If colon cancer is discovered at an advanced stage, the chances of recovery are still very low. Therapies with a single active substance are hardly effective. Scientists see new possibilities in the combination of several therapies. In collaboration with the German Cancer Research Center (DKFZ), scientists of the National Center for Tumor Diseases (NCT) and the Heidelberg University Hospital (UKHD) and the German Cancer Consortium (DKTK) simulated the effectiveness of several therapy methods in tumor samples of colorectal cancer patients in a computer model. They found out that the combination of an immunotherapy and a targeted therapy point to effectiveness.
The NCT Heidelberg is a joint institution of the German Cancer Research Center (DKFZ), the University Hospital Heidelberg (UKHD) and the German Cancer Aid.
Colorectal Cancer is the third most common cancer disease worldwide. When diagnosed at an early stage, the chances of recovery are over 90 percent. In a metastatic situation, however, the chances of recovery are still very low. Treatment with a single active substance is then often not very effective. For most patients with metastatic colorectal cancer chemotherapy is the only effective option. However, since chemotherapy can control advanced cancer diseases for a limited period of time, finding better treatment options is a high priority. New therapies like immunotherapy are currently being researched intensively. However, they still find little use in patients with colorectal cancer. Combination treatments have therefore gained in importance in recent years. They comprise two or more therapeutic methods with different mechanisms. “We believe that combination therapies are needed to fully exploit the benefits of new drugs, including immunotherapeutics“, says Niels Halama, senior physician and group leader in the Department of Medical Oncology at the NCT Heidelberg and scientist at the German Cancer Consortium (DKTK) at the DKFZ.
Combinations of active substances are very complex and it is often unclear, which combinations are suitable for the individual patients. Furthermore finding the right combination raises the amount of necessary preclinical and clinical trials. “For example, to test ten new drugs for a single drug treatment, ten clinical trials are required. In order to review all dual combinations of ten drugs, 45 clinical trials would be required theoretically”, explains Halama.
An alternative solution is now offered by the newly developed computer system of the Heidelberg researchers. "This allows us to reconstruct the distribution of immune cells and tumor cells in the tissue, creating a virtual tumor microenvironment", explains Jakob Nikolas Kather, first author of the publication and staff member of the Medical Oncology Division at NCT Heidelberg and DKFZ. The simulation was based on histological data from a total of 224 colon cancer patients from an American study and 37 patient samples from the NCT biobank. Additionally, results from laboratory cell culture experiments were incorporated into the system.
Finally, the analysis of all data yielded four different scenarios of how the cell milieu of cancer cells, immune cells and connective tissue cells in the patient can look. Using the computer model, the researchers were able to simulate the effect of individual therapies on the four scenarios and examine how the growth of cancer cells could be altered by the treatments.
Researchers found out that the combination of immunotherapy and a targeted therapy showed the most effective results in fighting tumor cells. Targeted therapy made the connective tissue cells around the tumor permeable so that the immune cells could attack the cancer cells in the computer model. The identified combination consists of two types of treatment that have not previously been used in metastatic colon cancer.
Remarkably, the treatment only worked in combination. In contrast, the use of only one of the treatments even promoted tumor growth in the model situation. “Like every model, our model is not a copy of reality. However, it indicates which therapies might work” explains Kather. “Digital simulations of tumor micro environment will help decide the treatment one day”, says Dirk Jäger, director of the NCT Heidelberg and Head of the Department of Medical Oncology. Further computer analysis will now identify new potential combinations that will subsequently be reviewed in clinical trials.
Kather JN, Poleszczuk J, Suarez-Carmona M, Krisam J, Charoentong P, Valous NA, Weis CA, Tavernar L, Leiss F, Herpel E, Klupp F, Ulrich A, Schneider M, Marx A, Jäger D, Halama N (2017) In Silico Modeling of Immunotherapy and Stroma-Targeting Therapies in Human Colorectal Cancer. Cancer Research 77(22):6442-6452, doi: 10.1158/0008-5472.
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caption: The computer model works with four different scenarios: (A) Cancer cells are surrounded by connective tissue and won’t be attacked by the immune system (B) Cancer cells are being attacked by immune cells (C) Cancer cells are being controlled by immune cells for a period of time but continue to grow (D) Cancer cells are being destroyed by immune cells. Red = cancer cells, blue = immune cells, yellow = connective tissue cells, black = dead cells.
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The National Center for Tumor Diseases (NCT) Heidelberg
The National Center for Tumor Diseases (NCT) Heidelberg is a joint institution of the German Cancer Research Center, Heidelberg University Hospital and German Cancer Aid. The NCT's goal is to link promising approaches from cancer research with patient care from diagnosis to treatment, aftercare and prevention. The interdisciplinary tumor outpatient clinic is the central element of the NCT. Here the patients benefit from an individual treatment plan prepared in a timely manner in interdisciplinary expert rounds, the so-called tumor boards. Participation in clinical studies provides access to innovative therapies. The NCT thereby acts as a pioneering platform that translates novel research results from the laboratory into clinical practice. The NCT cooperates with self-help groups and supports them in their work. 2015 the NCT Heidelberg established a partner location in Dresden.
The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)
The German Cancer Research Center (DKFZ) with its more than 3,000 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. In the German Consortium for Translational Cancer Research (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center is an important contribution to improving the chances of cancer patients. DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.
Heidelberg University Hospital and Medical Faculty Heidelberg
Heidelberg University Hospital is one of the most important medical centers in Germany; Heidelberg University's Medical Faculty is one of Europe's most prestigious biomedical research facilities. Their shared objective is the development of innovative diagnostics and treatments and their prompt implementation for the benefit of the patient. The hospital and faculty employ approximately 12 600 individuals and are involved in training and qualification. Every year approximately 66 000 patients are treated as inpatients or day patients in more than 50 specialized clinical departments with about 1 900 beds, with more than 1 million patients being treated as outpatients. The Heidelberg Curriculum Medicinale (HeiCuMed) is at the forefront of medical training in Germany. At present approx. 3500 prospective physicians are studying in Heidelberg.