These are T cells (red) that attack melanoma cells (green). The neo-antigen specific T cells in this picture are particularly effective at killing cancer cells. Credit: Weizmann Institute of Science
With new immunotherapies for melanoma, recovery rates have increased dramatically, in some cases even to about 50%. But they could be much higher: A new study, led by researchers from the Weizmann Institute of Science, showed in laboratory and animal studies that a highly personalized approach could help immune cells improve their ability to detect and kill cancer. The results of this study have been published in Cancer Discovery,
Today's immunotherapies involve the administration of antibodies to release the immune system's natural T cells that recognize and kill cancer cells; or they grow and reactivate these T cells outside the body and return them in a "weapon-ready" form. "But none of this will kill the cancer if the immune cells do not recognize the" markers "that mark cancer cells as foreign," says Prof. Yardena Samuels from the Institute of Molecular Cell Biology.
Groups around the world are looking for such landmarks – mutated peptides known as neo-antigens on the outer membranes of cancer cells. Identification of the particular peptides that present to the T cell can then help to develop personalized cancer vaccines based on neo-antigen profiles. However, one of the problems with the discovery of neoantigens in cancers such as melanoma is that they are presented by a complex of proteins called HLA, a complex that can be present in thousands of versions, even without the addition of cancerous mutations. In fact, the algorithms that are often used to search the cancer cell genome for potential neo-antigens have predicted hundreds of potential candidates.
Samuels and her PhD student Shelly Kalaora worked together with Prof. Arie Admon of the Technion – Israel Institute of Technology on algorithms methods. They used a method Admon had developed to remove the peptides from the HLA complex of melanoma cells and to study their interactions with T cells. Samuels: "We discovered that tumors have far fewer neo-antigens than we expected, and our neo-antigen and corresponding T-cell identification strategies were so robust that our neo-antigen-specific T cells accounted for 90% of their target antigens. Melanoma Cells Killed Both on Plates and in Mice, Suggesting Possible Clinical Applications in the Near Future: Some of the identified peptides are neo-antigens that did not appear in the algorithmic studies, that is, the method we used called HLA peptidomics , is really complementary to these methods.
Samuels and Kalaora worked with a team that Dr. Eytan Ruppin from the National Cancer Institute, USA included. Dr. Jennifer Wargo from the University of Texas MD Anderson Cancer Center, Houston; and Prof. Nir Friedman from the Department of Molecular Cell Biology at the Weizmann Institute of Science.
For some of the patients, the group had received several samples, and this allowed them to ask questions about metastases – for example, if the same neo-antigens were present on secondary tumors after the cancer had spread to other organs. "This is the first time that HLA peptide studies of multiple metastases from the same patient have ever been performed The significant similarity between the different HLA peptidomas has strong implications for the process of selecting neo-antigens for patient treatment," What this shows Not only is it important to identify the immunogenic peptides found on cancer cells, but also those that are common to the patient's metastases, which can then help to guide systemic therapeutic responses in patients with multiple metastases, "says Kalaora ,
And then the group took it one step further: using natural T cells from 14 of the patients, the researchers identified those who reacted most with the neo-antigens. They sequenced the genomes of these cells, grew them, and tested them in animal models with the patient's tumor cells. In both laboratory and mouse experiments, they showed that the response of the T cells they identified was highly effective in the fight against cancer.
Samuels points out: "Although this research is currently experimental, the results are very relevant for clinical research as groups around the world are already laying the groundwork for the development of neo-antigen therapeutic anti-cancer treatments Neo-antigens that have been found in patients to date are unique – and unique to the particular cancerous tissue – they represent an ideal class of anti-cancer targets. This would be the ultimate "personalized" cancer therapy – for which a new drug is being developed every patient. "
This article was published from materials of the Weizmann Institute. Note: Material may have been edited for length and content. For more information, please contact the source indicated.