Chimeric antigen receptor (CAR) T cells in the solid tumor microenvironment enter a partially dysfunctional state called T cell exhaustion. Interleukin (IL)-10-producing CAR T cells retain their metabolic fitness, resist T cell exhaustion and display unprecedented antitumor activity indicated by high cure rates and durable responses in mice. Clinical studies of IL-10-producing CAR T cells are underway.
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References
Yu, Y. R. et al. Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion. Nat. Immunol. 21, 1540–1551 (2020). This paper shows that disturbed mitochondrial dynamics reinforce T cell exhaustion in tumors.
Eyquem, J. et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumor rejection. Nature 543, 113–117 (2017). This paper shows that targeting CAR to the TRAC locus delays the differentiation and exhaustion of effector T cells.
Labanieh, L. & Mackall, C. L. CAR immune cells: design principles, resistance and the next generation. Nature 614, 635–648 (2023). This review summarizes the effects of various cytokines on CAR T cells.
Guo, Y. et al. Metabolic reprogramming of terminally exhausted CD8+ T cells by IL-10 enhances anti-tumor immunity. Nat. Immunol. 22, 746–756 (2021). This key paper reports that IL-10 reinvigorates terminally exhausted T cells within tumors.
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This is a summary of: Zhao, Y. et al. IL-10-expressing CAR T cells resist dysfunction and mediate durable clearance of solid tumors and metastases. Nat. Biotechnol. https://doi.org/10.1038/s41587-023-02060-8 (2024).
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Metabolically enhanced CAR T cells efficiently clear solid tumors in mice. Nat Biotechnol (2024). https://doi.org/10.1038/s41587-023-02061-7
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DOI: https://doi.org/10.1038/s41587-023-02061-7
