Research and Development of immune-regulatory CAR-T cells for intractable solid cancers玉田 耕治1) Adachi K and Tamada K. Paving the road to make chimeric antigen receptor-T-cell therapy effective against solid tumors. Cancer Sci. 2022. 113(12):4020-4029.2) Adachi K, Kano Y, Nagai T, et al. IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor. Nat Biotechnol. 2018. 36(4):346-351.3) Goto S, Sakoda Y, Adachi K, et al. Enhanced anti-tumor efficacy of IL-7/CCL19-producing human CAR-T cells in orthotopic and patient-derived xenograft tumor models. Cancer Immunol Immunother. 2021. 70(9):2503-2515.4) Ohta K, Sakoda Y, Adachi K, et al. Therapeutic Efficacy of IL7/CCL19-Expressing CAR-T Cells in Intractable Solid Tumor Models of Glioblastoma and Pancreatic Cancer. Cancer Res Commun. 2024. 4(9):2514-2524.山口大学 大学院医学系研究科 免疫学講座9. 難治性固形がんに対する免疫制御型 CAR-T 細胞の研究と開発Genetically engineered immune cell therapies are progressing worldwide and anticipated as the next-generation cancer immunotherapy. CAR-T cells are among the most advanced modalities, which have demonstrated an excellent effect on hematopoietic malignancies such as B-cell acute lymphocytic leukemia and multiple myeloma, leading to clinical approval in many countries including Japan. Current CAR-T cell therapy, however, harbors many hurdles to be overcome, including a necessity of target molecules specifically expressed on cancer cells, occurrence of severe adverse events, and tumor relapse after remission. Another major challenge is that CAR-T cell therapy has not yet demonstrated sufficient therapeutic efficacy against solid tumors. We have been engaged in the development of novel CAR-T cells that overcome these hurdles by adding various technological improvements to CAR structure1. As one of our strategies, we have developed immune-regulatory CAR-T cells that simultaneously express IL-7, a cytokine that enhances T cell proliferation and survival, and CCL19 which induces migration of T cells and dendritic cells2-4. IL-7/CCL19-producing CAR-T cells show potent therapeutic effects in solid tumor models by inducing host T cell responses specific to intrinsic tumor antigens through cross-presentation and epitope spreading. Recent updates in research and development of next-generation CAR-T cell therapies will be presented. Department of Immunology, Graduate School of Medicine, Yamaguchi UniversityKoji Tamada19
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