Towards personalized treatment of melanoma skin cancer

Recovery rates from melanoma skin cancer have increased significantly in recent years thanks to new immunotherapy treatments that successfully harness the cells of the immune system to fight cancer. In some cases of this cancer, recovery rates even reached 50%. A new study by scientists at the Weizmann Institute of Science shows that the recovery rates can be even higher: a new and personalized approach may significantly improve the ability of the cells of the immune system to identify cancer cells and destroy them. These findings are published today in the scientific journal Cancer Discovery

T cells of the immune system (in red) attack melanoma cancer cells (in green). T cells that "know" how to read "signposts" on the cancer cells are particularly effective in destroying them

The immunotherapy treatments available today are based on one of two methods - providing antibodies that stimulate the T cells of the immune system in the patient's body or growing and activating T cells in the laboratory and returning them to the patient's body in a more "militant" version. "But none of the methods will lead to the elimination of cancer, as long as the cells of the immune system fail to read the 'signposts' that mark the cancer cells as a foreign factor that must be fought," explains Prof. Jordana Samuels from the Department of Molecular Biology of the Cell.

Laboratories around the world are currently devoting many studies to the search for these markers called "neo-antigens": peptides that contain a mutation of the cancer cell, and are found on the surface of the cancer cell membranes. Identifying the peptides that can serve as markers for T cells may help to develop personalized vaccines against cancer. However, one of the problems in identifying these markers in melanoma cancer is that they are part of a protein array called HLA, which can appear in thousands of forms - and this is without taking into account the cancerous mutations shown. Thus, researchers trying to search for possible markers in the genome of the cancer cell with the help of algorithms have come up with many hundreds of possible candidates that require testing.

Almost all the neoantigens we have identified so far in patients were unique to both the patients and the specific cancer tissue - and therefore constitute an ideal bank of targets for anti-cancer treatments. This may be the ultimate personalized medicine - a new unique medicine for each patient"

Prof. Samuels with her research student Shelly Claora, in collaboration with Prof. Aryeh Edmon from the Technion, bypassed the need for an algorithm and significantly reduced the number of candidates. The scientists used the method developed by Prof. Edmon to separate peptides from the protein tangle on the melanoma cells, and then tested how the cells of the immune system react to these peptides. Says Prof. Samuels: "With this method, we discovered far fewer markers than one would have expected. The method was so effective that T cells that knew how to read the marker we identified eliminated 90% of the cancerous target cells - both in culture and in mice. These findings point to clinical applications are possible". The scientists collaborated with a team that included Dr. Ethan Rupin from the National Cancer Institute in the United States, Dr. Jennifer Vargo from the MD Cancer Center. Anderson at the University of Texas, and Prof. Nir Friedman from the department of molecular cell biology at the institute.

The researchers also checked whether the same signs appear in the cancer metastases that have spread among some of the patients. "This is the first time that peptides from different metastases of the same patient have been studied," says Claora. "In order to deliver a systemic blow to the cancer in patients with metastases, it is necessary to identify not only peptides that stimulate an immune response that are found on the cancer cells, but also those that are also found in the metastases cells in the patient's body."

Later, the scientists took the findings a step further: they took samples of T cells from 14 patients and tested how they reacted to the "neo-antigens" that had been identified. Then they selected the cells that reacted the strongest, sequenced their genomes, grew them in the laboratory, and injected mice that had been transplanted with cancer cells from the patients' bodies. The researchers showed that the selected T cells were more effective in eliminating the cancer, both in cultures and in mice.

Prof. Samuels concludes: "Although this is an experimental study at this stage, the findings are also highly relevant to clinical research, since anti-cancer treatments based on 'neo-antigens' are research-based. Given the fact that almost all the neo-antigens we have identified so far in patients were also unique For patients as well as for the specific cancerous tissue - they constitute an ideal bank of targets for anti-cancer treatments. This may be personalized medicine The ultimate - a new unique medicine for every patient."

Dr. Yohai Wolf, Dr. Itai Tirosh, Noir Kotov, Polina Greenberg and Ronan Levy from the department of molecular cell biology at the institute also participated in the research; Prof. Guy Shahar, Tali Pepperman, Erez Grinstein and Dan Rashef from the Department of Immunology at the Institute; Ofra Golani from the Department of Life Sciences Research Infrastructures at the Institute; Elon Barnea from the Technion; Alexander Reuven, Jianhua Zhang, Shizeng Mao, Xingjae Song, Chantal Branches, Kara Haymaker, Mary-Andre Forget, Caitlin Creasy, Brett Carter, and Zachary Cooper of the MD Cancer Center. Anderson at the University of Texas; Prof. Steven Rosenberg and Sushant Petkar from the National Cancer Institute, USA; Juliana Quincardt and Tana Omukoku from the German company BioNTech; Michal Lotem from the Hadassah Medical Center in Jerusalem, and Ugor Shahin from the Medical Center of the University of Mainz, Germany.

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