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Cancer Immunotherapy May Improve with Identification of New Mutations

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    The primary goal of cancer immunotherapy is to stimulate the human immune system to identify and destroy developing tumors. However, forcing immune cells to recognize tissues as foreign is proving to be much more difficult than researchers had hoped. However, a team of scientists at the Max Delbrück Center for Molecular Medicine (MDC) in Berlin has identified immunogenic mutations in T cell receptors that occur naturally in human melanoma.

    Though T cells typically migrate into tumors and potentially can recognize their antigens, the defense mechanism often seems to fail during the formation of tumors. T cells in the tumors are usually inactive and therapeutically almost useless.

    “It is possible to obtain fresh T cells from a patient’s blood and transfer tumor-specific T cell receptors into them,” explains lead study author Matthias Leisegang, Ph.D., group leader at MDC. “The transfer of the T cell receptor is carried out using genetically modified and functionally inactivated viruses that can insert their genetic material into millions of T cells. When these modified cells are infused into the patient, they are able to fight the tumor.”

    The researchers tested their hypothesis in mice by analyzing the genes of an individual mouse tumor. Interestingly, the investigators were able to identify a mutation that occurred in all regions of the tumor and also found its way to the surface as an antigen. T cells were then taken from the mouse, armed with a T cell receptor that would target this antigen, and were then administered back to the animal—almost completely destroying the tumor.

    “We generated T cells expressing a mutation-specific transgenic T cell receptor (TCR) to target different immunogenic mutations in cyclin-dependent kinase 4 (CDK4) that naturally occur in human melanoma,” the author wrote. “Two mutant CDK4 isoforms (R24C, R24L) similarly stimulated T cell responses in vitro and were analyzed as therapeutic targets for TCR gene therapy.”

    The findings from this study were published recently in the Journal of Clinical Investigation through an article entitled “Targeting human melanoma neoantigens by T cell receptor gene therapy.”

    “We found that both mutations differed dramatically as targets for TCR-modified T cells in vivo,” the authors added. “While T cells expanded efficiently and produced IFN-γ in response to R24L, R24C failed to induce an effective antitumor response.”

    This experimental model allowed the researchers to analyze the antigens and clearly distinguish between good and bad T cell targets by using a humanized mouse model, underscoring the importance of preliminary animal studies to ensure the final success of mutation-specific therapies.

    “This means that we have developed an animal model to test the therapeutic suitability of T cell receptors and antigens, which is an important prerequisite for clinical applications,” Dr. Leisegang noted.

    While the researchers were successful and excited by their ability to train immune cells to fight cancer by targeting mutations in mice, they emphasized that the patient individualized treatment is not yet ready for use in humans. Though clinical tests based on similar methods are currently underway, as of yet these therapies target only antigens without mutations—setting up a scenario wherein T cells could attack healthy tissue. The MDC research team’s technique is more complex but brings the field closer to true personalize medicine therapy.

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