Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Republic of Korea.
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
Nat Commun. 2024 Nov 18;15(1):9917. doi: 10.1038/s41467-024-53996-7.
Chimeric antigen receptor T (CAR-T) cells show remarkable efficacy for some hematological malignancies. However, CAR targets that are expressed at high level and selective to tumors are scarce. Several strategies have been proposed to tackle the on-target off-tumor toxicity of CAR-T cells that arise from suboptimal selectivity, but these are complicated, with many involving dual gene expression for specificity. In this study, we show that switchable CAR-T cells with a tumor targeting adaptor can mitigate on-target off-tumor toxicity against a low selectivity tumor antigen that cannot be targeted by conventional CAR-T cells, such as CD40. Our system is composed of anti-cotinine murine CAR-T cells and cotinine-labeled anti-CD40 single chain variable fragments (scFv), with which we show selective tumor killing while sparing CD40-expressing normal cells including macrophages in a mouse model of lymphoma. Simple replacement of the tumor-targeting adaptor with a suicidal drug-conjugated tag may further enhance safety by enabling permanent in vivo depletion of the switchable CAR-T cells when necessary. In summary, our switchable CAR system can control CAR-T cell toxicity while maintaining therapeutic efficacy, thereby expanding the range of CAR targets.
嵌合抗原受体 T（CAR-T）细胞在某些血液恶性肿瘤中显示出显著的疗效。然而，高表达且选择性针对肿瘤的 CAR 靶点却很少。已经提出了几种策略来解决由于选择性差而导致的 CAR-T 细胞的靶向肿瘤外毒性，但这些策略很复杂，许多策略都涉及到特异性的双重基因表达。在这项研究中，我们表明，具有肿瘤靶向接头的可切换 CAR-T 细胞可以减轻针对低选择性肿瘤抗原的靶向肿瘤外毒性，这些抗原不能被传统的 CAR-T 细胞靶向，例如 CD40。我们的系统由抗烟碱型乙酰胆碱受体的小鼠 CAR-T 细胞和烟碱标记的抗 CD40 单链可变片段（scFv）组成，我们在淋巴瘤小鼠模型中表明，该系统可以选择性地杀伤肿瘤，同时避免表达 CD40 的正常细胞，包括巨噬细胞。通过用自杀药物偶联标签简单地替换肿瘤靶向接头，可能会通过在需要时永久性地在体内耗尽可切换的 CAR-T 细胞，从而进一步提高安全性。总之，我们的可切换 CAR 系统可以在保持治疗效果的同时控制 CAR-T 细胞的毒性，从而扩大 CAR 靶点的范围。
