October 20, 2021
Keio University School of Medicine
Japan Agency for Medical Research and Development
A research group led by Professor Akihiko Yoshimura of the Department of Microbiology and Immunology, Keio University School of Medicine, has enabled more effective CAR-T therapy by developing a simple method to rejuvenate exhausted T-cells and convert them into T-cells with potent antitumor effects.
CAR-T therapy is a treatment in which T-cells derived from a cancer patient's peripheral blood are genetically engineered ex vivo with a CAR (chimeric antigen receptor) gene to recognize cancer, expanded, and then reinfused into the patient to attack cancer cells. T-cell therapies such as CAR-T therapy have attracted attention as highly effective cancer treatments, but they have a problem of reduced therapeutic efficacy due to a phenomenon called "exhaustion," where the cells wear out and lose their attack capabilities as they are expanded ex vivo or fight cancer cells in the body. Because CAR-T cells with a high proportion of exhausted T-cells are difficult to maintain in the patient's body and cannot achieve sufficient therapeutic effects, various efforts have been made to "rejuvenate" these exhausted T-cells. These young T-cells are called stem cell memory T-cells, and they can proliferate actively to generate a large number of cells capable of attacking cancer cells. However, a method for converting exhausted T-cells into stem cell memory T-cells has been unknown until now.
The research group found that by culturing the generated CAR-T cells with a combination of four factors (proteins)—IL-7, CXCL12, IGF-I, and a NOTCH ligand—they can be converted from an exhausted state into stem cell memory-like "young" T-cells. These stem cell memory-like CAR-T cells were confirmed to proliferate rapidly in response to cancer cells, have a long lifespan, and exert potent antitumor effects. As this culture method can produce more potent and long-lasting CAR-T cells compared to conventional ones, it is expected to be applied to cancer treatment in the near future.
The results of this research were published in "Cancer Research Communications," a journal of the American Association for Cancer Research (AACR), on October 19, 2021 (US time).
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