Therapeutic approaches that make use of the immune system are becoming increasingly important in the treatment of cancer. These new methods also include bispecific antibody fragments, so-called "BiTEs". BiTEs connect T cells with tumor cells and can thereby trigger programmed cell death in the cancer cells. So far, BiTEs are only successful in a few types of blood cancer and the treatment is sometimes associated with serious side effects. Researchers at the National Center for Tumor Diseases (NCT) Heidelberg, the German Cancer Research Center (DKFZ) and the Heidelberg University Hospital (UKHD) have now for the first time used modified measles viruses to produce BiTEs within the cancer cells themselves. They were able to increase the efficacy against solid tumors and make the procedure safer.
The NCT Heidelberg is a joint institution of the German Cancer Research Center (DKFZ), the Heidelberg University Hospital (UKHD) and the German Cancer Aid.
Artificially produced antibodies, so-called BiTEs ("bispecific T cell engagers"), consist of the binding regions of two antibodies, each of which "recognizes" different target structures. One of the two binding sites remains the same for all BiTEs and is reserved for the protein CD3 on T cells. The second binding region is varied and tumor-specific. The BiTE-mediated connection directs the T cell to the tumor cell and triggers programmed cell death in the cancer cell.
"For some forms of leukemia, such BiTE antibodies are effective, but so far not against solid tumors such as skin or colon cancer," states Christine Engeland, cancer researcher at NCT Heidelberg. "In addition, BiTEs must be administered as a continuous infusion, which can cause serious, sometimes life-threatening side effects." The researchers of the NCT Heidelberg Virotherapy Group led by Guy Ungerechts have now developed an approach to make BiTE treatment safer and to increase its success in the treatment of solid tumors. The results were published in the journal "Clinical Cancer Research".
In mouse experiments, the researchers used attenuated measles viruses that do not cause disease, but replicate in tumor cells. These viruses have been engineered to produce the BiTE antibody fragments in the cancer cells themselves. "The advantage of this approach is that BiTEs do not enter the bloodstream, thus avoiding side effects, and it also stimulates the body's own immune system, which makes the immune system aware of the cancer," Engeland explains. In mouse experiments, her doctoral students Tobias Speck and Johannes Heidbüchel were also able to show that treatment of skin and colon cancer with BiTE viruses can significantly prolong survival and in some animals even achieve a cure. In addition, no signs of toxicity were found. "We hope that this new therapeutic concept is an effective strategy also in the treatment of human tumors," Engeland says. With this aim in mind, the scientists will now perform further experiments.
Speck T, Heidbuechel JPW, Veinalde R, Jaeger D, von Kalle C, Ball CR, Ungerechts G, Engeland CE (2018) Targeted BiTE expression by an oncolytic vector augments therapeutic efficacy against solid tumors. Clin Cancer Res. 2018 Feb 6. pii: clincanres.2651.2017. DOI: 10.1158/1078-0432.CCR-17-2651.
Accompanying picture can be downloaded here:
Caption: Effectiveness of BiTE therapy with measles viruses.
Modified measles viruses (green) infect tumor cells (light blue), multiply and destroy them (gray). At the same time, the infected tumor cells produce so-called BiTEs. These artificial molecules consist of two antibody fragments (yellow / blue, image detail), which bind to CD3 on T cells (yellow) and to surface structures on tumor cells (blue). Through this connection, T cells (violet) "redirect" the body's own immune system to tumor cells and destroy them
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Nationales Centrum für Tumorerkrankungen (NCT) 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. 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.