Immunotherapy in metastatic colorectal cancer for the first time utilizes the innate immune system

Metastasized colorectal cancer is difficult to treat. Scientists at the National Center for Tumor Diseases (NCT) and the Heidelberg University Hospital in collaboration with the German Cancer Research Center (DKFZ) have now discovered that the immune system acts as an accomplice to the metastases.

Macrophages, also called scavenger cells, play a vital role in this process. The metastases in the liver influence macrophages in a way that helps tumor cells grow and spread. The reason for this is a signal pathway which is also used by the human immunodeficiency virus (HIV) as an entry point into human cells. One inhibitor is already being used therapeutically in HIV patients.

The scientists have now tested this drug in pre-clinical experiments and in a subsequent study involving 14 patients with advanced metastatic colorectal cancer. This Phase I study was funded by the Dietmar-Hopp Foundation and the promising results have just been published in Cancer Cell.

The NCT is a joint institution of the German Cancer Research Center (DKFZ), the Heidelberg University Hospital and the German Cancer Aid (Deutsch Krebshilfe).

The life expectancy of patients with non-operable metastasized colorectal cancer is about 24 months. In an advanced stage only few treatment options remain. Immunotherapeutic approaches have been fairly unsuccessful so far, although the necessary immune cells and their signaling molecules can been found around the cancer cells. Current immunotherapies are aimed at strengthening the acquired immune response, specifically activating T-cells against the tumor cells.

The scientists from Heidelberg and Hannover have now also managed to mobilize the innate part of the immune system by re-activation.

To do this, they closely examined the immune cells, particularly the macrophages from the tissue surrounding liver metastases of colorectal cancer patients. “Originally, it was assumed that the immune defense within the metastases also had an effectiveness against the tumor“, explains Dr. Niels Halama, physician and scientist at the Medical Oncology department at the NCT.

“We can now show that in colorectal cancer patients, the metastases manipulate the macrophages around them in a way that promotes cancer growth instead of fighting it.” The signal protein CCL5, which is normally involved in inflammatory process regulation as it pulls immune cells into the affected tissue, plays a major part. High concentrations of CCL5 are found in conditions such as rheumatoid arthritis, multiple sclerosis and Morbus Hodgkin. High concentrations of CCL5 and associated tumor-promoting effects have also been found in breast cancer metastases.

The scientists have shown that the T-cells close to the liver metastasis produce CCL5. In order for the protein to work, it needs to bind to its counterpart, the CCR5 receptor. This receptor is present on the cell surface of tumor cells and macrophages and induces upon activation tumor-promoting effects. The CCR5 receptor is already well known from research into HIV, because the HI virus also binds to CCR5 and penetrates the cells this way. An already registered drug blocks the surface protein CCR5 and is used therapeutically for HIV patients.

The scientists investigated the effectiveness of this HIV drug, initially in pre-clinical trials on liver metastases. The CCR5 blockage reversed the tumor-promoting effects of the macrophage in the tissue surrounding the metastasis and showed a repolarization with anti-tumoral effects. The re-programmed scavenger cells were able to destroy the cancer cells, sparing the healthy liver tissue. “The trials have improved our understanding of immune regulation in cancer. It appears that the CCL5-CCR5 axis is important for the activation of macrophages, not only in viral infections such as HIV but also in cancer”, explains Prof. Christine Falk who works at the Medical School Hannover.

Following the pre-clinical experiments, the investigators could confirm their findings in a Phase-I trial involving 14 patients and observed a regression of individual metastases. The clinical study was funded by the Dietmar Hopp Foundation with 300.000 Euros. Prof. Dirk Jäger, Medical Director at the NCT and Coordinator of the Tumor Immunology Program at DKFZ reports: “The data show that the HIV medication is very well-tolerated and the response in combination with chemotherapy is indeed very promising. “New immunotherapies could significantly improve the treatment options, especially for colorectal cancer patients“, adds Prof. Markus W. Büchler, Managing Director of the Surgical University Hospital in Heidelberg.

In this research project, macrophages were, for the first time successfully re-polarized through CCR5 inhibition with anti-tumoral effects. The scientists now hope to further develop this new immune therapy which uses the innate immune system. Niels Halama, who is also principle investigator of the colorectal cancer study adds: “Further clinical studies are in preparation that should improve our understanding of how this new therapy option could also be beneficial for the treatment of other types of tumors.”

An image for this press release is available at
https://www.nct-heidelberg.de/fileadmin/media/news/pressemitteilungen/PM_Cancer_…

Legend: The HIV drug Maraviroc blocks the surface protein CCR5. This activates the macrophages in the liver to fight the metastases. In this patient, the metastases in the liver (left) disappeared following treatment (right).

Literature:
Halama N, Zoernig I, Berthel A , Kahlert C, Klupp F, Suarez-Carmona M, Suetterlin T, Brand K, Krauss J, Lasitschka F, Lerchl T, Luckner-Minden C, Ulrich A, Koch M, Weitz J, Schneider M, Buechler M W, Zitvogel L, Herrmann T, Benner A, Kunz C, Luecke S, Springfeld C, Grabe N, Falk CS, Jaeger D (2016) Tumoral immune cell exploitation in colorectal cancer liver metastases can be targeted effectively by anti-CCR5 therapy in cancer patients. Cancer Cell 29: 587-601

Dr. Friederike Fellenberg
Nationales Centrum für Tumorerkrankungen (NCT) Heidelberg
Press and Public Relations
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Dr. Stefanie Seltmann
Deutsches Krebsforschungszentrum (DKFZ)
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Doris Rübsam-Brodkorb
Universitätsklinikum Heidelberg und Medizinische Fakultät der Universität Heidelberg
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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.

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
Health care, research and teaching of international standing
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.

http://www.nct-heidelberg.de