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Break the boundaries of immunotherapy

הA method that may make the new generation of cancer treatments accessible to more patients

The immunotherapy revolution is breathing a new and optimistic spirit into cancer medicine, but there are many bumps along the way: this therapeutic approach, which is based on the activation of the patients' immune system against the cancerous tumor, can be successful if and only if the immune system "sees" the tumor and recognizes it as foreign to the body in which it is found. There are indeed ways to sharpen the vision of the immune system, but these solutions are inherently limited, since by their very definition they must be personalized for each and every patient. Recently, Prof. Jordana Samuels and Dr. Avia Perry from the Weizmann Institute of Science, together with their research partners, a method that may allow more patients to benefit from personalized immunotherapy. The new method is based on the identification of "hot spots" for the elimination of cancer - characteristics that appear in many cancerous tumors and therefore may be used to develop treatments suitable for large groups of patients. in research published today in the scientific journal Journal of Clinical Investigation, Using this method, the scientists identified a hot spot that characterizes a particularly violent subtype of melanoma skin cancer.

Hot spots are actually molecular structures that are displayed on cancer cell membranes of many patients and are a weak point that may expose the tumor to the immune system. These structures, which contain mutated protein segments and are called neoantigens, can be detected by the combat soldiers of the immune system - T cells. After identifying the targets, T cells bind to these neoantigens and eliminate the cancer cells. This action of T cells is actually the final goal of all types of immunotherapy, but the problem is that most neoantigens are "boutique" proteins, meaning they arise from unique mutations that characterize specific tumors, and therefore when they are used for therapeutic purposes - to stimulate the T cells of A certain patient - the treatment is not suitable for other patients. Only a handful of neoantigens - those created as a result of common mutations that characterize many patients - can be considered "hot spots", but they are extremely difficult to locate. The difficulty is partly due to the fact that they are presented on the cell membranes using protein arrays called HLA, which in themselves appear in thousands of different versions, so that if the multiple cancer mutations are also taken into account, millions of possible molecular patterns are obtained.

Due to the huge variety, most of the hotspots have so far been discovered thanks to the efforts of the goddess of luck, that is, by chance. In the new study, the research team led by Prof. Samuels from the Department of Molecular Biology of the Cell developed an approach for the systematic identification of hotspots. First, the scientists used algorithms to search international databases containing genetic information of thousands of cancer patients. The researchers focused on melanoma, the type of cancer studied in Prof. Samuels' laboratory, and looked for common mutations in oncogenes - cancer-causing genes - shown by common variants of HLA arrays. This is how they identified some neoantigens that were candidates for being "hot spots" and isolated them in the laboratory to check how, if at all, T cells react to them. The research was led by Dr. Perry, a PhD student from Prof. Samuels' lab, alongside Prof. Nir The late Friedman from the Department of Immunology, Prof. Masha Niv from the Hebrew University of Jerusalem, Prof. Steven Rosenberg from the US National Cancer Institute, Prof. Cyril Cohen from Bar-Ilan University, Dr. Ansoman Sathefati from Stanford University and other researchers.

""Our approach may allow the development of treatments suitable for large groups of patients. Treatments of this type are expected to be cheaper and simpler to implement than personalized immunotherapy"

Using this new approach, the scientists identified a hot spot originating from RAS - an oncogene involved in approximately one third of all cancer cases of its various types. The hotspot that was discovered is related to a variant of RAS that causes an especially violent type of melanoma in about 20% of patients. In collaboration with the late Prof. Friedman and Dr. Satfati, the scientists isolated the T-cell receptor that recognizes the neo-antigen on the melanoma cells. Next, they made engineered T cells expressing the receptor and put them in a lab dish with tissue samples from suitable melanoma patients. Following exposure to the hot spot, T cells were activated and destroyed the tumor cells in a targeted manner, meaning only the cells that carried the hot spot.  

"We uncovered a neoantigen that appears in thousands of melanoma patients every year, and showed that it can be used to mark the tumor cells as a target for destruction by the immune system," says Dr. Perry. And there is another important advantage to the new method: since the approach is based on hot spots originating from oncogenes that are expressed in each and every cell of the tumor, the treatment is expected to eliminate all the tumor cells with a high probability, and not just a part of the tumor cells as may happen with treatments targeting more "boutique" neoantigens .

"Our new approach may lead to 'mass immunotherapy', that is, to the development of T-cell receptors that recognize hotspots and may be used to treat large groups of patients. Treatments of this type are expected to be cheaper and simpler to implement than the preparation of personalized T cells", says Prof. Samuels. "Also, this approach can be applied to many different types of cancer, not just melanoma, and it is ripe to move to the development stage for use in hospitals." In order to promote the transition from the laboratory to the clinic, the company "ידע", the intellectual property commercialization arm of the institute's scientists, is working to commercialize the technology through a company that is in the stages of establishment.

Erez Grinstein and Dr. Shlomit Reich Zeliger from the institute's immunology department also participated in the study; Dr. Michal Alon, Dr. Sheli Klaura, Chaya Barbulin, Dr. Ronan Levy and Polina Greenberg from the department of molecular cell biology of the institute; Joy Pai of Stanford University; Dr. Tamir Dinian from the Hebrew University of Jerusalem; Dr. Ilon Barnea and Prof. Aryeh Admon from the Technion; Claudia Arando-Paque and Prof. Noria López-Bigaz from the Institute of Technology of Barcelona; Dr. Barkat Desa and Dr. Esther Feldmaser from the Department of Life Science Research Infrastructures of the Institute; Ping Shang, Dr. James Wilmot and Prof. Richard Scolier from the University of Sydney; Dr. Yishai Levin mThe Israeli National Center for Personalized Medicine named after Nancy and Steven Grand; Dr. Gil Bendak and Prof. Michal Lotem from the Hadassah University Medical Center; Prof. Mitchell Labeck from the University of Zurich; Prof. David Adams from the Sanger Institute of the Valkam Foundation; and Dr. Goren Jonsson from Lund University.