The side effects of systemic chemotherapy used to treat cancer are often severe. For decades, oncologists have focused on treating the tumor, which may result in damage to the tumor‑bearing host and its immune system. Recently, much attention has been paid to the immune system of patients and its activation via biological therapies. Biological therapies, including immunotherapy and oncolytic virus (OV) therapy, are often more physiological and well tolerated. The review of Prof. Dr. Schirrmacher elucidates how these cancer therapies work and why these therapies may be better tolerated: i) In contrast to chemotherapy, immunotherapies induce a memory function of the adaptive immunity system; ii) immunotherapies aim to specifically activate the immune system against cancer; side effects are low due to immune tolerance mechanisms, which maintain the integrity of the body in the presence of B and T lymphocytes with their antigen‑receptor specificities and; iii) the type I interferon response, which is evoked by OVs, is an ancient innate immune defense system. Biological and physiological therapies, which support the immune system, may therefore benefit cancer treatment. The present review focused on immunotherapy, with the aim of reducing side effects and increasing long‑lasting efficacy in cancer therapy.
- From chemotherapy to biological therapy: A review of novel concepts to reduce the side effects of systemic cancer treatment (Review)
The Nobel Prize for Medicine 2018 being awarded to immune researchers Allison and Honjo is a further milestone for modern cancer therapy with the focus on the body’s powers to heal itself. Already in 2011 three immunologists were recognised for their work which revolutionised our understanding of the immune system and opened new doors to fighting cancer: Steinman described the functioning of dendritic cells and Hoffmann and Beutler discovered that a successful immune response requires danger signals. Our immunotherapy and vaccine production at the IOZK is based on these discoveries.
At the same time, the IOZK has been applying the principles of the basic research for which the current Nobel Prize was awarded for the last two years – they act as protection against tumour-specific immune cells that can attack tumour cells. The so-called check-point inhibitors improve the effectiveness of our therapy at the IOZK while also creating the conditions for the successful application of these medications. Because check-point inhibitor antibody therapies have only been able to help a small number of patients, namely those which have already developed an immune reaction against the tumour cells. In certain cases we can use the check-point inhibitor antibodies so that the tumour-specific activated immune system successfully destroys the tumour cells.
The IOZK team published a scientific article in the journal “Austin Oncology Case Report”. This work examines the compassionate-use treatments of patients with glioblastoma retrospectively. In addition to chemotherapy with Temodal, patients were treated with tumour-specific immune modulation in the form of electrohyperthermia combined with immunotherapy. The adjuvant therapy suggests a more effective treatment if an immunotherapy is administered in addition to the chemotherapy. The immunotherapy causes immunogenic cell death of the tumour cells and the biomarkers indicating this were shown.
The results suggest that a combination of hyperthermia and viral therapy during chemotherapy with Temodal has advantages when looking at the overall survival. While treatment with chemotherapy only shows effectiveness in dividing cancer cells, this additional method causes immunogenic cell death irrespective of cell division.
- The Induction of Immunogenic Cell Death (ICD) During Maintenance Chemotherapy and Subsequent Multimodal Immunotherapy for Glioblastoma (GBM). Autoren: Van Gool SW, Makalowski J, Feyen O, Prix L, Schirrmacher V and Stuecker W.
At the world-renowned annual meeting of the American Society of Clinical Oncology (ASCO) 2018, Dr. Marnix Bosch presented the interim results of a Phase III study on the application of a vaccine with dendritic cells (DCVax®) to treat glioblastoma. This is the most common tumour of the brain with a very bad prognosis.
The multi-centre, double-blind study was conducted with 331 selected patients who received the DC vaccine in addition to the standard therapy of an operation and radio/chemotherapy. Patients were included in the study directly after the diagnosis if they had a Karnofsky Index ≥ 70. Patients who had any other diseases, an advanced tumour, or a relapse were excluded. The interim results show that the vaccine is tolerated very well and, compared to the standard therapy alone, leads to an increased life expectancy.
The results of the study correspond with the clinical experience gained at the IOZK from our compassionate-use treatments where our DC vaccine is used in combination with an oncolytic virus for treatment.
- First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.
The IOZK participated at the annual conference of the ESHO (European Society for Hyperthermic Oncology) which took place at the Charité in Berlin. The IOZK presented on modulated electro-hyperthermia in the treatment of children with DIPG, an aggressive brain tumour (Hyperthermia as part of multimodal immunotherapy for children with DIPG, S. van Gool, J. Makalowski, V. Schirrmacher, W. Stuecker).
In this presentation, and many other presentations, the immunological effects of hyperthermia were discussed. Previously the focus was on achieving high temperatures in the tissue in order to damage the tumour tissue. New research shows that the increased temperature makes the immune system aware of the tumour, amongst other things. The tumour is altered through the hyperthermia and so becomes recognisable again to the immune cells. Thus hyperthermia supports the body’s own defences in fighting the tumour.
The GW Research Days took place at the George Washington University in Washington, D.C., on 11 April. The research group of Roger J. Packer und Javad Nazarian (Children’s National Health System, Washington / George Washington University / IOZK) presented on the effects of a multimodal immune therapy in a pontine glioma with the aid of liquid biopsy analysis. Pontine gliomas are inoperable tumours occurring at the brain stem and primarily occurring in children. Currently the progression of the disease is monitored through MRI. Based on a new liquid biopsy platform it is now possible to gain more precise results that cannot be misinterpreted due to pseudoprogression. The research shows a marked decline of molecular tumour antigens (allelic frequency H3F3A mutation) when using the treatment procedure used at the IOZK. It is hoped that the analysis method can give more precise insights into the progression of the disease and the response to the treatment.
Quo vadis cancer therapy is the title of Prof. Dr. Schirrmacher’s new book, a comprehensive guide on cancer. In the book different forms of treatment are discussed as well as how these were developed. The book highlights important findings from the fields of molecular biology, cancer biology, immunology, virology and physiology. A main part deals with new biological therapies from the last decades. An important section is the comparison of immune therapies with all other forms of cancer treatment.
The book is an appeal to the health care system to modernise the current forms of therapy and supplement these with new therapies available today. Cancer therapies should include more components from immune therapy, which reduces side effects and increases the long-term efficiency of the treatment. Take a look at the personal presentation.
Stefaan Van Gool presented the multimodal immune therapy of diffuse intrinsic pontine glioma (DIPG), a brain tumour occurring in children, at the annual meeting of the Society for Neuro-Oncology (SNO) in San Francisco. The SNO is a multidisciplinary organisation with a focus on advancing neuro-oncology through research and education.
Combination was the key word at this year’s function, e.g., between targeted therapies or between radiation and chemotherapy. Different combination options were also judged as gaining more importance in immune therapies: oncolytic viruses can be combined with dendritic cells vaccines or checkpoint inhibitors – or all three can be combined. The IOZK has already specialised in this approach in its compassionate use treatments.
The "International Journal of Molecular Sciences“ has published a review by Prof. Schirrmacher focusing on the role of Newcastle Disease Virus in tumor vaccinations.
- Immunobiology of Newcastle Disease Virus and its use for prophylactic vaccination in poultry and as adjuvant for therapeutic vaccination in cancer patients
The German publication „Deutsche Zeitschrift für Onkologie“ has published a bilingual review by Prof. Schirrmacher. It explains basics of immunotherapies and gives examples of strategies which have been particularly successful.
"Progress in the treatment of cancer is urgently needed to improve its efficacy. In the last 20 years, immunotherapy has emerged as a new biological method of treatment. Its impact has increased recently by the introduction of approved cancer immunotherapeutics. In comparison to chemo- and radiotheraphy immunotherapy is characterized by a higher specificity towards tumor cells."
The IOZK would like to answer some frequently asked questions here.
What does an individualised therapy mean?
The tumour-specific immune therapy is an individual, patient-adapted therapy. Through an autologous vaccine the immune system is activated and enabled to take up the fight against the cancer. This means that each individual patient receives a unique therapy tailored according to their physical disposition, genetic makeup, and medical history.
For this an autologous, patient-specific vaccine is produced according to the European Medicines Act and “Good Manufacturing Practice” (GMP) regulations for each individual patient as a personalised medicinal product. Thus patients at the IOZK receive the best possible immune therapy, tailored for them personally.
What is an “individueller Heilversuch”?
The IOZK treats patients under the German “individueller Heilversuch” regulation. There is no direct translation for this term or the German legalities associated with it, but the term can best be described as compassionate use treatment.
This approach is part of the medical therapeutic freedom. It represents a procedure which is primarily performed to the benefit of the patient when all other therapeutic options have been exhausted or which can be started earlier on one’s own account. Other than in clinical trials, the primary objective is not to gather general data on the patient’s response. There are no clinical values that need to be attained. A variation of this is a series of “Heilversuche”, where several of these treatments are performed in parallel or sequentially.
Does the IOZK adhere to formal regulations?
The tumour immunotherapy treatment at the IOZK is approved according to the Medicines Act §13. All services are charged according to the medical fee schedule (the German GebührenOrdnung für Ärzte – GOÄ).
Prof. Schirrmacher, Dr. Lorenzen, Prof. Van Gool and Dr. Stuecker published a review in Austin Oncology Case Reports which describes and explains the specific immunotherapy strategy that has been developed at the IOZK in Cologne.
- A New Strategy of Cancer Immunotherapy Combining Hyperthermia/Oncolytic Virus Pretreatment with Specific Autologous Anti-Tumor Vaccination
Prof. Stefaan Van Gool is specialised in paediatric oncology – the treatment of children with brain tumours is a focus at the IOZK. A recent article in the Washington Post shows that this treatment is being noticed internationally by affected parents.
The Deutsches Ärzteblatt informs about a clinical study where patients with a Ductal Carcinoma in Situ (DCIS) were injected with multiple DC vaccines before their operation. The DC vaccines were proven to be safe, well tolerated, and effective: there were no detectable cancer cells in the tumour in one in four patients at the point of the operation.
The German Society for Hyperthermia held its 20th Congress from 30.09.2016 to 02.10.2016 in Berlin. Research findings as well as case studies were presented.
Dr. Bettina Weigelin (Department of Cell Biology, RIMLS, Radboud University Medical Center, Nijmegen/The University of Texas MD Anderson Cancer Center, Houston) presented video evidence from living cells showing that the interaction between immune cells and the attack of tumour cells at elevated body temperature shows a higher intensity.
Prof. Elizabeth Repasky, PhD (Professor of Oncology am Department of Immunology vom Roswell Park Cancer Institute) proved in her research that moderate whole body hyperthermia has a positive impact on immunological tumour therapy.
Prof. Dr. Marion Schneider (Sektion Experimentelle Anästhesiologie, Universitätsklinikum Ulm) presented her results on the on the immune reaction of macrophages under different different conditions elevating body temperature. This shows the positive influence of moderate hyperthermia, also in combination with antiinflammatory factors.
The first tumour immunology symposium at the Catholic University Leuven in Belgium took place from 12-14 September. The symposium focussed on results from current research and the therapy options resulting from these. In a presentation titled "Cancer cell death with a twist: Towards next-generation dendritic cell immunotherapy". Dr. Abhishek Garg (from the research group of Prof. Dr. Patrizia Agostinis, Catholic University Leuven), the IOZK was introduced as partner and centre for translation.
Prof. Schirrmacher has published a review on "Fifty Years of Clinical Application of Newcastle Disease Virus" in Biomedicines.
Our new FAQ information booklet for patients is now available on the "Patient Information" section of our website. As our therapy is quite complex, we would like to answer some questions that many patients have. We will gladly answer further questions in a consultation.
Prof. Schirrmacher holds the keynote lecture at the annual meeting of the "Dutch Tumor Immunology Meeting (DTIM)" on 10 June with the title "Oncolytic virus-enhanced immunotherapy of cancer"
Stefan Van Gool MD. PhD. has coauthored a scientific paper about a special dendritic cell preparation method.
Dr. Dirk Lorenzen presented the treatment concept of the IOZK to interested investors and hospital managers in Shengzhou and Shanghai. He also gathered information about the local cancer hospitals as well as specialised research centres and current developments.
Prof. Schirrmacher, Head of Tumour Immunology at the IOZK, has published a review in the "International Journal of Oncology" on cancer-reactive memory T-cells from bone marrow and their therapeutic potential.
- Cancer-reactive memory T cells from bone marrow: Spontaneous induction and therapeutic potential (Review)
Stefaan Van Gool has joined the IOZK.
Stefan van Gool MD. PhD. is an internationally renowned immunologist who was actively involved in research at the University of Leuven in Belgium for the past 20 years. His research focus has been on:
- Paediatric neuro-oncology and histiocytic disorders
- Tumour immunology: preclinical research and clinical studies on brain tumours
- Long-term effects of chemotherapy
An important reason for his move to the IOZK was the manufacturing authorisation granted to the IOZK in May for the first autologous anti-tumour vaccine. “I am delighted to continue working in my area of interest. The manufacturing authorisation now makes it easier to provide patients with this therapy. At the same time, I realise that exciting new developments in preclinical research can be translated into clinical practice with the future-oriented team and network of the IOZK,” said Dr. van Gool.
New antibodies for immunological cancer therapy have been approved in Germany. These antibody therapies support tumour-specific immune cells fighting cancer cells. These are known as checkpoint inhibitor antibodies: PD-1 antibody (Nivolumab / trade name: Opdivo®) and PD-L-1 antibody (Pembrolizumab / trade name: Keytruda®),
A case study on the longer-term survival of a patient with breast cancer is published in the british journal “Immunotherapy”.
- Long-term survival of a breast cancer patient with extensive liver metastases upon immune and virotherapy: a case report
IOZK launches new website.
The IOZK received the GMP certification as well as the manufacturing authorisation in accordance with the Medicines Act for ATMPs for its autologous tumour vaccine in combination with an oncolytic virus.
The Paul Ehrlich Institute awards the Paul Ehrlich- und Ludwig Darmstaedter-Preis 2015 for special achievements in immune therapy.
Prof. Schirrmacher publishes an e-book on virus-mediated anti-tumour therapy.
The IOZK publishes a case report on the successful treatment of metastasised prostate cancer in “Oncology Letters”.
- Long‑term remission of prostate cancer with extensive bone metastases upon immuno‑ and virotherapy: A case report
The UNESCO-L’Oreal Prize for “Women in Science” in the area medicine and immunology is awarded to Prof. Kayo Inaba of the Graduate School of Biosciences at the Kyoto University in Japan. Her field of research is dendritic cells. She was the first scientist who could prove that these cells can be primed outside the body and then reinjected to raise an immune response.
“Science” names immunotherapy for the treatment of cancer as the Breakthrough of the Year 2013. According to scientists, the studies published in 2013 show a clear turning point for the importance of immunotherapies.
Current development of tumour detection in our laboratory: The IOZK has been working with current laboratory methods to detect tumours at an early stage as well as monitoring the course of a patient’s cancer. These laboratory tests have successfully been evaluated at the University of Tübingen.
"Will Dendritic Cell Subsets help us address the challenges of Cancer, Autoimmunity and Viral Diseases?“ The lecture by Jacques Banchereau on the importance of the different subtypes of dendritic cells in malignant and infectious diseases.
- Video via YouTube (National Institutes of Health)
Nobel Prize 2011 awarded for research on immune therapies. The immunologists Ralph Steinman. Bruce Beutler, and Jules Hoffmann were awarded the Nobel Prize for medicine for the discovery of basic immunological mechanisms which form the basis of an immunotherapy against cancer.