. PMID 18483377

Dendritic cell immunotherapy for malignant gliomas.
May 2008 | Luptrawan, Anne; Liu, Gentao; Yu, John S
The prognosis for patients with malignant gliomas remains poor despite advances in surgical technique, chemotherapy and radiation therapy. Median survival for glioblastoma multiforme, the most aggressive and deadliest form of brain cancer, remains only fifteen months even after optimal treatment with surgical resection followed by chemoradiation therapy. The grim prognosis can be attributed to the infiltrative nature of the disease, a central nervous system microenvironment that can escape immune surveillance and resistance of the tumor to chemotherapy. In recent trials, dendritic cells have demonstrated an ability to promote an effective anti-tumor immune response and sensitize glioma cells to chemotherapy. This review will discuss the results of dendritic-cell based immunotherapy clinical trials for the treatment of malignant gliomas and explore the future strategies of DC vaccines for glioma immunotherapy. PMID 18474011

Cell- and peptide-based immunotherapeutic approaches for glioma.
May 2008 | Yamanaka, Ryuya
Glioblastoma multiforme (GBM) is the most common and lethal primary malignant brain tumor. Although considerable progress has been made in surgical and radiation treatment for glioma patients, the impact of these advances on clinical outcome has been disappointing. Therefore, the development of novel therapeutic approaches is essential. Recent reports demonstrate that systemic immunotherapy using dendritic cells (DCs) or peptide vaccines is capable of inducing an antiglioma response. These approaches successfully induce an antitumor immune response and prolong survival in patients with glioma without major side effects. There are several types of glioma, so to achieve effective therapy, it might be necessary to evaluate the molecular genetic abnormalities in individual patient tumors and design novel immunotherapeutic strategies based on the pharmacogenomic findings. Here, we review recent advances in DC- and peptide-based immunotherapy approaches for patients with gliomas. PMID 18403264

Immunotherapy of hematological malignancies using dendritic cells.
Apr 2008 | Van de Velde, Ann L R; Berneman, Zwi N; Van Tendeloo, Viggo F I
The arsenal of therapeutic weapons against hematological malignancies is constantly growing. Unravelling the secrets of tumor immunobiology has allowed researchers to manipulate the immune system in order to stimulate tumor immunity or to bypass tumor-induced immunosuppression. An area of great interest is active specific immunotherapy where dendritic cell (DC)-based therapeutic vaccines for cancer have definitely grabbed the spotlight. DC are intensively investigated as cellular adjuvants to harness the immune system to fight off cancer by augmenting the number and effector functions of tumor-specific CD8+ cytotoxic T lymphocytes. In the present review we present a comprehensive synopsis and an update of the use of DC in hematological malignancies. In the future, more basic research as well as more clinical trials are warranted to fully establish the value of DC vaccination as an adjuvant therapy for modern hematological oncology. PMID 18390412

Dendritic cell vaccines in melanoma: from promise to proof?
Apr 2008 | Lesterhuis, W J; Aarntzen, E H J G; De Vries, I J M; Schuurhuis, D H; Figdor, C G; Adema, G J; Punt, C J A
Dendritic cells (DC) are the directors of the immune system, capable of inducing tumour antigen-specific T- and B-cell responses. As such, they are currently applied in clinical studies in cancer patients. Early small clinical trials showed promising results, with frequent induction of anti-cancer immune reactivity and clinical responses. In recent years, additional trials have been carried out in melanoma patients, and although immunological responses are often reported, objective clinical responses remain anecdotal with objective response rates not exceeding 5-10%. Thus, DC vaccination research has now entered a stage in between 'proof of principle' and 'proof of efficacy' trials. Crucial questions to answer at this moment are why the clinical responses remain scarce and what can be done to improve the efficacy of vaccination. The answers to these questions probably lie in the preparation and administration of the DC vaccines. Predominantly, cytokine-matured DC are used in clinical studies, while from preclinical studies it is evident that DC that are activated by pathogen-associated molecules are much more potent T cell activators. For sake of easy accessibility monocyte-derived DC are often used, but are these cells also the most potent type of DC? Other yet unsettled issues include the optimal antigen-loading strategy and route of administration. In addition, trials are needed to investigate the value of manipulating tolerizing mechanisms, such as depletion of regulatory T cells or blockade of the inhibitory T cell molecule CTLA-4. These issues need to be addressed in well-designed comparative clinical studies with biological endpoints in order to determine the optimal vaccine characteristics. DC vaccination can then be put to the ultimate test of randomized clinical trials. Here, we review the immunobiology of DC with emphasis on the different aspects that are most relevant for the induction of anti-tumour responses in vivo. The different variables in preparing and administering DC vaccines are discussed in this context and the immunological and clinical results of studies with DC vaccines in melanoma patients are summarized. PMID 18262431

Delivery of whole tumor lysate into dendritic cells for cancer vaccination.
Mar 2008 | Liu, Linda N; Shivakumar, Rama; Allen, Cornell; Fratantoni, Joseph C
Results from multiple human studies have continued to spur the development of dendritic cells (DCs) as therapeutic vaccines for the treatment of cancer, chronic viral infections, and autoimmune diseases. The antigen-specific activity of DCs is dependent on the ability of the DCs to take up and process tumor-associated antigens for presentation to the immune system. Although immature DCs have been shown to naturally take up tumor-associated antigens by phagocytosis, approaches that significantly affect antigen delivery need further evaluation, especially if such methodologies can be demonstrated to result in the elicitation of more robust and comprehensive immune responses. We have developed a rapid, robust, scalable, and regulatory-compliant process for loading DCs with whole tumor lysate. The use of whole tumor lysate facilitates the generation of a more robust immune response targeting multiple unique antigenic determinants in patient's tumors and likely reduces the tumor's potential of immune escape. We demonstrate that DCs electroloaded with tumor lysate elicit significantly stronger antitumor responses both in a tumor challenge model and in a therapeutic vaccination model for preexisting metastasic disease. These effects are observed in a processing scheme that requires 20- to 40-fold lower amounts of tumor lysate when compared with the standard coincubation/coculture methods employed in loading DCs. PMID 18370195

Copulsing tumor antigen-pulsed dendritic cells with zoledronate efficiently enhance the expansion of tumor antigen-specific CD8+ T cells via Vgamma9gammadelta T cell activation.
Feb 2008 | Takahara, Masashi; Miyai, Manami; Tomiyama, Mai; Mutou, Masato; Nicol, Andrew J; Nieda, Mie
We demonstrate that Vgamma9gammadelta T cells activated by zoledronate can link innate and acquired immunity through crosstalk with dendritic cells (DCs) in a way that can amplify activation and proliferation of tumor antigen-specific CD8+ T cells. DCs pulsed with antigen alone or antigen plus zoledronate were used to stimulate the in vitro expansion of antigen-specific CD8+ T cells. MART-1-modified peptide (A27L peptide) and apoptotic HLA-A*0201-positive, MART-1-positive JCOCB tumor cell lines were used as tumor antigen sources. The percentage of A27L-specific CD8+ T cells within the responding lymphocytes on Day 7 when immature DCs (imDCs) were cultured in the presence of A27L peptide and 0.01 microM zoledronate was significantly higher (P=0.002, n=11) than that observed when imDCs were cultured with the lymphocytes in the presence of the A27L peptide alone. This enhancing effect of zoledronate was significantly reduced when gammadelta T cells were depleted from responding lymphocytes (P=0.030, n=5), indicating that the effect is mediated mainly through Vgamma9gammadelta T cells activated by zoledronate-pulsed imDCs. When imDCs copulsed with zoledronate and apoptotic JCOCB tumor cell lines were used, the percentage of A27L-specific CD8+ T cells was higher than that observed using imDCs with the apoptotic JCOCB lines alone, suggesting that zoledronate treatment of imDCs enhances the cross-presentation ability of DCs. These findings suggest a potentially valuable role for Vgamma9gammadelta T cell activation for expanding antigen-specific CD8+T cells using DCs copulsed with tumor antigen and zoledronate in the design of vaccine therapies for malignancy. PMID 18156189

Dendritic cell vaccination induces tumor epitope-specific Th1 immune response in medullary thyroid carcinoma.
Feb 2008 | Papewalis, C; Wuttke, M; Jacobs, B; Domberg, J; Willenberg, H; Baehring, T; Cupisti, K; Raffel, A; Chao, L; Fenk, R; Seissler, J; Scherbaum, W A; Schott, M
The existence of inherited aggressive forms of medullary thyroid carcinoma (MTC) and their resistance to classical therapies make it a prime candidate for adoptive immunotherapy. Highly potent antigen-presenting cells, namely dendritic cells (DCs), may serve as an interesting tool for anticancer vaccination. Here we report on the IN VITRO findings of a vaccination trial in five MTC patients, who were treated with a new DC generation protocol consisting of granulocyte-macrophage colony-stimulating factor and interferon-alpha (IFN-DCs). These cells were pulsed with tumor-specific calcitonin and administered twice. In two patients who responded to therapy we found a large increase (in mean 2.9+/-1.9%) of antigen-specific IFN-gamma-secreting CD4+ cells as well as an increase of granzyme B positive CD8+ cells (mean 2.2+/-0.2%) in the peripheral blood. In parallel, a decrease of CD4+/CD25+/FoxP3+ regulatory T cells was seen. Importantly, IN VITRO stimulation of PBMC with 10 different 15mer calcitonin peptides resulted in the identification of two HLA class II epitope regions within the central part of full-length calcitonin. These data were in accordance with the results drawn from the computer-based algorithm epitope prediction software SYFPEITHI. Measurement of different pro- and anti-angiogenic factors did not allow for a distinct outcome of prediction of the treated patients. In summary, we have demonstrated that immunization with IFN-DCs leads to a tumor epitope-specific immune response in MTC patients and may, therefore, represent a promising tool for future vaccination trials. PMID 18283628

Immunotherapy opportunities in ovarian cancer.
Feb 2008 | Chu, Christina S; Kim, Sarah H; June, Carl H; Coukos, George
Ovarian cancer is responsible for the majority of gynecologic cancer deaths and despite the highest standard of multimodality therapy with surgery and cytotoxic chemotherapy, long-term survival remains low. With compelling evidence that epithelial ovarian cancer is an immunogenic tumor capable of stimulating an antitumor immune response, renewed efforts to develop immune therapies to augment the efficacy of traditional therapies are underway. Current immunotherapies focus on varied modes of antitumor vaccine development, particularly with the use of dendritic cell vaccines, effective methods for adoptive T-cell transfer and combinatorial approaches with immune modulatory therapy subverting natural tolerance mechanisms or boosting effector mechanisms. Additional combinatorial approaches include the use of cytokines and/or chemotherapy with immune therapy. PMID 18279065

[Effects of intratumoral injection therapy of dendritic cells combined with hyperthermia for cancer patients].
Jan 2008 | Takeda, Tsutomu; Dong, Xianhui; Takeda, Hiroko; Haba, Akinao; Takeda, Yutaka
We proceeded with intratumoral injection therapy of dendritic cells (DC) in combination with hyperthermia for 41 cancer patients in the past two years. We confirmed a total of two CR cases (one of them already reported). We report two successful cases in this paper. Case 1: A uterine cervical cancer patient with metastases in cervical and abdominal lymphnodes was treated with intratumoral DC injection therapy combined with hyperthermia in cervical. She showed a CR not only in cervical but also in abdominal lymph nodes. Case 2: A sialyl grand cancer patient with metastases in cervical and axillary lymphnodes was treated with intratumoral DC injection therapy combined with hyperthermia in cervical. She showed a PR. PMID 18219848

The 'kiss of death' by dendritic cells to cancer cells.
Dec 2007 | Chan, C W; Housseau, F
Dendritic cells (DCs) are professional antigen-presenting cells (APCs) specialized in the stimulation of naïve T lymphocytes, which are key components of antiviral and antitumor immunity. DCs are 'sentinels' of the immune system endowed with the mission to (1) sense invading pathogens as well as any form of tissue distress and (2) alert the effectors of the immune response. They represent a very heterogeneous population including subsets characterized by their anatomical locations and specific missions. Beyond their unique APC features, DCs exhibit a large array of effector functions that play critical roles in the induction and regulation of the cell-mediated as well as humoral immune responses. In the course of the antitumor immune response, DCs are unique in engulfing tumor cells killed by natural killer (NK) cells and cross-presenting tumor-associated antigens to cytotoxic T lymphocytes (CTLs). However, while DCs mediate antitumor immune responses by stimulating tumor-specific CTLs and NK cells, direct tumoricidal mechanisms have been recently evoked. This review addresses the other face of DCs to directly deliver apoptotic signals to stressed cells, their role in tumor cell death, and its implication in the design of DC-based cancer immunotherapies. PMID 17948029

Numerical and functional defects of blood dendritic cells in early- and late-stage breast cancer.
Oct 2007 | Pinzon-Charry, A; Ho, C S K; Maxwell, T; McGuckin, M A; Schmidt, C; Furnival, C; Pyke, C M; López, J A
The generation of antitumour immunity depends on the nature of dendritic cell (DC)-tumour interactions. These have been studied mostly by using in vitro-derived DC which may not reflect the natural biology of DC in vivo. In breast cancer, only one report has compared blood DC at different stages and no longitudinal evaluation has been performed. Here we conducted three cross-sectional and one one-year longitudinal assessments of blood DC in patients with early (stage I/II, n=137) and advanced (stage IV, n=36) disease compared to healthy controls (n=66). Patients with advanced disease exhibit markedly reduced blood DC counts at diagnosis. Patients with early disease show minimally reduced counts at diagnosis but a prolonged period (1 year) of marked DC suppression after tumour resection. While differing in frequency, DC from both patients with early and advanced disease exhibit reduced expression of CD86 and HLA-DR and decreased immunostimulatory capacities. Finally, by comparing a range of clinically available maturation stimuli, we demonstrate that conditioning with soluble CD40L induces the highest level of maturation and improved T-cell priming. We conclude that although circulating DC are compromised by loco-regional and systemic breast cancer, they respond vigorously to ex vivo conditioning, thus enhancing their immunostimulatory capacity and potential for immunotherapy. PMID 17923873

Regression of intestinal adenomas by vaccination with heat shock protein 105-pulsed bone marrow-derived dendritic cells in Apc(Min/+) mice.
Oct 2007 | Yokomine, Kazunori; Nakatsura, Tetsuya; Senju, Satoru; Nakagata, Naomi; Minohara, Motozumi; Kira, Jun-Ichi; Motomura, Yutaka; Kubo, Tatsuko; Sasaki, Yutaka; Nishimura, Yasuharu
Heat shock protein (HSP) 105 is overexpressed in various cancers, but is expressed at low levels in many normal tissues, except for the testis. A vaccination with HSP105-pulsed bone marrow-derived dendritic cells (BM-DC) induced antitumor immunity without causing an autoimmune reaction in a mouse model. Because Apc(Min/+) mice develop multiple adenomas throughout the intestinal tract by 4 months of age, the mice provide a clinically relevant model of human intestinal tumor. In the present study, we investigated the efficacy of the HSP105-pulsed BM-DC vaccine on tumor regression in the Apc(Min/+) mouse. Western blot and immunohistochemical analyses revealed that the tumors of the Apc(Min/+) mice endogenously overexpressed HSP105. Immunization of the Apc(Min/+) mice with a HSP105-pulsed BM-DC vaccine at 6, 8, and 10 weeks of age significantly reduced the number of small-intestinal polyps accompanied by infiltration of both CD4(+) and CD8(+) T cells in the tumors. Cell depletion experiments proved that both CD4(+) and CD8(+) T cells play a critical role in the activation of antitumor immunity induced by these vaccinations. These findings indicate that the HSP105-pulsed BM-DC vaccine can provide potent immunotherapy for tumors that appear spontaneously as a result of the inactivation of a tumor suppressor gene, such as in the Apc(Min/+) mouse model. PMID 17892515

Phase I/II clinical trial of sequential subcutaneous and intravenous delivery of dendritic cell vaccination for refractory multiple myeloma using patient-specific tumour idiotype protein or idiotype (VDJ)-derived class I-restricted peptides.
Oct 2007 | Curti, Antonio; Tosi, Patrizia; Comoli, Patrizia; Terragna, Carolina; Ferri, Elisa; Cellini, Claudia; Massaia, Massimo; D'Addio, Alessandra; Giudice, Valeria; Di Bello, Cristiana; Cavo, Michele; Conte, Roberto; Gugliotta, Gabriele; Baccarani, Michele; Lemoli, Roberto M
Fifteen multiple myeloma (MM) patients who had failed maintenance therapy after tandem autologous stem cell transplantation underwent anti-idiotype (Id) vaccination with dendritic cells (DCs). CD14(+)-derived DCs were loaded with the autologous Id as whole protein (=6) or Id-derived class I-restricted peptides (=9) and keyhole limpet hemocyanin (KLH). Vaccination consisted of three subcutaneous (sc) and two intravenous injections of increasing DC doses at 2 weeks interval. DC therapy was well tolerated. Most patients developed both humoral and T-cell responses to KLH, suggesting immunocompetence. Eight of 15 patients developed an Id-specific T-cell proliferative response, 8/15 increased interferon-gamma-secreting T cells and 4/15 showed an Id-positive delayed-type hypersensitivity test. Anti-Id cytotoxic T-lymphocyte precursors increased after DC vaccination in 2/2 evaluable patients. A more robust T-cell response was observed after sc DC injections and increased Id-specific T-cell proliferation was found up to 1 year after vaccination. VDJ-derived peptides were as effective as the whole protein in stimulating T-cell responses. Clinically, 7/15 patients have stable disease after a median follow-up of 26 months, one patient achieved durable partial remission after 40 months, and seven patients progressed. In conclusion, sc injections of cryopreserved Id-pulsed DCs were safe and, in contrast with intravenous administrations, induced anti-MM T-cell responses. PMID 17910631

Dendritic cells fused with allogeneic breast cancer cell line induce tumor antigen-specific CTL responses against autologous breast cancer cells.
Sep 2007 | Zhang, Yunfei; Ma, Baoan; Zhou, Yong; Zhang, Minghua; Qiu, Xiuchun; Sui, Yanfang; Zhang, Xiumin; Ma, Bin; Fan, Qingyu
Dendritic cell (DC)/tumor cell fusion vaccine has been revealed as a promising tool for the antitumor immunotherapy. Previous research has shown that fusion hybrids of human DCs and autologous tumor cells can induce cytotoxic T lymphocyte (CTL) responses against autologous tumor cells in animal models and human clinical trials. However, a major restriction factor for the clinical use is the difficulty for preparation of sufficient amount of autologous tumor cells especially for the patients with metastasis cancer whose primary tumor lesion is not clear or has been resected. In this study, allogeneic breast cancer cell line MCF-7 cells were electrofused to autologous DCs from patient with breast cancer as a strategy to deliver shared breast cancer antigens to DCs. Fusion cells generated by autologous DCs and allogeneic MCF-7 were able to induce autologous T lymphocytes proliferation, high levels of IFN-gamma production and CTL responses. CTLs induced by DCs/allogeneic MCF-7 fusion cells were able to kill autologous breast cancer cells in an antigen specific and HLA restriction manner. Our study may provide the experiment basis for the use of allogeneic breast cancer cell line in the DC/tumor cell fusion cell vaccination strategy. PMID 17187233

DC immunotherapy is highly effective for the inhibition of tumor metastasis or recurrence, although it is not efficient for the eradication of established solid tumors.
Aug 2007 | Lim, Dae-Seog; Kim, Jeong-Hwan; Lee, Dong-Seong; Yoon, Cheol-Hee; Bae, Yong-Soo
Dendritic cell (DC)-based immunotherapy has not been as effective as expected in most solid tumors even in the murine model, particularly in renal cell carcinoma (RCC). Our investigation was initiated to identify what causes the limitations of DC-based immunotherapy in solid RCC. We have investigated immunosuppressive factors from tumors and their effects on DC migration, as well as cytotoxic T lymphocyte (CTL) response and lymphocyte infiltration into the tumor mass upon vaccination with mouse renal adenocarcinoma (Renca) cell lysate-pulsed bone marrow (Bm)-derived DC in tumor-bearing mice. We also investigated pulmonary metastasis- and tumor recurrence-inhibitory effects of DC-vaccination in the solid tumor-bearing mice. In these experiments, we found that the limitations of DC-based immunotherapy to solid RCC likely result from tumor-mediated TGF-beta hindrance of immune attack rather than insufficient immune induction by DC therapy. In fact, the CTL response induced by DC therapy was quite sufficient and functional for the inhibition of tumor recurrence after surgery or of tumor metastasis induced by additional tumor-challenge to the tumor-bearing mice. Taken together, our present results obtained in mouse model suggest the potential of DC immunotherapy in tumor patients for hindering or blocking disease progression by inhibition of tumor metastasis and/or tumor recurrence after surgery. PMID 17443323

Immunization of NSCLC patients with antigen-pulsed immature autologous dendritic cells.
Aug 2007 | Hirschowitz, Edward A; Foody, Terry; Hidalgo, Giovanna E; Yannelli, John R
Only a handful of NSCLC patients have been included in dendritic cell (DC) vaccine clinical trials. We had previously reported a series of 16 individuals with stages IA-IIIB NSCLC who received autologous DC vaccines matured with dendritic cell/T cell-derived maturation factor (DCTCMF). Here we report the results of a continuation study with similar inclusion criteria, immunization protocol, and analysis, using an immature DC vaccine. Of the 14 participants, 7 had undergone surgical resection (stage I/II), with or without adjuvant therapy, and 7 with unresectable stage III had been treated with chemo-radiation alone. Autologous DCs were pulsed with apoptotic bodies derived from an allogeneic NSCLC cell line that over-expresses Her2/neu, CEA, WT1, Mage2, and survivin. DCs were not exposed to any maturation stimulus. Individuals received two intradermal vaccines (average 8.1x10(7) DC per immunization) 1 month apart. Immune responses were measured by IFN-gamma ELISPOT, comparing relative number of antigen-reactive T-cells from pre-vaccine to timepoints post-immunization. Immunologic responses were seen in 4/7 stage III unresectable, and 6/7 stage I/II surgically resected patients, including 3/3 resected patients who had also received adjuvant chemo-radiation. There were no related adverse events. One of seven surgically resected patients recurred and 4/7 stage III patients progressed. Three of five patients with progressive disease showed no immunologic response. Data indicate that immature DC pulsed with apoptotic tumour cells have similar biologic activity to a DCTCMF-matured DC preparation delivered in a similar clinical protocol. Therapeutic efficacy is unknown and clinical outcomes are anecdotal. PMID 17509725

Immunological role of dendritic cells in cervical cancer.
Aug 2007 | Manickam, Alagar; Sivanandham, Muthukumaran; Tourkova, Irina L
Cervical cancer is the second most frequent gynecological malignancy in the world. Human papillomavirus (HPV) infection is the primary etiologic agent of cervical cancer. However, HPV alone is not sufficient for tumor progression. The clinical manifestation of HPV infection depends also on the host's immune status. Both innate and adaptive immunity play a role in controlling HPV infection. In untransformed HPV-infected keratinocytes, the innate immunity is induced to eliminate the invading HPV pathogen through sensitization to HPV-related proteins by epithelial-residing Langerhans cells (LCs), macrophages, and other immune cells. Once the HPV infection escapes from initial patrolling by innate immunity, cellular immunity becomes in charge of killing the HPV-infected keratinocytes of the uterine cervix through systemic immune response developing by dendritic cells (DCs) in the regional lymphoid organs or through local immune response developing by LCs in the cervix. Thereby, DC/LC plays a critical role in eliciting innate and adaptive cellular immune responses against HPV infection. HPV-associated cervical malignancies might be prevented or treated by induction of the appropriate virus-specific immune responses in patients. Encouraging results from experimental vaccination systems in animal models have led to several prophylactic and therapeutic vaccine clinical trials. PMID 17713002

Localized hyperthermia combined with intratumoral dendritic cells induces systemic antitumor immunity.
Aug 2007 | Mukhopadhaya, Arunika; Mendecki, Joseph; Dong, Xinyuan; Liu, Laibin; Kalnicki, Shalom; Garg, Madhur; Alfieri, Alan; Guha, Chandan
Prostate adenocarcinoma, treated with localized tumor hyperthermia (LTH), can potentially serve as a source of tumor antigen, where dying apoptotic/necrotic cells release tumor peptides slowly over time. In addition, LTH-treated cells can release heat shock proteins that can chaperone antigenic peptides to antigen-presenting cells, such as dendritic cells. We attempted to discern whether sequential LTH and intratumoral dendritic cell and/or systemic granulocyte macrophage colony-stimulating factor (GM-CSF) would activate antitumor immune response in a syngeneic murine model of prostate cancer (RM-1). Palpable RM-1 tumors, grown in the distal appendage of C57BL/6 male mice, were subjected to LTH (43.7 degrees C for 1 h) x 2, separated by 5 days. Following the second LTH treatment, animals received either PBS or dendritic cells (2 x 10(6)) intratumorally (every 3 days for three injections). Separate cohorts also received i.v. injection of recombinant adenovirus-expressing murine GM-CSF (AdGMCSF), 1 day after LTH. Control animals received AdenoLacZ or AdenoGFP. Intratumoral dendritic cell injection induced tumor-specific T-helper cell activity (IFNgamma ELISPOTS) and CTL activity, which was further augmented by AdGMCSF, indicating amplification of tumor-specific TH1 immunity. The combination of LTH, AdGMCSF, and intratumoral dendritic cell injection resulted in significant tumor growth delays when compared with animal cohorts that received LTH alone. These results support an in situ autovaccination strategy where systemic administration of GM-CSF and/or intratumoral injection of autologous dendritic cells, when combined with LTH, could be an effective treatment for local and systemic recurrence of prostate cancer. PMID 17699785

A combination of chemoimmunotherapies can efficiently break self-tolerance and induce antitumor immunity in a tolerogenic murine tumor model.
Aug 2007 | Ko, Hyun-Jeong; Kim, Yeon-Jeong; Kim, Yun-Sun; Chang, Woo-Sung; Ko, Sung-Youl; Chang, Sun-Young; Sakaguchi, Shimon; Kang, Chang-Yuil
Her-2/neu is a well-characterized tumor-associated antigen overexpressed in human carcinomas such as breast cancer. Because Her-2/neu is a self-antigen with poor immunogenicity due to immunologic tolerance, active immunotherapy targeting Her-2/neu should incorporate methods to overcome immunologic tolerance to self-proteins. In this study, we developed a tolerogenic tumor model in mice using mouse Her-2/neu as self-antigen and investigated whether genetic vaccination with DNA plasmid and/or adenoviral vector expressing the extracellular and transmembrane domain of syngeneic mouse Her-2/neu or xenogenic human Her-2/neu could induce mouse Her-2/neu-specific CTL responses. Interestingly, adenoviral vectors expressing xenogenic human Her-2/neu (AdhHM) proved capable of breaking immune tolerance and of thereby inducing self-reactive CTL and antibodies, but not to the degree required to induce therapeutic antitumor immunity. In attempting to generate therapeutic antitumor immunity against established tumors, we adopted several approaches. Treatment with agonistic anti-glucocorticoid-induced TNFR family-related receptor (GITR) antibody plus AdhHM immunization significantly increased self-reactive CTL responses, and alpha-galactosylceramide (alphaGalCer)-loaded dendritic cells (DC) transduced with AdhHM were shown to break self-tolerance in a tolerogenic murine tumor model. Furthermore, gemcitabine treatment together with either AdhHM plus agonistic anti-GITR antibody administration or alphaGalCer-loaded DC transduced with AdhHM showed potent therapeutic antitumor immunity and perfect protection against preexisting tumors. Gemcitabine treatment attenuated the tumor-suppressive environment by eliminating CD11b(+)/Gr-1(+) myeloid-derived suppressor cells. When combined with immunotherapies, gemcitabine offers a promising strategy for the Ag-specific treatment of human cancer. PMID 17671218

Vaccination with p53 peptide-pulsed dendritic cells is associated with disease stabilization in patients with p53 expressing advanced breast cancer; monitoring of serum YKL-40 and IL-6 as response biomarkers.
Jun 2007 | Svane, Inge Marie; Pedersen, Anders E; Johansen, Julia S; Johnsen, Hans E; Nielsen, Dorte; Kamby, Claus; Ottesen, Svend; Balslev, Eva; Gaarsdal, Eva; Nikolajsen, Kirsten; Claesson, Mogens H
p53 Mutations are found in up to 30% of breast cancers and peptides derived from over-expressed p53 protein are presented by class I HLA molecules and may act as tumor-associated epitopes in cancer vaccines. A dendritic cell (DC) based p53 targeting vaccine was analyzed in HLA-A2+ patients with progressive advanced breast cancer. DCs were loaded with 3 wild-type and 3 P2 anchor modified HLA-A2 binding p53 peptides. Patients received up to 10 sc vaccinations with 5 x 10(6) p53-peptide loaded DC with 1-2 weeks interval. Concomitantly, 6 MIU/m(2) interleukine-2 was administered sc. Results from a phase II trial including 26 patients with verified progressive breast cancer are presented. Seven patients discontinued treatment after only 2-3 vaccination weeks due to rapid disease progression or death. Nineteen patients were available for first evaluation after 6 vaccinations; 8/19 evaluable patients attained stable disease (SD) or minor regression while 11/19 patients had progressive disease (PD), indicating an effect of p53-specific immune therapy. This was supported by: (1) a positive correlation between p53 expression of tumor and observed SD, (2) therapy induced p53 specific T cells in 4/7 patients with SD but only in 2/9 patients with PD, and (3) significant response associated changes in serum YKL-40 and IL-6 levels identifying these biomarkers as possible candidates for monitoring of response in connection with DC based cancer immunotherapy. In conclusion, a significant fraction of breast cancer patients obtained SD during p53-targeting DC therapy. Data encourage initiation of a randomized trial in p53 positive patients evaluating the impact on progression free survival. PMID 17285289

Intratumoral injection of dendritic cells in combination with local hyperthermia induces systemic antitumor effect in patients with advanced melanoma.
Apr 2007 | Guo, Jun; Zhu, Jun; Sheng, Xinan; Wang, Xiaopei; Qu, Li; Han, Yan; Liu, Yuexiang; Zhang, Hui; Huo, Ling; Zhang, Shuhui; Lin, Baohe; Yang, Zhi
Dendritic cells (DC) are potent antigen-presenting cells that can present tumor antigens chaperoned by heat shock proteins (HSPs), while local hyperthermia (LHT) can increase the expression of HSPs. In this study, we determine if intratumoral injection of immature DC after LHT (LHT+IT-DC) induces systemic antitumor immunity in patients with advanced melanoma, and investigate the potential immunological mechanisms involved in the treatments. Patients were randomly assigned to intratumoral administration of autologous immature DC triweekly, with (LHT+IT-DC, arm A, n = 9) or without (IT-DC, arm B, n = 9) LHT. Our results showed that there were no grade 3/4 toxicities. The time to progress (TTP) of arm A was 5 months, significantly longer than that in arm B (2 months, p < 0.05). However, the overall survival time had no statistical difference (13 months vs. 6 months, p > 0.05) between the 2 groups. Our ELISPOT assay showed a significantly increased melanoma-specific IFN-gamma production in arm A, suggesting that LHT+IT-DC was more effective in the induction of cytotoxic T lymphocytes (CTL) than IT-DC alone. Furthermore, we detected an increased HSPs expression 4 hr after the first LHT, an enhanced Th1/Th2 chemokines production 24 hr after the first LHT+IT-DC treatment, a promoted migration of DC to afferent lymph nodes, and a decreased infiltration of regulatory T cells (CD4(+)CD25(+)) and an increased infiltration of active CTL (CD8(+)CD28(+)) 48 hr after the third DC injection in arm A patients. Therefore, LHT+IT-DC can induce effective specific antitumor immunity and facilitate a Th1-polarized immune response in patients with advanced melanoma. PMID 17294445

Enhanced T-cell immunity induced by dendritic cells with phagocytosis of heat shock protein 70 gene-transfected tumor cells in early phase of apoptosis.
Mar 2007 | Chan, T; Chen, Z; Hao, S; Xu, S; Yuan, J; Saxena, A; Qureshi, M; Zheng, C; Xiang, J
The dual role of heat shock protein 70 (HSP70), as antigenic peptide chaperone and danger signal, makes it especially important in dendritic cell (DC)-based vaccination. In this study, we investigated the impacts of apoptotic transgenic MCA/HSP tumor cells expressing HSP70 on DC maturation, T-cell stimulation and vaccine efficacy. We found that DCs with phagocytosis of MCA/HSP in early phase of apoptosis expressed more pMHC I complexes, stimulated stronger cytotoxic T lymphocyte (CTL) responses (40% specific killing at an E:T cell ratio of 50) and induced immune protection in 90% of mice against MCA tumor cell challenge, compared with 25% specific CTL killing activity and 60% immune protection seen in mice immunized with DC with phagocytosis of MCA/HSP in late phase of apoptosis (P<0.05). Similar results were confirmed in another EG7 tumor model also expressing HSP70. Taken together, our data demonstrate that HSP70 on apoptotic tumor cells stimulate DC maturation, and DC with phagocytosis of apoptotic tumor cells expressing HSP70 in early phase of apoptosis more efficiently induced tumor-specific CTL responses and immunity than DCs with phagocytosis of apoptotic tumor cells in late phase of apoptosis. These results may have an important impact in designing DC-based antitumor vaccines. PMID 17235354

Generation of functional dendritic cells (DC) in adult acute lymphoblastic leukemia: rationale for a DC-based vaccination program for patients in complete hematological remission.
Feb 2007 | Maggio, Roberta; Peragine, Nadia; Calabrese, Elisabetta; De Propris, Maria Stefania; Intoppa, Stefania; Della Starza, Irene; Ariola, Cristina; Vitale, Antonella; Foà, Robin; Guarini, Anna
The capacity to generate effective dendritic cells (DC) from adult acute lymphoblastic leukemia (ALL) patients in complete remission (CR) and off-therapy was investigated. Monocyte-derived DC cultured in the presence of granulocyte-macrophage colony-stimulating factor, interleukin (IL)-4 and tumor necrosis factor (TNF)-alpha expressed maturation markers, produced IL-12 and loaded apoptotic bodies to a similar extent to normal DC. Patients' circulating T and NK lymphocytes were normally represented and, after stimulation, were capable of producing TNF-alpha and interferon-gamma to a similar extent to control lymphocytes. DC loaded with leukemia-derived apoptotic bodies increased their ability to stimulate both allogeneic and autologous lymphocytes, and to generate specific anti-leukemic CD3 + cells. These findings offer a rationale for the design of DC-based vaccine programs for adult ALL patients in CR with the aim of controlling/eradicating the disease. PMID 17325890

Targeting HER-2/neu in early breast cancer development using dendritic cells with staged interleukin-12 burst secretion.
Feb 2007 | Czerniecki, Brian J; Koski, Gary K; Koldovsky, Ursula; Xu, Shuwen; Cohen, Peter A; Mick, Rosemarie; Nisenbaum, Harvey; Pasha, Terry; Xu, Min; Fox, Kevin R; Weinstein, Susan; Orel, Susan G; Vonderheide, Robert; Coukos, George; DeMichele, Angela; Araujo, Louis; Spitz, Francis R; Rosen, Mark; Levine, Bruce L; June, Carl; Zhang, Paul J
Overexpression of HER-2/neu (c-erbB2) is associated with increased risk of recurrent disease in ductal carcinoma in situ (DCIS) and a poorer prognosis in node-positive breast cancer. We therefore examined the early immunotherapeutic targeting of HER-2/neu in DCIS. Before surgical resection, HER-2/neu(pos) DCIS patients (n = 13) received 4 weekly vaccinations of dendritic cells pulsed with HER-2/neu HLA class I and II peptides. The vaccine dendritic cells were activated in vitro with IFN-gamma and bacterial lipopolysaccharide to become highly polarized DC1-type dendritic cells that secrete high levels of interleukin-12p70 (IL-12p70). Intranodal delivery of dendritic cells supplied both antigenic stimulation and a synchronized preconditioned burst of IL-12p70 production directly to the anatomic site of T-cell sensitization. Before vaccination, many subjects possessed HER-2/neu-HLA-A2 tetramer-staining CD8(pos) T cells that expressed low levels of CD28 and high levels of the inhibitory B7 ligand CTLA-4, but this ratio inverted after vaccination. The vaccinated subjects also showed high rates of peptide-specific sensitization for both IFN-gamma-secreting CD4(pos) (85%) and CD8(pos) (80%) T cells, with recognition of antigenically relevant breast cancer lines, accumulation of T and B lymphocytes in the breast, and induction of complement-dependent, tumor-lytic antibodies. Seven of 11 evaluable patients also showed markedly decreased HER-2/neu expression in surgical tumor specimens, often with measurable decreases in residual DCIS, suggesting an active process of "immunoediting" for HER-2/neu-expressing tumor cells following vaccination. DC1 vaccination strategies may therefore have potential for both the prevention and the treatment of early breast cancer. PMID 17293384

Results of a phase I clinical study using dendritic cell vaccinations for thyroid cancer.
Feb 2007 | Kuwabara, Koichiro; Nishishita, Toshihide; Morishita, Mariko; Oyaizu, Naoki; Yamashita, Shunichi; Kanematsu, Takashi; Obara, Takao; Mimura, Yoshikazu; Inoue, Yusuke; Kaminishi, Michio; Kaga, Kimitaka; Amino, Nobuyuki; Kitaoka, Masafumi; Ito, Koichi; Miyauchi, Akira; Noguchi, Shiro; Uchimaru, Kaoru; Akagawa, Eiji; Watanabe, Nobukazu; Takahashi, Tsuneo A; Sato, Kaori; Inazawa, Takeshi; Nakaoka, Takashi; Yamashita, Naohide
We assessed the feasibility and efficacy of dendritic cell (DC) therapy for advanced thyroid papillary and follicular cancer. PMID 17274750

Production of interferons by dendritic cells, plasmacytoid cells, natural killer cells, and interferon-producing killer dendritic cells.
Jan 2007 | Vremec, David; O'Keeffe, Meredith; Hochrein, Hubertus; Fuchsberger, Martina; Caminschi, Irina; Lahoud, Mireille; Shortman, Ken
The capacity of mouse spleen conventional dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs) to produce interferon-gamma (IFN-gamma) or IFN-alpha was assessed, and compared with that of natural killer (NK) cells and the recently identified interferon-producing killer dendritic cells (IKDCs), both of which are frequent contaminants in DC preparations. Fully developed cDCs or pDCs, if free of NK cells or IKDCs, showed little capacity for IFN-gamma production. However, an early developmental form of the CD4-8+ cDC subtype, and the Ly6C- Ly49Q- pDC subtype, both were able to produce moderate amounts of IFN-gamma, although less than IKDCs. In response to toll-like receptor 9 stimuli, both the Ly6C+ Ly49Q+ and the Ly6C- Ly49Q- pDC subtypes were effective producers of IFN-alpha. However, IKDCs, which efficiently produced IFN-gamma and showed immediate cytotoxicity on NK target cells, did not produce IFN-alpha under these conditions. PMID 17038535

[Successful immunotherapy combined with hyperthermia therapy for cancer patients].
Jan 2007 | Takeda, Tsutomu; Dong, Xianhui; Takeda, Hiroko; Haba, Akinao; Takeda, Yutaka
We proceeded with activated lymphocytes immunotherapy for 149 cancer patients, and hyperthermia therapy for 126 patients, and DC therapy for 20 patients in the past year. We were successful in two cases. Case 1: A metastatic pelvic cancer (unknown origin) patient treated with lymphocytes and hyperthermia therapy. She showed a drastic response. Case 2: A metastatic lymph node cancer patient treated with DC, lymphocytes and hyperthermia therapy. She showed a CR. PMID 17212092

Combined use of dendritic cells enhances specific antileukemia immunity by leukemia cell-derived heat shock protein 70 in a mouse model with minimal residual leukemia cells.
Dec 2006 | Iuchi, Yasuyuki; Torimoto, Yoshihiro; Sato, Kazuya; Tamura, Yasuaki; Jimbo, Junko; Inamura, Junki; Shindo, Motohiro; Ikuta, Katsuya; Ohnishi, Kouhei; Kohgo, Yutaka
We have reported that immunotherapy using leukemia cell-derived heat shock proteins (HSPs) is effective against minimal residual disease (MRD) after syngeneic stem cell transplantation (SCT) in mice. However, leukemia patients after SCT are usually immunocompromised and immunologically tolerant to leukemia cells. We investigated whether the use of dendritic cells (DCs) in combination with HSP70 enhances cytotoxicity against B-cell leukemia cell line A20 in mice after syngeneic SCT. All unimmunized mice died of leukemia early after A20 cell inoculation, whereas mice immunized with HSP70 or HSP70-pulsed DCs survived significantly longer. Although only 60% of the HSP70-immunized mice survived, all mice immunized with HSP70-pulsed DCs survived without MRD. In addition, the cytotoxicities against A20 cells for splenocytes from mice immunized with HSP70-pulsed DCs were significantly higher than those of HSP70-immunized mice, and the cytotoxicities against A20 cells were significantly blocked by anti-CD8 antibody and by major histocompatibility complex class I antibody, but not by anti-CD4 antibody. Moreover, abnormalities were detected in neither the biochemical data nor the histopathologic findings. These findings indicate that the combined use of DCs and leukemia cell-derived HSP70 enhances the antileukemia effect by inducing the specific cytotoxicities of CD8+ cytotoxic T-cells, thereby eradicating MRD effectively and safely, even in an immunocompromised state after syngeneic SCT. This approach may thus be useful for further application of HSP in leukemia patients after autologous SCT. PMID 17189229

Steady-state and inflammatory dendritic-cell development.
Dec 2006 | Shortman, Ken; Naik, Shalin H
The developmental pathways that lead to the production of antigen-presenting dendritic cells (DCs) are beginning to be understood. These are the last of the pathways of haematopoiesis to be mapped. The existence of many specialized subtypes of DC has complicated this endeavour, as has the need to distinguish the DCs formed in steady state from those produced during an inflammatory response. Here we review studies that lead to the concept that different types of DC develop through different branches of haematopoietic pathways that involve different immediate precursor cells. Furthermore, these studies show that many individual tissues generate their own DCs locally, from a reservoir of immediate DC precursors, rather than depending on a continuous flux of DCs from the bone marrow. PMID 17170756

In vitro assessment of dendritic cells pulsed with apoptotic tumor cells as a vaccine for ovarian cancer patients.
Dec 2006 | Tobiásová, Zuzana; Pospísilová, Dagmar; Miller, Ashley M; Minárik, Ivo; Sochorová, Klára; Spísek, Radek; Rob, Lukás; Bartůnková, Jirina
Surgery and chemotherapy are standard treatments in ovarian cancer, but patients have a high rate of relapse. Dendritic cell (DC)-based vaccines are a new treatment option for elimination of residual tumor disease. We aim to explore the feasibility and immunogenicity of DC vaccines pulsed with autologous irradiated tumor cells from ovarian cancer patients. Monocyte-derived DC were generated and pulsed with autologous tumor-derived bodies, matured and subsequently cocultured with autologous lymphocytes. The ability of DC to activate lymphocytes was evaluated by proliferation and IFN-gamma ELISPOT. Induction of tumor cell apoptosis was optimal at 24 h, and DC pulsing optimal at 4 h. Maturation of DC and proliferation of lymphocytes were achieved in 75% of patients tested. Lymphocyte IFN-gamma production increased in response to tumor antigen-pulsed DC. We show the feasibility of preparing individual DC-based vaccines in ovarian cancer patients and the potential for induction of lymphocyte responses. PMID 17059893

Dendritic cell-based immunotherapy.
Dec 2006 | Osada, Takuya; Clay, Timothy M; Woo, Christopher Y; Morse, Michael A; Lyerly, H Kim
Dendritic cells (DCs) play a crucial role in the induction of antigen-specific T-cell responses, and therefore their use for the active immunotherapy of malignancies has been studied with considerable interest. More than a decade has passed since the publication of the first clinical data of DC-based vaccines, and through this and subsequent studies, a number of important developmental insights have been gleaned. These include the ideal source and type of DCs, the discovery of novel antigens and methods of loading DCs, the role of DC maturation, and the most efficient route of immunization. The generation of immune responses against tumor antigens after DC immunization has been demonstrated, and favorable clinical responses have been reported in some patients; however, it is difficult to pool the results as a whole, and thus the body of data remains inconclusive, in part because of varying DC preparation and vaccination protocols, the use of different forms of antigens, and, most importantly, a lack of rigorous criteria for defining clinical responses. As such, the standardization of clinical and immunologic criteria utilized, as well as DC preparations employed, will allow for the comparison of results across multiple clinical studies and is required in order for future trials to measure the true value and role of this treatment modality. In addition, issues regarding the optimal dose and clinical setting for the application of DC vaccines remain to be resolved, and recent clinical studies have been designed to begin to address these questions. PMID 17169781

Heat shock treatment of tumor lysate-pulsed dendritic cells enhances their capacity to elicit antitumor T cell responses against medullary thyroid carcinoma.
Nov 2006 | Bachleitner-Hofmann, Thomas; Strohschneider, Michaela; Krieger, Peter; Sachet, Monika; Dubsky, Peter; Hayden, Hubert; Schoppmann, Sebastian F; Pfragner, Roswitha; Gnant, Michael; Friedl, Josef; Stift, Anton
In vitro and in vivo studies have shown that dendritic cells (DCs) can stimulate antitumor T cell responses against medullary thyroid carcinoma (MTC). However, despite promising results in selected cases, the clinical efficacy of DC immunotherapy in patients with MTC has been limited. Recently, it has been demonstrated in mice that heat shock enhances the capacity of bone-marrow-derived DCs to stimulate antigen-specific T cells. The aim of our investigations was to evaluate whether heat shock also increases the capacity of human monocyte-derived DCs to stimulate antitumor T cell responses against MTC tumor cells. PMID 16954161

Current status of immunotherapy in B cell malignancies.
Oct 2006 | Kofler, D M; Mayr, C; Wendtner, C-M
Conventional treatment of hematologic malignancies mainly consists of chemotherapeutic agents or a combination of both, chemotherapy and monoclonal antibodies. Despite recent advances, chemotherapeutic treatments often remain unsatisfying due to severe side effects and incomplete long-term remission. Therefore the evaluation of novel therapeutic options is of great interest. B cell malignancies, in particularly follicular lymphomas, chronic lymphocytic leukemia and multiple myeloma, represent the most immune-responsive types of all human cancer. Several immunotherapeutic strategies are presently employed to combat these B-cell malignancies. Active immunotherapies include vaccination strategies with dendritic cells (DCs) and genetically-modified tumor cell preparations as well as DNA and protein vaccination. Most of these vaccines target the tumor-specific immunoglobulin idiotype and have already demonstrated some anti-lymphoma activity in early phase clinical trials while their definitive impact is evaluated in ongoing phase III randomized trials. In contrast to these active immunizations, T cells transduced with chimeric antigen receptors and donor leukocyte infusions (DLI) represent adoptive (passive) immunotherapies. Recent advances of gene transduction technologies enabled improvement of immunotherapeutic strategies based on genetic modification of malignant cells or adoptive T cells. Current early phase clinical trials are investigating the potential of these innovative approaches. At the moment it remains unclear if the novel immunotherapeutic strategies will be able to play a similar role in the treatment of B cell malignancies than the already established antibody-based immunotherapy. PMID 17073599

[Combined radiotherapy and endovascular x-ray therapy for invasive cancer of the urinary bladder].
Oct 2006 | Zharinov, G M; Agafonova, M V; Tarazov, P G; Suvorova, Iu V; Kozlov, A A; Metelev, V V; Neklasova, N Iu
The data are presented on treatment of 131 patients with transitional cell carcinoma of the urinary bladder. Radiotherapy was received by 57, regional intraarterial chemotherapy (RIAT)--27. Radiotherapy was combined with RIAT and selective hyperglycemia (HG) in 18 cases. Local super high-frequency (SHF) hyperthermia was given additionally to another 29 patients. Radiotherapy alone was followed by primary clinical cure, a 9.6-months relapse-free period and 3-months survival (36.8%), mean survival time being 26 months. In the RIAT group, these indices were 29.6%, 10.8 mos, 51.9% and 36 mos, respectively. Combination of radiotherapy, RIAT and selective HG yielded significantly improved indices: complete response--44.4%, relapse-free period--13.6 mos, 3-year survival--66.7% and mean survival time--43 mos. After addition of SHF hyperthermia, complete response rose to 69.0%, relapse-free period--18.2 mos, 3-year survival--75.8% and mean survival time--61 mos. Joint use of radiotherapy, RIAT, HG and SHF hyperthermia caused more damage to tumor, stimulated complete response and increased 3-year survival and mean survival time. PMID 17037035

HER-2/neu-gene engineered dendritic cell vaccine stimulates stronger HER-2/neu-specific immune responses compared to DNA vaccination.
Sep 2006 | Chan, T; Sami, A; El-Gayed, A; Guo, X; Xiang, J
HER-2/neu is a candidate for developing breast cancer-targeted immunotherapeutics. Although DNA-based and HER-2/neu transgene-modified dendritic cell (DC)-based vaccines are potent at eliciting HER-2/neu-specific antitumor immunity, there has been no side-by-side study comparing them directly. The present study utilizes an in vivo murine tumor model expressing HER-2/neu antigen to compare the efficacy between adenovirus (AdVneu)-transfected dendritic cells (DC(neu)) and plasmid DNA (pcDNAneu) vaccine. Our data showed that DC(neu) upregulated the expression of immunologically important molecules and inflammatory cytokines and partially converted regulatory T (Tr)-cell suppression through interleukin-6 (IL-6) secretion. Vaccination of DC(neu) induced stronger HER-2/neu-specific humoral and cellular immune responses than DNA vaccination, which downregulated HER-2/neu expression and lysed HER-2/neu-positive tumor cells in vitro, respectively. In two HER-2/neu-expressing tumor models, DC(neu) completely protected mice from tumor cell challenge compared to partial or no protection observed in DNA-immunized mice. In addition, DC(neu) significantly delayed breast cancer development in transgenic mice in comparison to DNA vaccine (P<0.05). Taken together, we have demonstrated that HER-2/neu-gene-modified DC vaccine is more potent than DNA vaccine in both protective and preventive animal tumor models. Therefore, DCs genetically engineered to express tumor antigens such as HER-2/neu represent a new direction in DC vaccine of breast cancer. PMID 16724093

Immunesurveillance by dendritic cells: potential implication for immunotherapy of endocrine cancers.
Sep 2006 | Schott, Matthias
Dendritic cells (DCs) are highly efficient antigen-presenting cells in the immune system with the potential to regulate the system and induce a cytotoxic T-cell response. As a proof of principle, a multitude of animal and human studies has demonstrated that immunization with antigen-loaded DCs may lead to anti-tumour immune responses with tumour regression and rejection of cancer. The identification of tumour antigens that can be recognized by T lymphocytes has facilitated the development of new protocols and enabled immunologists to monitor immune responses. However, to date, long-term clinical effects on larger numbers of cancer patients are missing, and there is no generally accepted DC generation or activation protocol. This review will focus on the most important findings on the role of DCs within the immune system and how to generate and activate these cells in order to induce cytotoxic immunity in non-endocrine and endocrine malignancies. Recently, we and other researchers reported on DC vaccinations in patients with endocrine malignancies mainly in metastasized medullary thyroid carcinoma resulting in tumour-specific immunity and partial clinical responses in some cases. Based on these and other in vitro data, new DC vaccination protocols for the treatment of patients with endocrine tumours have now been conducted. PMID 16954430

Dendritic cell-based multi-epitope immunotherapy of hormone-refractory prostate carcinoma.
Sep 2006 | Waeckerle-Men, Ying; Uetz-von Allmen, Edith; Fopp, Markus; von Moos, Roger; Böhme, Christel; Schmid, Hans-Peter; Ackermann, Daniel; Cerny, Thomas; Ludewig, Burkhard; Groettrup, Marcus; Gillessen, Silke
Dendritic cell (DC)-based immunotherapy is a promising approach to augment tumor antigen-specific T cell responses in cancer patients. However, tumor escape with down-regulation or complete loss of target antigens may limit the susceptibility of tumor cells to the immune attack. Concomitant generation of T cell responses against several immunodominant antigens may circumvent this potential drawback. In this trial, we determined the immunostimulatory capacity of autologous DC pulsed with multiple T cell epitopes derived from four different prostate-specific antigens in patients with advanced hormone-refractory prostate cancer. PMID 16612599

Generation of DC-based vaccine for therapy of B-CLL patients. Comparison of two methods for enriching monocytic precursors.
Aug 2006 | Kokhaei, P; Adamson, L; Palma, M; Osterborg, A; Pisa, P; Choudhury, A; Mellstedt, H
The generation of Ag-loaded DC under good manufacturing practice (GMP) conditions is logistically challenging and further compounded when the starting precursors need to be purified from B-CLL patients who have overwhelming numbers of circulating B-CLL cells and decreased numbers of monocytes. PMID 16923607

Virology- and immunology-based gene therapy for cancer.
Aug 2006 | Tagawa, Masatoshi; Kawamura, Kiyoko; Shimozato, Osamu; Ma, Guangyu; Li, Quanhai; Suzuki, Nobuo; Shimada, Hideaki; Ochiai, Takenori
Current strategies for cancer gene therapy consist mainly of direct inhibition of tumor cell growth and activation of systemic host defense mechanisms. Conventional chemotherapy and radiotherapy, even considered to be temporally suppressing tumor growth, suppress immune responses; therefore, we examined potential clinical feasibility of virus-mediated tumor destruction, which can rather enhance immunity. We showed that human tumors were more susceptible to adenoviruses (Ad) in which the E1A expression was controlled by a putative tumor promoter than normal cells, and that a replication of the Ad was greater in tumor cells than in normal cells. We also demonstrated that the intratumoral injection of the Ad bearing a tumor promoter inhibited the subsequent tumor growth in vivo. The E1A expression was detected in the tumors injected with the Ad but not in non-tumorous tissues of the same mice. The Ad modified to show the regulated E1A expression is thereby oncolytic in nature. Antitumor immune responses are initiated after the acquisition of putative tumor antigen(s) by dendritic cells (DCs); therefore, enhanced antigen presentation is a crucial step for the early phase of cell-mediated immunity. Destruction of tumors can release the tumor antigens and DCs come to recognize them thereafter. We found that the stimulation of Fas expressed on DCs with Fas ligand (FasL) did not induce apoptosis of DCs but rather enhanced the antigen presentation. Activation of DCs induced production of a number of cytokines, and we showed that the interleukin-12 family secreted from tumors could induce systemic antitumor immunity. We presume that the administration of oncolytic Ad, which can destroy local tumors and subsequently make the putative tumor antigen(s) released from the tumors, stimulation of DCs with the Fas/FasL signal pathway and secretion of DCs-derived cytokines coordinately produce synergistic antitumor effects and that a combinatory application of these procedures can be a possible therapeutic strategy for cancer treatment. PMID 16691360

Treatment of a patient by vaccination with autologous dendritic cells pulsed with allogeneic major histocompatibility complex class I-matched tumor peptides. Case Report.
Jul 2006 | Liau, L M; Black, K L; Martin, N A; Sykes, S N; Bronstein, J M; Jouben-Steele, L; Mischel, P S; Belldegrun, A; Cloughesy, T F
Dendritic cells (DCs) are antigen-presenting cells that play a central role in the initiation and modulation of antitumor immune responses. In this pilot study, we investigated the ability of autologous DCs pulsed ex vivo with allogeneic major histocompatibility complex class I-matched glioblastoma peptides to stimulate host antitumor immune responses when injected as a vaccine. A patient with recurrent brainstem glioblastoma multiforme (GBM) received a series of three intradermal immunizations of antigen-pulsed DCs on an outpatient basis following surgical debulking of her posterior fossa tumor. Dendritic cell vaccination was well tolerated, and no clinical signs of autoimmunity or experimental allergic encephalomyelitis were detected. She developed a measurable cellular immune response against the allogeneic glioblastoma peptides used in her vaccine preparation, as demonstrated by in vitro T-cell proliferation assays. In addition, increased T-cell infiltration was noted within the intracranial tumor site in the biopsy sample obtained following DC vaccination. An objective clinical response, however, was not evident, and this patient eventually died 21 months after her disease was diagnosed. To our knowledge, this is the first patient with brain cancer ever to be treated with DC-based immunotherapy. This case illustrates that vaccination with DCs pulsed with acid-eluted glioblastoma peptides is feasible and can induce systemic antigen-specific immunity in a patient with recurrent GBM. Additional studies are necessary to determine the optimum DC doses and antigen loading conditions that may translate into clinical effectiveness and survival benefit for patients with brain tumors. Phase I trials for malignant glioma are currently underway. PMID 16817691

Production of myeloid dendritic cells (DC) pulsed with tumor-specific idiotype protein for vaccination of patients with multiple myeloma.
Jun 2006 | Guardino, A E; Rajapaksa, R; Ong, K H; Sheehan, K; Levy, R
Immunotherapy of cancer with DC vaccines has produced encouraging results in clinical trials. Antigen (Ag)-pulsed DC have elicited CD4+ and CD8+ T-cell immunity and tumor regression in humans. However, there is no standard method of DC production. The DC phenotype, number and Ag-loading process used in these studies have varied, making comparisons between trials difficult. PMID 16793736

Current state and perspectives of dendritic cell vaccination in cancer immunotherapy.
Jun 2006 | Farkas, A; Conrad, C; Tonel, G; Borbenyi, Z; Kemeny, L; Dobozy, A; Nestle, F O
Recent progress in the approach towards immunotherapy of cancer consists in molecular definition of tumor antigens, new tools for phenotypical and functional characterization of tumor-specific effector cells and clinical use of novel adjuvants for optimal stimulation of a cancer-specific immune response such as dendritic cells. In spite of these advances and immunological as well as clinical responses in selected patients, mechanisms involved in dendritic-cell-based cancer immunotherapy are still poorly understood. Therefore, a standardized study design and small pilot trials are needed to explore open scientific questions in future clinical trials. This review focuses on the different parameters of dendritic cell biology relevant to cancer immunotherapy and on innovative approaches to hopefully enhance the efficacy of dendritic cell vaccination. PMID 16612139

Vaccination of colorectal cancer patients with CEA-loaded dendritic cells: antigen-specific T cell responses in DTH skin tests.
May 2006 | Lesterhuis, W J; de Vries, I J M; Schuurhuis, D H; Boullart, A C I; Jacobs, J F M; de Boer, A J; Scharenborg, N M; Brouwer, H M H; van de Rakt, M W M M; Figdor, C G; Ruers, T J; Adema, G J; Punt, C J A
Dendritic cells (DCs) are the professional antigen-presenting cells of the immune system. As such they are currently used in clinical vaccination protocols in cancer patients. PMID 16600979

[Efficacy of autologous renal tumor cell lysate-loaded dendritic cell vaccine in combination with cytokine-induced killer cells on advanced renal cell carcinoma--a report of ten cases].
May 2006 | Wang, Huan; Zhou, Fang-Jian; Wang, Qi-Jing; Qin, Zi-Ke; Huang, Li-Xi; Liu, Zhuo-Wei; Han, Hui; Li, Yong-Qiang; Chen, Shi-Ping; Xia, Jian-Chuan
Nowadays, operation is the main treatment for renal cell carcinoma (RCC). But the prognosis of advanced RCC is poor because of its high recurrence rate and resistance to conventional treatments, such as chemotherapy and radiotherapy. Hence, novel and more effective therapeutic options for advanced RCC are needed. This study was to evaluate the clinical efficacy of autologous renal tumor lysate-loaded dendritic cells (DCs) in combination with cytokine-induced killer (CIK) cells on advanced RCC. PMID 16687087

Chemo-immunotherapy of breast cancer using vesiculated alpha-tocopheryl succinate in combination with dendritic cell vaccination.
Mar 2006 | Ramanathapuram, Lalitha V; Hahn, Tobias; Dial, Sharon M; Akporiaye, Emmanuel T
In this study, we evaluated the efficacy of vesiculated alpha-tocopheryl succinate (Valpha-TOS) in combination with non-antigen pulsed, nonmatured dendritic cells (nmDC) to treat pre-established tumors of the highly metastatic murine mammary cancer cell line 4T1. We demonstrated that Valpha-TOS in combination with non-antigen pulsed nmDC significantly inhibits the growth of established tumors in vivo and prolongs survival of treated mice. In addition, when initiated after resection of the established primary tumor, the combination treatment dramatically inhibits residual metastatic disease. The clinical response achieved with the combination therapy was correlated with increased interferon-gamma and interleukin-4 (IL-4) production by splenic lymphocytes and draining lymph node cells. Interestingly, when used in combination with Valpha-TOS, nmDC were as effective as tumor necrosis factor-alpha matured DC at inhibiting the growth of pre-established tumors. Valpha-TOS-induced cellular factors collected by high-speed centrifugation of supernatant from Valpha-TOS-treated tumor cells caused maturation of DC as evidenced by the up-regulation of co-stimulatory molecules and secretion of IL-12p70. These results demonstrate the potential usefulness of Valpha-TOS + DC chemo-immunotherapy in treating established primary mammary tumors as well as residual metastatic disease. PMID 16573379

Immunization with heat shock protein 105-pulsed dendritic cells leads to tumor rejection in mice.
Mar 2006 | Yokomine, Kazunori; Nakatsura, Tetsuya; Minohara, Motozumi; Kira, Jun-ichi; Kubo, Tatsuko; Sasaki, Yutaka; Nishimura, Yasuharu
Recently, we reported that heat shock protein 105 (HSP105) DNA vaccination induced anti-tumor immunity. In this study, we set up a preclinical study to investigate the usefulness of dendritic cells (DCs) pulsed with mouse HSP105 as a whole protein for cancer immunotherapy in vivo. The recombinant HSP105 did not induce DC maturation, and the mice vaccinated with HSP105-pulsed BM-DCs were markedly prevented from the growth of subcutaneous tumors, accompanied with a massive infiltration of both CD4+ T cells and CD8+ T cells into the tumors. In depletion experiments, we proved that both CD4+ T cells and CD8+ T cells play a crucial role in anti-tumor immunity. Both CD4+ T cells and CD8+ T cells specific to HSP105 were induced by stimulation with HSP105-pulsed DCs. As a result, vaccination of mice with BM-DCs pulsed with HSP105 itself could elicit a stronger tumor rejection in comparison to DNA vaccination. PMID 16540092

Dendritic cell defects in patients with cancer: mechanisms and significance.
Mar 2006 | Lenahan, Corrine; Avigan, David
Dendritic cells (DCs) are a complex network of antigen-presenting cells that have an essential role in the modulation of primary immunity. There has been increasing evidence that DCs isolated from patients with malignancy demonstrate functional deficiencies that inhibit the capacity to mount an effective anti-tumor response. In this issue of Breast Cancer Research, Pinzon-Charry and colleagues investigate one of the possible mechanisms by which tumors induce DC dysfunction to evade host immune surveillance. They demonstrate that DCs isolated from the circulation of patients with early-stage breast cancer exhibit increased rates of spontaneous apoptosis. In vitro studies suggest that a soluble factor secreted by breast cancer cells is responsible for this phenomenon. In contrast, ex vivo conditioning of DCs with CD-40 ligand and IL-12 was protective against tumor-induced apoptosis. PMID 16469120

HPV16/18 E7-pulsed dendritic cell vaccination in cervical cancer patients with recurrent disease refractory to standard treatment modalities.
Feb 2006 | Santin, Alessandro D; Bellone, Stefania; Palmieri, Michela; Ravaggi, Antonella; Romani, Chiara; Tassi, Renata; Roman, Juan J; Burnett, Alexander; Pecorelli, Sergio; Cannon, Martin J
To evaluate the potential of human papillomavirus (HPV) type 16 and 18 E7 antigen-loaded autologous dendritic cells (DC) as a therapeutic cellular vaccine in a case series of cervical cancer patients harboring recurrent/metastatic disease refractory to standard treatment modalities. PMID 16249018

Combination of p53 cancer vaccine with chemotherapy in patients with extensive stage small cell lung cancer.
Feb 2006 | Antonia, Scott J; Mirza, Noweeda; Fricke, Ingo; Chiappori, Alberto; Thompson, Patricia; Williams, Nicholas; Bepler, Gerold; Simon, George; Janssen, William; Lee, Ji-Hyun; Menander, Kerstin; Chada, Sunil; Gabrilovich, Dmitry I
The initial goal of this study was to test the immunologic and clinical effects of a new cancer vaccine consisting of dendritic cells (DC) transduced with the full-length wild-type p53 gene delivered via an adenoviral vector in patients with extensive stage small cell lung cancer. PMID 16467102

Immunization with antigen-pulsed dendritic cells significantly improves the immune response to weak self-antigens.
Jan 2006 | Vargas, Pablo; Cortés, Claudio; Vargas, Leonardo; Rosemblatt, Mario; Bono, María Rosa
Dendritic cells (DCs) are the only professional antigen-presenting cells endowed with the ability to stimulate naïve T cells and initiate a primary immune response. For this reason, DC-based immunization has been shown to be highly effective in eliciting CTL responses to viruses and tumor-associated antigens. Here we report on the use of DC immunization to enhance the B cell-mediated humoral immune response to highly conserved proteins and the application of this approach to the generation of monoclonal antibodies (mAbs) against these proteins. To illustrate the technique we describe the production of mAbs to class II transactivator (CIITA), the major histocompatibility complex (MHC) CIITA, a difficult immunogen owing to its high degree of identity among species. We show that mice immunized with a combination of an intravenous injection of DCs pulsed with recombinant fragments of CIITA followed by intraperitoneal injection of the antigen in incomplete Freund's adjuvant induced a detectable antibody response against CIITA, while sera from mice immunized using the traditional method (i.e. intraperitoneal immunization with 50mug of protein in complete Freund's adjuvant) gave an almost undetectable response. Furthermore, a total of four fusion experiments demonstrate that immunization with Ag-pulsed DCs is necessary for the efficient generation of hybridomas and a good yield of mAbs specific for the recombinant and the native endogenous CIITA protein. Conversely, four independent fusions carried out with splenocytes from mice immunized using the traditional method failed to produce anti-CIITA hybridomas. We propose that immunization with antigen-loaded DCs should be the method of preference when attempting to raise mAbs against weak self-immunogens. PMID 16446168

Vaccine strategies to treat lymphoproliferative disorders.
Dec 2005 | Radford, Kristen J; Vari, Frank; Hart, Derek N J
Lymphoproliferative disorders, including follicular lymphoma (FL), multiple myeloma (MM) and chronic lymphatic leukaemia (CLL), are slowly progressive malignancies which remain incurable despite advances in therapy. Harnessing the immune system to recognise and destroy tumours is a promising new approach to treating these diseases. Dendritic cells (DC) are unique antigen-presenting cells that play a central role in the initiation and direction of immune responses. DC loaded ex vivo with tumour-associated antigens and administered as a vaccine have already shown promise in early clinical trials for a number of lymphoproliferative disorders, but the need for improvement is widely agreed. Recent advances in the understanding of basic DC biology and lessons from early clinical trials have provided exciting new insights into the generation of anti-tumour immune responses and the design of vaccine strategies. In this review we provide an overview of our current understanding of DC biology and their function in patients with lymphoproliferative disorders. We discuss the current status of clinical trials and new approaches to exploit the antigen presenting capacity of DC to design vaccines of the future. PMID 16373232

Genetically modified dendritic cells for therapeutic immunity.
Dec 2005 | Kikuchi, Toshiaki
Dendritic cells are professional antigen presenting cells, which show an extraordinary capacity to initiate primary immune responses by stimulating T cells. This established function of dendritic cells has attracted much attention in efforts to develop useful vaccines for the treatment of cancer and infectious diseases. Designing effective strategies to generate clinical dendritic cell-based vaccine protocols remains a challenging field of research. The successful realization of immunotherapy utilizing dendritic cells will depend on modifications of these protocols to optimize the natural stimulatory properties of dendritic cells, such as genetic modification of dendritic cells. This review focuses on dendritic cell gene modifications for enhancing the multiple effector functions of dendritic cells, including viral and non-viral gene transfer into dendritic cells, and a variety of transferred genes, such as those encoding antigens, co-stimulatory molecules, cytokines, and chemokines. PMID 16340167

Immunomodulatory dendritic cells require autologous serum to circumvent nonspecific immunosuppressive activity in vivo.
Dec 2005 | Haase, Claus; Ejrnaes, Mette; Juedes, Amy E; Wolfe, Tom; Markholst, Helle; von Herrath, Matthias G
In immunotherapy, dendritic cells (DCs) can be used as powerful antigen-presenting cells to enhance or suppress antigen-specific immunity upon in vivo transfer in mice or humans. However, to generate sufficient numbers of DCs, most protocols include an ex vivo culture step, wherein the cells are exposed to heterologous serum and/or antigenic stimuli. In mouse models of virus infection and virus-induced autoimmunity, we tested how heterologous serum affects the immunomodulatory capacity of immature DCs generated in the presence of IL-10 by comparing fetal bovine serum (FBS)- or normal mouse serum (NMS)-supplemented DC cultures. We show that FBS-exposed DCs induce a systemic immune deviation characterized by reduction of virus-specific T cells, delayed viral clearance, and enhanced systemic production of interleukin 4 (IL-4), IL-5, and IL-10 to FBS-derived antigens, including bovine serum albumin (BSA). By contrast, DCs generated in NMS-supplemented cultures modulated immunity and autoimmunity in an antigen-specific fashion. These cells did not induce systemic IL-4, IL-5, or IL-10 production and inhibited generation of virus-specific T cells or autoimmunity only if pulsed with a viral antigen. These data underscore the importance of using autologous serum-derived immature DCs in preclinical animal studies to accurately assess their immunomodulatory potential in future human therapeutic settings, where application of FBS is not feasible. PMID 16118326

Combined vaccination with idiotype-pulsed allogeneic dendritic cells and soluble protein idiotype for multiple myeloma patients relapsing after reduced-intensity conditioning allogeneic stem cell transplantation.
Dec 2005 | Bendandi, Maurizio; Rodríguez-Calvillo, Mercedes; Inogés, Susana; López-Díaz de Cerio, Ascensión; Pérez-Simón, José Antonio; Rodríguez-Caballero, Arancha; García-Montero, Andres; Almeida, Julia; Zabalegui, Natalia; Giraldo, Pilar; San Miguel, Jesús; Orfao, Alberto
To combine the use of idiotype-pulsed allogeneic dendritic cells (alloDC) and soluble protein Id conjugated with KLH (Id-KLH) in a vaccine strategy for multiple myeloma (MM). PMID 16321824

Medullary thyroid carcinoma: autologous tumor cell lines for dendritic cell vaccination.
Nov 2005 | Pfragner, Roswitha; Skofitsch, Gerhard; Höger, Harald; Jech, Marion; Rinner, Beate; Siegl, Veronika; Niederle, Bruno; Gnant, Michael; Friedl, Josef; Stift, Anton
Medullary thyroid carcinoma (MTC) is a calcitonin-producing tumor of the parafollicular C-cells, accounting for 5-10% of all thyroid tumors. To date, the only effective treatment is the early and total surgical removal of all neoplastic tissue. As the prognosis of patients with advanced MTC, unresectable or distant metastases is poor, and chemotherapy or irradiation is of no significant value, alternative strategies have been sought. PMID 16309220

Emerging evidence indicates that physiologically relevant thermal stress regulates dendritic cell function.
Nov 2005 | Ostberg, Julie R; Repasky, Elizabeth A
Elevations in temperature that are associated with inflammation or fever have been linked to improved survival from infections, enhanced immunological functions, and increased control of tumor growth. Over the past few years, several groups have begun to explore the possible linkage among these observations and have tested the hypothesis that various immune cells are especially sensitive to thermal stimulation. However, relatively little is known regarding the effects of thermal stimulation on antigen presenting cells (APCs), such as dendritic cells (DCs). Very recently, several groups have begun to examine the ability of thermal stimuli to regulate the function of these cells which are known to play a pivotal role in the efficacy of vaccines and other immunotherapies. In this review, we summarize what has been discovered about the role of mild thermal stress in regulating various Dendritic cell (DC) activities. Excitingly, it appears that mild elevations of temperature have the potential to enhance antigen uptake, activation associated migration, maturation, cytokine expression and T cell stimulatory activity of DCs. While these studies reveal that the timing, temperature and duration of heating is important, they also set the stage for essential questions that now need to be investigated regarding the molecular mechanisms by which elevated temperatures regulate DC function. With this information, we may soon be able to maximize the strategic use of thermal therapy as an adjuvant, i.e., combining its use with cancer immunotherapies such as vaccines, which depend upon the function of DCs. Several possible strategies and timepoints involving the clinical application of hyperthermia in combination with immunotherapy are presented. PMID 15864585

Chaperone-rich cell lysates, immune activation and tumor vaccination.
Nov 2005 | Zeng, Yi; Graner, Michael W; Katsanis, Emmanuel
We have utilized a free-solution-isoelectric focusing technique (FS-IEF) to obtain chaperone-rich cell lysates (CRCL) fractions from clarified tumor homogenates. The FS-IEF technique for enriching multiple chaperones from tumor lysate is relatively easy and rapid, yielding sufficient immunogenic material for clinical use. We have shown that tumor-derived CRCL carry antigenic peptides. Dendritic cells (DCs) uptake CRCL and cross-present the chaperoned peptides to T cells. Tumor-derived CRCL induce protective immune responses against a diverse range of murine tumor types in different genetic backgrounds. When compared to purified heat shock protein 70 (HSP70), single antigenic peptide or unfractionated lysate, CRCL have superior ability to activate/mature DCs and are able to induce potent, long lasting and tumor specific T-cell-mediated immunity. While CRCL vaccines were effective as stand-alone therapies, the enhanced immunogenicity arising from CRCL-pulsed DC as a vaccine indicates that CRCL could be the antigen source of choice for DC-based anti-cancer immunotherapies. The nature of CRCL's enhanced immunogenicity may lie in the broader antigenic peptide repertoire as well as the superior immune activation capacity of CRCL. Exongenous CRCL also supply danger signals in the context of apoptotic tumor cells and enhance the immunogenicity of apoptotic tumor cells, leading to tumor-specific T cell dependent long-term immunity. Moreover, CRCL based vaccines can be effectively combined with chemotherapy to treat cancer. Our findings indicate that CRCL have prominent adjuvant effects and are effective sources of tumor antigens for pulsing DCs. Tumor-derived CRCL are promising anti-cancer vaccines that warrant clinical research and development. PMID 15887013

Combination therapy with tumor cell-pulsed dendritic cells and activated lymphocytes for patients with disseminated carcinomas.
Nov 2005 | Katano, Mitsuo; Morisaki, Takashi; Koga, Kennichiro; Nakamura, Mitsunari; Onishi, Hideya; Matsumoto, Kotaro; Tasaki, Akira; Nakashima, Hiroshi; Akiyoshi, Takashi; Nakamura, Masafumi
This phase I study was performed to assess the safety and immune response of tumor cell-pulsed dendritic cell (DC) vaccine therapy against cancer patients with multiple metastases. DCs, generated from adherent cells of peripheral blood mononuclear cells (PBMCs) using interleukin-4 (IL-4) and granulocyte/monocyte colony-stimulating factor, were loaded with autologous necrotic whole tumor cells. Thereafter, the DCs were matured with culture supernatants of OK-432-stimulated PBMCs. Activated lymphocytes were also induced from non-adherent cells of PBMCs using OKT-3 and IL-2. Patients received a subcutaneous injection of DCs loaded with tumor cells every 2 weeks and received an intravenous injection of activated lymphocytes every 4 weeks. This combination therapy was named tumor-pulsed DC vaccine therapy. Tumor-pulsed DC vaccine therapy was continued as long as possible in 19 patients. No particular adverse reactions, except for low-grade fever, were found. The patients could be divided into two groups according to the survival time, i.e., 6 responders (long survival patients) and 13 non-responders (short survival patients). Based on the laboratory data of responders, eligibility criteria were determined. Using the eligibility criteria, a phase I/II study was recently performed with 15 patients. A delayed-type hypersensitivity reaction against tumor-pulsed DCs became positive in 13 of the 15 patients within 6 months after the therapy. This therapy was again safe, and no evidence of autoimmune disease was noted. The survival time of these 15 patients was significantly prolonged compared with that of the 13 non-responders of the phase I study (p < 0.0001). This continuous tumor-pulsed DC vaccine therapy was well tolerated in patients with disseminated carcinomas. PMID 16302738

Dendritic cell immunizations alone or combined with low doses of interleukin-2 induce specific immune responses in melanoma patients.
Nov 2005 | Escobar, A; López, M; Serrano, A; Ramirez, M; Pérez, C; Aguirre, A; González, R; Alfaro, J; Larrondo, M; Fodor, M; Ferrada, C; Salazar-Onfray, F
Dendritic cell (DC)-based therapy has proved to be effective in patients with a variety of malignancies. However, an optimal immunization protocol using DCs and the best means for delivering antigens has not yet been described. In this study, 20 patients with malignant melanoma in stages III or IV were vaccinated with autologous DCs pulsed with a melanoma cell lysate, alone (n = 13) or in combination with low doses of subcutaneous (s.c.) interleukin (IL)-2 injections (n = 7), to assess toxicity, immunological and clinical responses. Monocyte-derived DCs were morphological, phenotypic and functionally characterized in vitro. Peripheral blood mononuclear cells (PBMC), harvested from patients either prior to and after the treatment, were analysed using enzyme-linked immunosorbent spot (ELISPOT). After vaccination, 50% of the patients tested (seven of 13) from the first group and (three of seven) from the second, showed an increase in interferon (IFN)-gamma production in response to allogeneic melanoma cell lines but not to controls. Four of five tested human leucocyte antigen (HLA)-A2(+) patients with anti-melanoma activity also showed specific T cell responses against peptides derived from melanoma-associated antigens. Delayed type IV hypersensitivity reaction (DTH) against melanoma cell lysate was observed in six of 13 patients from the group treated with DC vaccines only and four of seven from the group treated with the combination of DCs and IL-2. Significant correlations were found between DTH-positive responses against tumour lysate and both disease stability and post-vaccination survival on the stage IV patients. There were no toxicities associated with the vaccines or evidence of autoimmunity including vitiligo. Furthermore, no significant enhancement was observed as a result of combining DC vaccination with IL-2. Our data suggest that autologous DCs pulsed with tumour lysate may provide a standardized and widely applicable source of melanoma specific antigens for clinical use. It is safe and causes no significant side effects and has been demonstrated to be partially efficient at triggering effective anti-melanoma immunity. PMID 16297169

Therapeutic vaccines for cervical cancer: dendritic cell-based immunotherapy.
Oct 2005 | Santin, Alessandro D; Bellone, Stefania; Roman, Juan J; Burnett, Alexander; Cannon, Martin J; Pecorelli, Sergio
Human papillomavirus (HPV) infection represents the most important risk factor for the development of cervical dysplasia and cervical cancer. Several lines of evidence suggest that cell-mediated immune responses are important in controlling both HPV infections and HPV-associated neoplasia. Since HPV E6 and E7 oncoproteins are expressed in these lesions and are necessary for the maintenance of the malignant phenotype, these proteins might be potential tumor-specific target antigens for immunotherapy of cervical cancer. The gold standard treatment for locally advanced cervical cancer is primary radiation therapy combined with chemotherapy. A potential drawback of this potentially curative treatment is a profound and long lasting negative effect on the immune system. Treatment-induced immunosuppression combined with tumor-induced subversion of the immune system may therefore impose severe limitations on the efficacy of conventional vaccination strategies in late stage cervical cancer patients. The recognition of dendritic cells (DC) as powerful antigen-presenting cells capable of inducing primary T cell responses in vitro and in vivo, has recently generated widespread interest in DC-based immunotherapy of several human malignancies. Here, we review various therapeutic HPV vaccines being developed and implemented in human clinical trials, with a particular emphasis on the use of autologous DC pulsed with full-length HPV 16 or 18 E7 oncoproteins as a novel strategy to induce HPV E7-specific and tumor-specific T cell responses in cervical cancer patients following conventional treatment. PMID 16248803

Immunotherapy and cancer vaccines in the management of breast cancer.
Oct 2005 | Sauer, Georg; Kurzeder, Christian; Heilmann, Volker; Kreienberg, Rolf; Deissler, Helmut
Besides the traditional therapeutic options, treatment with antibodies specific for the receptor tyrosine kinase HER-2/neu has been established as a standard therapy in the clinical management of advanced breast cancer. Ongoing clinical studies focus on the improvement of application protocols in order to minimize side effects and evaluate the potential therapeutic benefit of anti-HER-2/neu antibodies in combination with conventional chemotherapy. Various similar strategies to target other tumour-associated antigens or proangiogenic factors with inhibitory antibodies are currently investigated in promising preclinical and clinical trials. In addition, research efforts are made to develop procedures to generate tumour-specific cellular immune responses in breast cancer patients. Therapeutic vaccination is, however, still at an early stage of development, despite encouraging results of animal studies. We summarise and discuss vaccination strategies with tumour-specific proteins or peptides, pulsed dendritic cells, and modified tumour cells as well as antibody-based therapeutic concepts to target HER-2/neu, EGF receptor, MUC-1, uPA/uPAR, and VEGF. PMID 16248802

Natural killer-dendritic cell cross-talk in cancer immunotherapy.
Oct 2005 | Kalinski, Pawel; Mailliard, Robbie B; Giermasz, Adam; Zeh, Herbert J; Basse, Per; Bartlett, David L; Kirkwood, John M; Lotze, Michael T; Herberman, Ronald B
Natural killer (NK) cells and dendritic cells (DCs), two important components of the immune system, can exchange bidirectional activating signals in a positive feedback. Myeloid DCs, the cell type specialised in the presentation of antigen and initiation of antigen-specific immune responses, have recently been documented to be involved in supporting innate immunity, promoting the production of cytokines and cytotoxicity of NK cells, and enhancing their tumouricidal activity. Natural interferon-producing cells/plasmacytoid DCs (IPCs/PDCs) play an additional role in NK cell activation. Reciprocally, NK cells, traditionally considered to be major innate effector cells, have also recently been shown to play immunoregulatory 'helper' functions, being able to activate DCs and to enhance their ability to produce pro-inflammatory cytokines, and to stimulate T helper (Th) 1 and cytotoxic T lymphocyte (CTL) responses of tumour-specific CD4+ and CD8+ T cells. Activated NK cells induce the maturation of myeloid DCs into stable type-1 polarised DCs (DC1), characterised by up to a 100-fold enhanced ability to produce IL-12p70 in response to subsequent interaction with Th cells. In addition, the ability of NK cells to kill tumour cells may facilitate the generation of tumour-related antigenic material, further accelerating the induction of tumour-specific immunity. DC1, induced by NK cells or by NK cell-related soluble factors, are stable, resistant to tumour-related suppressive factors, and demonstrate a strongly enhanced ability to induce Th1 and CTL responses in human in vitro and mouse in vivo models. Compared with the standard mature DCs that are used in clinical trials at present, human NK cell-induced DC1s act as superior inducers of anticancer CTL responses during in vitro sensitisation. This provides a strong rationale for the combined use of NK cells and DCs in the immunotherapy of patients with cancer and patients with chronic infections that are resistant to standard forms of treatment. Stage I/II clinical trials that are being implemented at present should allow evaluation of the immunological and clinical efficacy of combined NK-DC therapy of melanoma and other cancers. PMID 16197336

Natural-killer cells and dendritic cells: "l'union fait la force".
Sep 2005 | Walzer, Thierry; Dalod, Marc; Robbins, Scott H; Zitvogel, Laurence; Vivier, Eric
Several recent publications have focused on the newly described interactions between natural-killer (NK) cells and dendritic cells (DCs). Activated NK cells induce DC maturation either directly or in synergy with suboptimal levels of microbial signals. Immature DCs appear susceptible to autologous NK-cell-mediated cytolysis while mature DCs are protected. NK-cell-induced DC activation is dependent on both tumor necrosis factor-alpha (TNF-alpha)/interferon-gamma (IFN-gamma) secretion and a cell-cell contact involving NKp30. In vitro, interleukin-12 (IL-12)/IL-18, IL-15, and IFN-alpha/beta production by activated DCs enhance, in turn, NK-cell IFN-gamma production, proliferation, and cytotoxic potential, respectively. In vivo, NK-cell/DC interactions may occur in lymphoid organs as well as in nonlymphoid tissues, and their consequences are multiple. By inducing DC activation, NK-cell activation induced by tumor cells can indirectly promote antitumoral T-cell responses. Reciprocally, DCs activated through Toll-like receptors (TLRs) induce potent NK-cell activation in antiviral responses. Thus, DCs and NK cells are equipped with complementary sets of receptors that allow the recognition of various pathogenic agents, emphasizing the role of NK-cell/DC crosstalk in the coordination of innate and adaptive immune responses. PMID 15933055

Allogeneic dendritic cells pulsed with tumor lysates or apoptotic bodies as immunotherapy for patients with early-stage B-cell chronic lymphocytic leukemia.
Aug 2005 | Hus, I; Roliński, J; Tabarkiewicz, J; Wojas, K; Bojarska-Junak, A; Greiner, J; Giannopoulos, K; Dmoszyńska, A; Schmitt, M
Recently, immunotherapies with allogeneic dendritic cells (DCs) pulsed with tumor antigens to generate specific T-cell responses have been tested in clinical trials for patients with solid tumors. This is the first report on a clinical vaccination study with DCs for patients with B-cell chronic lymphocytic leukemia (B-CLL). The potential of allogeneic DCs pulsed ex vivo with tumor cell lysates or apoptotic bodies to stimulate antitumor immunity in patients with B-CLL in early stages was evaluated. Monocyte-derived DCs were obtained from unrelated healthy donors. Nine patients (clinical stage 0 and 1 according to Rai) were vaccinated five times with a mean number of 32 x 10(6) stimulated DCs administered intradermally once every 2-3 weeks. No signs of autoimmunity were detected, and only mild local skin reactions were noted. During the treatment period, we observed a decrease of peripheral blood leukocytes and CD19+/CD5+ leukemic cells. In one patient, a significant increase of specific cytotoxic T lymphocytes against RHAMM/CD168, a recently characterized leukemia-associated antigen, could be detected after DC vaccination. Taken together, the study demonstrated that DC vaccination in CLL patients is feasible and safe. Immunological and to some extent hematological responses could be noted, justifying further investigation on this immuno-therapeutical approach. PMID 15990861

Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment.
Aug 2005 | Liau, Linda M; Prins, Robert M; Kiertscher, Sylvia M; Odesa, Sylvia K; Kremen, Thomas J; Giovannone, Adrian J; Lin, Jia-Wei; Chute, Dennis J; Mischel, Paul S; Cloughesy, Timothy F; Roth, Michael D
We previously reported that autologous dendritic cells pulsed with acid-eluted tumor peptides can stimulate T cell-mediated antitumor immune responses against brain tumors in animal models. As a next step in vaccine development, a phase I clinical trial was established to evaluate this strategy for its feasibility, safety, and induction of systemic and intracranial T-cell responses in patients with glioblastoma multiforme. PMID 16061868

Maturation requirements for dendritic cells in T cell stimulation leading to tolerance versus immunity.
Jul 2005 | Tan, Jonathan K H; O'Neill, Helen C
The model that dendritic cell (DC) "maturation" describes the change from an immature, antigen-capturing cell to a mature, antigen-presenting cell is well-established. Classification of DCs in terms of function has been problematic previously. It is therefore proposed that mature and not immature DCs are responsible for antigen presentation and stimulation of T cells. Furthermore, DC antigen presentation to T cells can have two outcomes: tolerance or immunity. The particular outcomes appear to be determined by the activation state of the mature DC. DCs can be activated by a range of environmental stimuli or "danger signals". Here, the hypothesis is advanced that activated, mature DCs induce T cell immunity, and resting, nonactivated but fully differentiated mature antigen-presenting DCs can induce tolerance. This proposal extends to conventional DCs and plasmacytoid DCs. The paper also concentrates on the spleen as a site for DC maturation, in light of evidence from this laboratory for differentiation of DCs from splenic precursors in long-term, stroma-dependent cultures. The hypothesis advanced here serves to simplify many current issues regarding DC maturation and function. PMID 15809288

Tumor lysate and IL-18 loaded dendritic cells elicits Th1 response, tumor-specific CD8+ cytotoxic T cells in patients with malignant glioma.
May 2005 | Yamanaka, Ryuya; Honma, Junpei; Tsuchiya, Naoto; Yajima, Naoki; Kobayashi, Tsutomu; Tanaka, Ryuichi
In this study, we demonstrate that tumor lysate-loaded dendritic cells can elicit a specific CD8+ cytotoxic T lymphocyte response against autologous tumor cells in patients with malignant glioma. CTL from three of five patients expressed strong cytolytic activity against autologous glioma cells, did not lyse autologous lymphoblasts and were variably cytotoxic against the LAK-sensitive cell line Daudi. Also, DCs pulsed normal brain lysate failed to induce cytolytic activity against autologous glioma cells, suggesting the lack of autoimmune response. Two of five patients CD8+ T cells expressed a modest cytotoxicity against autologous glioma cells. CD8+ T cells isolated during these ineffective primings secreted large amounts of IL-10, less amounts of IFN-gamma as detected by ELISA, Type 2 bias in the CD8+ T cell response accounts for the lack of cytotoxic effector function from these patients. Cytotoxicity against autologous glioma cells could be significantly inhibited by anti-HLA class I antibody. These data demonstrate that tumor lysate-loaded DC can be an effective tool in inducing glioma-specific CD8+ CTL able to kill autologous glioma cells in vitro. However, high levels of tumor specific tolerance in some patients may account for a significant barrier to therapeutic vaccination. Moreover, cytotoxic responses were augmented by transfecting DC with the gene for IL-18. For all five patients, CD8+T cells treated with IL18 transfected DC produced Th1 response. These results may have important implications for the treatment of malignant glioma patients with immunotherapy. DCs loaded with total tumor lysate and IL-18 may represent a method for inducing Th1 immunoresponses against the entire repertoire of glioma antigens. PMID 15925989

Immunotherapy of murine malignant mesothelioma using tumor lysate-pulsed dendritic cells.
May 2005 | Hegmans, Joost P J J; Hemmes, Annabrita; Aerts, Joachim G; Hoogsteden, Henk C; Lambrecht, Bart N
Exploiting the immunostimulatory capacities of dendritic cells holds great promise for cancer immunotherapy. Currently, dendritic cell-based immunotherapy is evaluated clinically in a number of malignancies, including melanoma and urogenital and lung cancer, showing variable but promising results. PMID 15764728

The large scale generation of dendritic cells for the immunization of patients with non-small cell lung cancer (NSCLC).
Feb 2005 | Yannelli, John R; Sturgill, Jamie; Foody, Terry; Hirschowitz, Edward
In the current study, we generated large numbers of dendritic cells (DCs) from patients with non-small cell lung cancer (NSCLC) for a vaccine trial. The DCs were generated from CD14+ cells obtained by immuno-magnetic bead column separation technique. The CD14+ cells were placed in culture in the presence of granulocyte macrophage colony stimulating factor (GMCSF) and Interleukin 4 (IL-4). At Day 7, apoptotic bodies derived from an allogeneic NSCLC line 1650-TC were added to the cultures at a DC:tumor cell ratio of 1:1. At Day 8, the DCs were harvested, washed and injected intradermally into patients. Using this protocol we have prepared DCs for 16 patients. An average of 9.3 x 10(7) DCs was injected for the priming dose and 8.2 x 10(7) DCs for the boost. Clinical evaluation of the patients and immune assessment are presented in a separate report. The current report provides evidence for the large scale production of functional DCs derived from patients with NSCLC which can be used as vaccines in clinical trials. PMID 15713517

Dendritic cell-based therapeutics for breast cancer.
Feb 2005 | Pilon-Thomas, Shari A; Verhaegen, Monique E; Mulé, James J
Continual attempts to stimulate the immune system against malignancies have led to the development of various strategies based on active immunotherapy treatments. Dendritic cells are the most potent antigen presenting cells with the capacity to stimulate naive T cells and induce primary and secondary immune responses. Due to the pivotal role that DC play in eliciting and maintaining functional anti-tumor T cell responses, DC have been exploited as vaccines in an attempt to actively immunize patients. Initial solid tumor clinical trials involving DC-based immunization have shown progress in terms of eliciting T-cell reactivity and mediating tumor regression. These early promising data have led to multiple research endeavors to also employ DC immunotherapy for the treatment of poorly immunogenic malignancies such as breast cancer. Various strategies to load DC with tumor associated antigens in murine models of breast cancer as well as the state of human clinical trials are reviewed. PMID 15687708

Phenotypic and functional characterization of clinical grade dendritic cells generated from patients with advanced breast cancer for therapeutic vaccination.
Feb 2005 | Pedersen, A E; Thorn, M; Gad, M; Walter, M R; Johnsen, H E; Gaarsdal, E; Nikolajsen, K; Buus, S; Claesson, M H; Svane, I M
Dendritic cells (DC) are promising candidates for cancer immunotherapy. However, it is not known whether in vitro-generated monocyte-derived DC from cancer patients are altered compared with DC from healthy donors. In a clinical phase I/II study, monocyte-derived DC were generated in vitro utilizing granulocyte macrophage colony-stimulating factor and rh-interleukin-4 (IL-4) and used for cancer immunotherapy. In this study, we tested the effect of various maturation cocktails and performed a comparative evaluation of the DC phenotype and functional characteristics. Polyriboinosinic polyribocytidylic acid (Poly I:C) + tumour necrosis factor-alpha (TNF-alpha) induced significant IL-12 p70 secretion, which was increased after addition of a decoy IL-10 receptor. The lymph node homing chemokine receptor CCR-7 expression was induced by TNF-alpha + IL-1beta + IL-6 + prostaglandin E2 but was not induced by Poly I:C + TNF-alpha. In general, DC from patients had an intermediate maturity phenotype with a significantly higher expression of CD40 and CD54 compared with healthy donors. In vitro analyses showed an unimpaired capacity of the patient-derived DC for antigen-specific (cytomegalovirus, tetanus and keyhole limpet haemocyanin) T-cell stimulation, whereas the allostimulatory capacity of patient-derived DC was significantly decreased. These data suggest that patient-derived DC are more differentiated but are less sensitive to maturation-inducing agents than DC obtained from healthy individuals. PMID 15683451

Dendritic cells in clinical trials for multiple myeloma.
Dec 2004 | Reichardt, Volker L; Brossart, Peter
Due to the existence of the truly specific tumor antigen idiotype in multiple myeloma and based on encouraging data from dendritic cell vaccinated B-cell non-Hodgkin's lymphoma (NHL) patients, dendritic cell-based vaccination was first initiated in myeloma patients in 1995. This overview will summarize published and ongoing clinical trials in patients with multiple myeloma who are treated with idiotype-based dendritic cell (Id/DC) vaccination. All groups of investigators have found that Id/DC vaccination of multiple-myeloma patients is feasible and that myeloma-specific immunity can be induced in heavily pretreated individuals. In future trials, new dendritic cell-based immunization strategies will be investigated based on techniques like RNA transfection of DC. PMID 15585918

Vaccination of glioma patients with fusions of dendritic and glioma cells and recombinant human interleukin 12.
Nov 2004 | Kikuchi, Tetsuro; Akasaki, Yasuharu; Abe, Toshiaki; Fukuda, Takahiro; Saotome, Hideo; Ryan, John L; Kufe, Donald W; Ohno, Tsuneya
Despite aggressive treatment, the median survival of patients with high-grade malignant astrocytoma is about 1 year. The authors investigated the safety and clinical response to immunotherapy using fusions of dendritic and glioma cells combined with recombinant human interleukin 12 (rhIL-12) for the treatment of malignant glioma. Fifteen patients with malignant glioma participated in this study. Dendritic cells were generated from peripheral blood. Cultured autologous glioma cells were established from surgical specimens in each case. Fusion cells were prepared from dendritic and glioma cells using polyethylene glycol. All patients received fusion cells intradermally on day 1. rhIL-12 was injected subcutaneously at the same site on days 3 and 7. Response to the treatment was evaluated by clinical observations and radiologic findings. No serious adverse effects were observed. In four patients, magnetic resonance imaging showed a greater than 50% reduction in tumor size. One patient had a mixed response. These results show that administration of fusion cells and rhIL-12 safely induces clinical antitumor effects in some patients with malignant glioma. PMID 15534489

Vaccination by genetically modified dendritic cells expressing a truncated neu oncogene prevents development of breast cancer in transgenic mice.
Nov 2004 | Sakai, Yoshio; Morrison, Brian J; Burke, J Douglas; Park, Jong-Myun; Terabe, Masaki; Janik, John E; Forni, Guido; Berzofsky, Jay A; Morris, John C
Dendritic cells (DCs) are powerful antigen-presenting cells that process antigens and present peptide epitopes in the context of the major histocompatibility complex molecules to generate immune responses. DCs are being studied as potential anticancer vaccines because of their ability to present antigens to naive T cells and to stimulate the expansion of antigen-specific T-cell populations. We investigated an antitumor vaccination using DCs modified by transfer of a nonsignaling neu oncogene, a homologue of human HER-2/neu, in a transgenic model of breast cancer. BALB-neuT mice develop breast cancers as a consequence of mammary gland-specific expression of an activated neu oncogene. We vaccinated BALB-neuT mice with bone marrow-derived DCs transduced with Ad.Neu, a recombinant adenovirus expressing a truncated neu oncoprotein. The vaccine stimulated the production of specific anti-neu antibodies, enhanced interferon-gamma expression by T cells, and prevented or delayed the onset of mammary carcinomas in the mice. Over 65% of vaccinated mice remained tumor free at 28 weeks of age, whereas all of the mice in the control groups developed tumors. When challenged with a neu-expressing breast cancer cell line, vaccinated tumor-free animals had delayed tumor growth compared with controls. The antitumor effect of the vaccine was specific for expression of neu. Studies showed that CD4+ T cells were required in order to generate antitumor immunity. Importantly, the effectiveness of the vaccine was not diminished by preexisting immunity to adenovirus, whereas the protection afforded by vaccination that used direct injection of Ad.Neu was markedly reduced in mice with anti-adenovirus antibody titers. DCs modified by recombinant adenoviruses expressing tumor-associated antigens may provide an effective antitumor vaccination strategy. PMID 15520211

Surgery and adjuvant dendritic cell-based tumour vaccination for patients with relapsed malignant glioma, a feasibility study.
Oct 2004 | Rutkowski, S; De Vleeschouwer, S; Kaempgen, E; Wolff, J E A; Kühl, J; Demaerel, P; Warmuth-Metz, M; Flamen, P; Van Calenbergh, F; Plets, C; Sörensen, N; Opitz, A; Van Gool, S W
Patients with relapsed malignant glioma have a poor prognosis. We developed a strategy of vaccination using autologous mature dendritic cells loaded with autologous tumour homogenate. In total, 12 patients with a median age of 36 years (range: 11-78) were treated. All had relapsing malignant glioma. After surgery, vaccines were given at weeks 1 and 3, and later every 4 weeks. A median of 5 (range: 2-7) vaccines was given. There were no serious adverse events except in one patient with gross residual tumour prior to vaccination, who repetitively developed vaccine-related peritumoral oedema. Minor toxicities were recorded in four out of 12 patients. In six patients with postoperative residual tumour, vaccination induced one stable disease during 8 weeks, and one partial response. Two of six patients with complete resection are in CCR for 3 years. Tumour vaccination for patients with relapsed malignant glioma is feasible and likely beneficial for patients with minimal residual tumour burden. PMID 15477864

Antitumor vaccination of patients with glioblastoma multiforme: a pilot study to assess feasibility, safety, and clinical benefit.
Oct 2004 | Steiner, Hans Herbert; Bonsanto, Matteo Mario; Beckhove, Philipp; Brysch, Michael; Geletneky, Karsten; Ahmadi, Rezvan; Schuele-Freyer, Rebecca; Kremer, Paul; Ranaie, Golamreza; Matejic, Dejana; Bauer, Harald; Kiessling, Marika; Kunze, Stefan; Schirrmacher, Volker; Herold-Mende, Christel
Prognosis of patients with glioblastoma is poor. Therefore, in glioblastoma patients, we analyzed whether antitumor vaccination with a virus-modified autologous tumor cell vaccine is feasible and safe. Also, we determined the influence on progression-free survival and overall survival and on vaccination-induced antitumor reactivity. PMID 15452186

Therapeutic cancer vaccines: using unique antigens.
Oct 2004 | Lewis, Jonathan J
A decade ago, it seemed rational that our rapidly increasing knowledge of the molecular identities of tumor antigens and a deeper understanding of basic immunology would point the way to an effective therapeutic cancer vaccine. Significant progress has been made, but we do not yet have a cancer vaccine that can reliably and consistently induce tumor destruction or improve patient survival. Random mutations in cancer cells generate unique antigens in each individual, and this may be important in terms of generating a therapeutic immune response. Autologous heat shock protein-peptide complexes produced from each patient's tumor is a logical personalized approach that may obviate the need to identify the unique antigens contained in the individual vaccine. Heat shock proteins elicit adaptive and innate immune responses and have been tested in a variety of animal models and different human cancers. Activity has been seen in several animal studies. Early-phase human studies have also suggested some activity in certain cancers. Large, randomized phase 3 studies are ongoing, and these will effectively answer the question of efficacy regarding this approach to therapeutic vaccination. There are sufficient data to support the notion that cancer vaccines can induce anti-tumor immune responses in humans with cancer. How best to translate this increase in immune responsiveness to consistently and reproducibly induce objective cancer regression or increased survival remains unclear at this time. PMID 15297620

Dendritic cell-based immunotherapy in thyroid malignancies.
Sep 2004 | Schott, Matthias; Scherbaum, Werner A; Seissler, Jochen
A new approach for anti-tumor immunotherapy is to use dendritic cells (DCs) as adjuvants in order to actively immunize cancer patients with antigens specifically expressed in tumor cells. DCs possess a unique capacity to effectively activate CD4+ T helper cells and CD8+ cytotoxic T cells. During the last years, several clinical trials in various malignancies demonstrated that immunizations with tumor antigen pulsed DCs could break the tolerance of the immune system against antigens expressed by the tumor cells resulting in partial or complete remission in some cases. This review describes the most important findings on the interaction between DCs and T cells as well as natural killer cells and summarizes recent data on DC vaccination of endocrine and non-endocrine malignancies. The results from current pilot studies suggest that DC vaccination may represent a promising strategy for the development of an anti-cancer vaccine to treat chemotherapy and radioresistant endocrine malignancies. PMID 15379726

Generation of dendritic cells from positively selected CD14+ monocytes for anti-tumor immunotherapy.
Sep 2004 | Curti, Antonio; Isidori, Alessandro; Ferri, Elisa; Terragna, Carolina; Neyroz, Paolo; Cellini, Claudia; Ratta, Marina; Baccarani, Michele; Lemoli, Roberto M
Peripheral blood CD14+ monocytes from multiple myeloma (MM) patients can be induced to differentiate into fully functional, mature, CD83+ dendritic cells (DCs) which are highly efficient in priming autologous T lymphocytes in response to the patient-specific tumor idiotype (Id). We have recently scaled up our manufacturing protocol for application in a phase I-II clinical trial of anti-Id vaccination with DCs in MM patients. Elegible patients received a series of by-monthly immunizations consisting of three subcutaneous and two intravenous injections of Id-keyhole limpet hemocyanin (KLH)-pulsed DCs (5 x -, 10 x -, 50 x 10(6) cells and 10 x -, 50 x 10(6) cells, respectively). To generate DCs, monocytes were labeled with clinical grade anti-CD14 conjugates and positively selected by immunomagnetic separation. Cells were then cultured, according to Good Manufacturing Practice guidelines, in FCS-free medium in cell culture bags, and differentiated to DCs with GM-CSF plus IL-4 followed by TNF-alpha or, more recently, by a cocktail of IL-1beta, IL-6, TNF-alpha and prostaglandin-E2. Before maturation, Mo-DCs were pulsed with the autologous Id as whole protein or Id (VDJ)-derived HLA class I restricted peptides. Ten MM patients, who had been treated with two courses of high-dose chemotherapy with peripheral blood stem cell support, entered into the clinical study. CD14+ monocytes were enriched from 16.1+/-5.7% to 95.5+/-3.2% (recovery 67.9+/-15%, viability > 97%). After cell culture, phenotypic analysis showed that 89.6+/-6.6% of the cells were mature DCs. We obtained 2.89+/-1 x 10(8) DCs/leukapheresis which represented 24.5+/-9% of the initial number of CD14+ cells. Notably, the cytokine cocktail induced a significantly higher percentage and yield (31+/-10.9 of initial CD14+ cells) of DCs than TNF-alpha alone, secretion of larger amounts of IL-12, potent stimulatory activity on allogeneic and autologous T cells. Storage in liquid nitrogen did not modify the phenotype or functional characteristics of pre-loaded DCs. The recovery of thawed, viable DCs, was 78+/-10%. Thus, positive selection of CD14+ monocytes allows the generation of a uniform population of mature pre-loaded DCs which can be cryopreserved with no effects on phenotype and function and are suitable for clinical trials. Based on these results, a DCs-based phase II trial of anti-Id vaccination with VDJ-derived HLA class I-restricted peptides and KLH is underway for lymphoma patients. PMID 15359643

Clinical responsiveness of glioblastoma multiforme to chemotherapy after vaccination.
Aug 2004 | Wheeler, Christopher J; Das, Asha; Liu, Gentao; Yu, John S; Black, Keith L
Although the development of immune-based therapies for various cancers including malignant glioma has been heralded with much hope and optimism, objective clinical improvements in most vaccinated cancer patients have not been realized. To broaden the search for vaccine-induced benefits, we examined synergy of vaccines with conventional chemotherapy. PMID 15328167

Dendritic cells can be rapidly expanded ex vivo and safely administered in patients with metastatic breast cancer.
Aug 2004 | Dees, E Claire; McKinnon, Karen P; Kuhns, Jennifer J; Chwastiak, Kathryn A; Sparks, Scotty; Myers, Mary; Collins, Edward J; Frelinger, Jeffrey A; Van Deventer, Henrik; Collichio, Frances; Carey, Lisa A; Brecher, Mark E; Graham, Mark; Earp, H Shelton; Serody, Jonathan S
Immunotherapy using either dendritic cells (DCs) or expanded cytotoxic T cells (CTLs) has received increased interest in the treatment of specific malignancies including metastatic breast cancer (MBC). DCs can be generated ex vivo from monocytes or CD34+ precursors. The ability to expand and safely administer CD34-derived DCs in patients with MBC that have received prior cytotoxic chemotherapy has not been evaluated. PMID 15185007

Transient local response and persistent tumor control in a child with recurrent malignant glioma: treatment with combination therapy including dendritic cell therapy. Case report.
Aug 2004 | De Vleeschouwer, Steven; Van Calenbergh, Frank; Demaerel, Philippe; Flamen, Patrick; Rutkowski, Stefan; Kaempgen, Eckhart; Wolff, Johannes E; Plets, Christian; Sciot, Raf; Van Gool, Stefaan W
Treatment of malignant glioma is difficult and discouraging. Even after resection and maximal adjuvant therapy, the prognosis remains poor. The authors sought a novel form of treatment, such as stimulating the patient's own immune response against the tumor, and developed a protocol of tumor vaccination in which autologous dendritic cells (DCs) were used in patients with recurrent malignant glioma. A 4-year-old girl was treated by means of biopsy sampling and radiotherapy for a rolandic low-grade glioma. Ten years later, a Grade III recurrence was discovered and treated with subtotal resection, interstitial radiation, six courses of oral temozolomide, and 12 courses of oral VP 16. At the end of the chemotherapy cycle, a new rapidly growing recurrence was diagnosed. A macroscopically complete resection was performed. Afterward, the girl was vaccinated with autologous DCs that had been pulsed ex vivo with the homogenate of the resection specimen. She received six vaccines in total. The efficacy of immunization was checked by a positive delayed-type hypersensitivity skin reaction after the second injection. After the fifth vaccine, a transient contrast enhancement without mass effect was visualized on magnetic resonance imaging. Simultaneously, positron emission tomography imaging revealed a transient increase of metabolic activity around the resection cavity, but the metabolic uptake ratio remained below 1.8. The patient's disease is still in complete remission 24 months after the last surgery. She is clinically well with minor and stable left hemiparesis. This case report illustrates the potential of vaccination with DCs loaded with crude tumor homogenate as adjuvant therapy to induce prolonged tumor control of malignant glioma and the objective noninvasively monitored immune response against infiltrating tumor cells. PMID 15287461

Fusion cell vaccination of patients with metastatic breast and renal cancer induces immunological and clinical responses.
Jul 2004 | Avigan, David; Vasir, Baldev; Gong, Jianlin; Borges, Virginia; Wu, Zekui; Uhl, Lynne; Atkins, Michael; Mier, James; McDermott, David; Smith, Therese; Giallambardo, Nancy; Stone, Carolyn; Schadt, Kim; Dolgoff, Jennifer; Tetreault, Jean-Claude; Villarroel, Marisa; Kufe, Donald
Dendritic cells (DCs) are potent antigen-presenting cells that are uniquely capable of inducing tumor-specific immune responses. We have conducted a Phase I trial in which patients with metastatic breast and renal cancer were treated with a vaccine prepared by fusing autologous tumor and DCs. PMID 15269142

Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma.
Jul 2004 | Yu, John S; Liu, Gentao; Ying, Han; Yong, William H; Black, Keith L; Wheeler, Christopher J
The primary goal of this Phase I study was to assess the safety and bioactivity of tumor lysate-pulsed dendritic cell (DC) vaccination to treat patients with glioblastoma multiforme and anaplastic astrocytoma. Adverse events, survival, and cytotoxicity against autologous tumor and tumor-associated antigens were measured. Fourteen patients were thrice vaccinated 2 weeks apart with autologous DCs pulsed with tumor lysate. Peripheral blood mononuclear cells were differentiated into phenotypically and functionally confirmed DCs. Vaccination with tumor lysate-pulsed DCs was safe, and no evidence of autoimmune disease was noted. Ten patients were tested for the development of cytotoxicity through a quantitative PCR-based assay. Six of 10 patients demonstrated robust systemic cytotoxicity as demonstrated by IFN-gamma expression by peripheral blood mononuclear cells in response to tumor lysate after vaccination. Using HLA-restricted tetramer staining, we identified a significant expansion in CD8+ antigen-specific T-cell clones against one or more of tumor-associated antigens MAGE-1, gp100, and HER-2 after DC vaccination in four of nine patients. A significant CD8+ T-cell infiltrate was noted intratumorally in three of six patients who underwent reoperation. The median survival for patients with recurrent glioblastoma multiforme in this study (n = 8) was 133 weeks. This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous tumor lysate-pulsed DC vaccine for patients with malignant glioma. We demonstrate for the first time the ability of an active immunotherapy strategy to generate antigen-specific cytotoxicity in brain tumor patients. PMID 15256471

Autologous dendritic cell vaccines for non-small-cell lung cancer.
Jul 2004 | Hirschowitz, Edward A; Foody, Terry; Kryscio, Richard; Dickson, Larry; Sturgill, Jamie; Yannelli, John
Therapeutic outcomes of definitively treated non-small-cell lung cancer (NSCLC) are unacceptably poor. A wealth of preclinical information, and a modest amount of clinical information indicate that dendritic cell (DC) vaccines have therapeutic potential. Only a handful of NSCLC patients have been included in DC clinical trials. We delivered autologous DC vaccines to 16 individuals with stage IA to IIIB NSCLC treated with surgery, chemoradiation, or multimodality therapy. The objectives of the study were to evaluate tolerability and measure immunologic responses to DC vaccines in a heterogeneous group of NSCLC patients. PMID 15254048

The immune response to breast cancer, and the case for DC immunotherapy.
Jun 2004 | Allan, C P; Turtle, C J; Mainwaring, P N; Pyke, C; Hart, D N J
The long-held belief that breast cancer is a weakly immunogenic tumor and a poor candidate for immunotherapy should be reappraised. There is ample evidence for the existence of an immune response, which is, however, attenuated by multiple inhibitory factors. Many tumor-associated antigens (TAA) have been identified in breast cancer, some of which appear to play a critical role in tumorigenesis and may be attractive targets for immunotherapy. There is evidence for DC recruitment and activation within breast cancers, and the presence of intratumoral activated DCs impacts favorably upon survival. Furthermore, there is a striking paucity of activated DCs within the primary draining or sentinel lymph nodes of breast cancers. Tumor infiltrating lymphocytes (TIL) are often documented, however, their function is impaired by inhibitory cytokines, increased regulatory T lymphocyte activity, tumor cell MHC molecule alterations, and aberrant Fas ligand expression, amongst others. DCs are recognized as one of the critical interfaces between a cancer and the immune system, and have emerged as a promising platform for cancer vaccination via ex vivo immunomodulation. Clinical evaluation of DC vaccination in breast cancer is still relatively limited, although evolving. This article details evidence for the immune response in breast cancer and its many failings, and reviews the clinical trials and significant preclinical data which, taken together, validate the concept of DC vaccination in breast cancer. PMID 15203992

Cytotoxic T cell responses against mesothelioma by apoptotic cell-pulsed dendritic cells.
Jun 2004 | Ebstein, Frédéric; Sapede, Carole; Royer, Pierre-Joseph; Marcq, Marie; Ligeza-Poisson, Catherine; Barbieux, Isabelle; Cellerin, Laurent; Dabouis, Gérard; Grégoire, Marc
Malignant pleural mesothelioma is an uncommon tumor largely confined to the thoracic cavity, which is resistant to conventional therapies, therefore prompting an intensive search for effective treatment alternatives. This study focuses on dendritic cell (DC) vaccination for malignant pleural mesothelioma and evaluates the in vitro efficacy of antigen-loaded DC-based vaccines for the induction of major histocompatibility complex Class I-restricted antimesothelioma cytotoxic T lymphocyte responses. The source of tumor-associated antigens for HLA-A2(+) DCs from healthy donors was apoptotic HLA-A2(-) mesothelioma cells either lacking or expressing heat shock protein 70 according to whether tumor cells were heat shocked or not before ultraviolet-mediated apoptosis. Our results show that both apoptotic preparations were equivalent regarding the responsiveness of DCs to combined treatment with tumor necrosis factor-alpha and poly(inosinic-cytidylic) acid, as determined by similar increased expression of costimulatory molecules and interleukin-12 production. However, only DCs loaded with apoptotic heat shock protein 70-expressing cells were found to be potent in vitro inducers of cytotoxic T lymphocyte activity against HLA-A2(+) mesothelioma cells. Such elicited cytotoxic T lymphocytes also exhibit cytotoxic activity against an HLA-A2(+) melanoma cell line, suggesting recognition of shared antigens. These findings therefore carry the potential of offering an alternative, promising approach for the therapy of patients with malignant pleural mesothelioma. PMID 15070823

Characterization of CD34+ progenitor-derived dendritic cells pulsed with tumor cell lysate for a vaccination strategy in children with malignant solid tumors and a poor prognosis.
Jun 2004 | Ackermann, B; Tröger, A; Glouchkova, L; Körholz, D; Göbel, U; Dilloo, D
Children and adolescents with primary multifocal, refractory or relapsed malignant extracranial solid tumors still have a poor prognosis inspite of intensive standard radio-/chemotherapy. Here complementary immunomodulatory treatment modalities may prove beneficial as consolidation therapy following cytoreduction. Neuroblastoma, Ewing tumor and soft tissue sarcoma cells have principally been shown to be susceptible towards both cytotoxic and humoral effector mechanisms. Yet in vivo they are not capable of inducing an effective antitumor response which has been attributed to low level MHC expression and lack of costimulatory surface molecules. Professional antigen - presenting cells such as dendritic cells (DCs) in contrast are capable of activating unprimed T cells and are therefore ideal tools for vaccine generation. PMID 15175963

Vaccination with p53-peptide-pulsed dendritic cells, of patients with advanced breast cancer: report from a phase I study.
Jun 2004 | Svane, Inge Marie; Pedersen, Anders E; Johnsen, Hans E; Nielsen, Dorte; Kamby, Claus; Gaarsdal, Eva; Nikolajsen, Kirsten; Buus, Søren; Claesson, Mogens H
Peptides derived from over-expressed p53 protein are presented by class I MHC molecules and may act as tumour-associated epitopes. Due to the diversity of p53 mutations, immunogenic peptides representing wild-type sequences are preferable as a basis for a broad-spectrum p53-targeting cancer vaccine. Our preclinical studies have shown that wild-type p53-derived HLA-A2-binding peptides are able to activate human T cells and that the generated effector T cells are cytotoxic to human HLA-A2+, p53+ tumour cells. In this phase I pilot study, the toxicity and efficacy of autologous dendritic cells (DCs) loaded with a cocktail of three wild-type and three modified p53 peptides are being analysed in six HLA-A2+ patients with progressive advanced breast cancer. Vaccinations were well tolerated and no toxicity was observed. Disease stabilisation was seen in two of six patients, one patient had a transient regression of a single lymph node and one had a mixed response. ELISpot analyses showed that the p53-peptide-loaded DCs were able to induce specific T-cell responses against modified and unmodified p53 peptides in three patients, including two of the patients with a possible clinical benefit from the treatment. In conclusion, the strategy for p53-DC vaccination seems safe and without toxicity. Furthermore, indications of both immunologic and clinical effect were found in heavily pretreated patients with advanced breast cancer. An independent clinical effect of repeated administration of DCs and IL-2 can not of course be excluded; further studies are necessary to answer these questions. PMID 14985857

Accomplishments and perspectives of immunological interventions in lymphoproliferative disorders.
May 2004 | Milosević, D B
The purpose of this review is to consider evidences accumulated in the last few years which might lead to a new therapeutic strategy for lymphoproliferative disorders. Tumor-targeted and immunologically designed therapy has already started. Clinical effectiveness also includes the primary and secondary prevention of these malignancies. The fortifying of body's defense through vaccination as primary prevention with tumor-specific cell surface antigen, has been seen over the past few years, and will lead to health patient's improvement. Data collected from clinical trials and in vitro analysis indicated that the immune system of patients could recognize and eliminate neoplastic cells while sparing normal cells. In B-cell lymphomas and myelomas, the tumor-idiotype (Id) produced by a single B-cell clone, has been used for vaccination. Therapeutic Id vaccination used two types of antigen-presenting cells as natural adjuvants for the induction of antigen-specific T cell response. Dendritic cells (DCs)--based vaccines are under active investigation and are entering clinical evaluation. Current research focuses on optimization of DCs source, choice and loading of antigen, mode of injection, as well as immune monitoring. Some preliminary results were obtained and no significant side effects of dendritic cells vaccination of lymphoma and myeloma patients have so far been reported. The over-estimation of clinical effectiveness, at this moment, is still limited by the small number of patients included in this kind of treatment. The challenge for the future will be to extend these early results to reproducible vaccination strategy according to current standards of good clinical practice (GCP). PMID 15149145

Dendritic cell-based combined immunotherapy with autologous tumor-pulsed dendritic cell vaccine and activated T cells for cancer patients: rationale, current progress, and perspectives.
May 2004 | Morisaki, Takashi; Matsumoto, Kotaro; Onishi, Hideya; Kuroki, Hideo; Baba, Eishi; Tasaki, Akira; Kubo, Makoto; Nakamura, Mitsunari; Inaba, Syoichi; Yamaguchi, Koji; Tanaka, Masao; Katano, Mitsuo
Effective adoptive cancer immunotherapy depends on an ability to generate tumor-antigen-presenting cells and tumor-reactive effector lymphocytes and to deliver these effector cells to the tumor. Dendritic cells (DCs) are the most potent antigen-presenting cells, capable of sensitizing T cells to new and recall antigens. Many studies have shown that tumors express unique proteins that can be loaded on DCs to trigger an immune response. The current experimental and clinical statuses of adoptive transfer of tumor antigen-pulsed DCs and vaccine-primed activated T cells are summarized herein. Clinical trials of antigen-pulsed DCs have been conducted in patients with various types of cancer, including non-Hodgkin lymphoma, multiple myeloma, prostate cancer, renal cell carcinoma, malignant melanoma, colorectal cancer, and non-small cell lung cancer. These studies have shown that antigen-loaded DC vaccination is safe and promising for the treatment of cancer. In addition, tumor vaccine-primed T cells have been shown to induce antitumor activity in vivo. Several clinical studies are being conducted on the use of vaccine-primed T cells such as tumor-drainage lymph node. It is reasonable to consider using both tumor antigen-pulsed DCs and vaccine-primed lymphocytes as adjuvants. We are now investigating the use of autologous whole tumor antigen-pulsed DCs and the DC vaccine-primed activated lymphocytes in patients with multiple metastasis of solid tumors. PMID 15147037

Dendritic cell vaccination in medullary thyroid carcinoma.
May 2004 | Stift, Anton; Sachet, Monika; Yagubian, Rubina; Bittermann, Clemens; Dubsky, Peter; Brostjan, Christine; Pfragner, Roswitha; Niederle, Bruno; Jakesz, Raimund; Gnant, Michael; Friedl, Josef
Prognosis and treatment effectiveness for medullary thyroid carcinoma (MTC) are strictly related to tumor stage. Palliative treatment options show no significant benefit. A promising treatment approach for human cancer is based on the vaccination of autologous dendritic cells (DCs). PMID 15131029

Generation of carcinoembryonic antigen (CEA)-specific T-cell responses in HLA-A*0201 and HLA-A*2402 late-stage colorectal cancer patients after vaccination with dendritic cells loaded with CEA peptides.
Apr 2004 | Liu, Ko-Jiunn; Wang, Chuan-Cheng; Chen, Li-Tzong; Cheng, Ann-Lii; Lin, Dong-Tsamn; Wu, Yu-Chen; Yu, Wei-Lan; Hung, Yi-Mei; Yang, Hui-Yu; Juang, Shin-Hun; Whang-Peng, Jacqueline
We intranodally immunized metastatic colorectal carcinoma patients, who had failed standard chemotherapy, with dendritic cells (DCs) pulsed with HLA-A*0201- or HLA-A*2402-restricted carcinoembryonic antigen (CEA) peptides to evaluate the safety of this treatment and the immune response against CEA peptides before and after the treatment. PMID 15102666

Tumour cell/dendritic cell fusions as a vaccination strategy for multiple myeloma.
Apr 2004 | Raje, Noopur; Hideshima, Teru; Davies, Faith E; Chauhan, Dharminder; Treon, Steven P; Young, Gloria; Tai, Yu-Tzu; Avigan, David; Gong, Jianlin; Schlossman, Robert L; Richardson, Paul; Kufe, Donald W; Anderson, Kenneth C
Multiple myeloma (MM) cells express certain tumour-associated antigens (TAAs) that could serve as targets for active-specific immunotherapy. The aim of the present study was to test the MM/dendritic cell (DC) fusion as a vaccination strategy. We fused MM cells with DC to generate fusion cells (FCs) and tested their antigen presenting cell (APC) function in mixed lymphocyte reactions and cytotoxicity assays. First, the HS Sultan and SK0-007 HAT sensitive human MM cell lines and DCs generated from peripheral blood of normal donors were fused in the presence of 50% polyethylene glycol to form FCs. Next, tumour cells freshly isolated from patients were similarly fused with autologous DCs to generate FCs. The FCs demonstrated a biphenotypic profile, confirmed both by flow-cytometry and dual immunofluorescence microscopy. These FCs induced MM-specific cytotoxicity. FCs, but not MM cells or DCs alone, were potent stimulators of autologous patient T cells. More importantly, FC-primed autologous peripheral blood mononuclear cells demonstrated major histocompatibility complex-restricted MM-specific cytolysis. These studies therefore demonstrated that MM/DC FC can trigger an autologous immune response to MM cells and formed the framework for a clinical trial currently underway. PMID 15086415

Tumor-derived heat shock protein 70-pulsed dendritic cells elicit tumor-specific cytotoxic T lymphocytes (CTLs) and tumor immunity.
Mar 2004 | Ueda, Gosei; Tamura, Yasuaki; Hirai, Itaru; Kamiguchi, Kenjirou; Ichimiya, Shingo; Torigoe, Toshihiko; Hiratsuka, Hiroyoshi; Sunakawa, Hajime; Sato, Noriyuki
Vaccination with autologous tumor-derived heat shock proteins (Hsp), such as Hsp70, Hsp90 and gp96, has been demonstrated to elicit specific immune responses against the tumor from which the Hsps were isolated. The effect of Hsp immunization is wholly dependent on the presence of functional antigen-presenting cells (APCs) in the immunized host, and Hsp receptors on APCs have recently been identified. Here we show that bone marrow-derived dendritic cells (DCs) are able to internalize HSP-peptide complex and that peptides are re-presented by DCs via the major histocompatibility complex (MHC) class I presentation pathway. In addition, immunization with tumor-derived HSP-pulsed DCs induces strong cytotoxic T cell (CTL) responses against multiple antigenic peptides in a transporter-associated antigen processing (TAP)-dependent manner. The results of the present study provide strong evidence of an efficient cross-priming activity of Hsp70, which could be exploited in the development of new and more effective immunotherapeutic strategies for cancer patients. PMID 15016325