August 20, 2024
Keio University School of Medicine
CAR-T cell therapy is a treatment in which T cells are collected from a patient's peripheral blood, genetically engineered ex vivo with a chimeric antigen receptor (CAR) to recognize and attack cancer cells, and then reinfused into the patient. While it is currently in clinical use for B-cell hematological malignancies, the efficacy of CAR-T cell therapy against solid tumors has been limited. One contributing factor is a phenomenon known as "exhaustion," where CAR-T cells become depleted and lose their potency as they combat cancer cells within the body. Previously, a research group led by Professor Akihiko Yoshimura of the Research Institute for Biomedical Sciences, Tokyo University of Science (at the time of the research: Department of Microbiology and Immunology, Keio University School of Medicine), reported in a mouse experimental model that eliminating NR4A, a regulator of exhaustion, makes CAR-T cells less prone to exhaustion and allows them to exert strong antitumor effects (Nature 2019; 567: 530–534). However, the effects of suppressing NR4A expression in human T cells and the potential mechanisms for avoiding exhaustion had not yet been clarified.
Now, a research group including Kensuke Nakagawara, a graduate student (JSPS Research Fellow) at the Division of Pulmonary Medicine, Department of Internal Medicine, Keio University School of Medicine, Professor Koichi Fukunaga, and Professor Akihiko Yoshimura of Tokyo University of Science has successfully created human-derived CAR-T cells that completely lack NR4A expression and has evaluated their antitumor effects. It was confirmed that, when co-cultured with cancer cells, the NR4A-deficient CAR-T cells exhibited higher proliferative capacity and resistance to exhaustion compared to wild-type CAR-T cells, and they persistently exerted strong antitumor effects. The study also revealed that CAR-T cells with suppressed NR4A expression have enhanced mitochondrial homeostasis and superior metabolic activity. Furthermore, in an experimental mouse model transplanted with a human lung cancer cell line, the NR4A-deficient CAR-T cells demonstrated enhanced therapeutic effects against human lung cancer and were able to extend the lifespan of the mice.
This research leads to a new therapeutic strategy for CAR-T cell therapy against solid tumors and is expected to have applications in immunotherapy for solid tumors.
The results of this research were published on August 16, 2024 (British Summer Time), in the Journal for ImmunoTherapy of Cancer , the official journal of the Society for Immunotherapy of Cancer .
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