肿瘤细胞治疗研究
英文原题：Deletion of the inhibitory co-receptor CTLA-4 enhances and invigorates chimeric antigen receptor T cells.
靶向 CD19 的嵌合抗原受体（CAR）T 细胞疗法在治疗 B 细胞恶性肿瘤方面取得了巨大成功；然而，部分患者因自体 T 细胞适应性差而未能产生应答。
靶向CD19的嵌合抗原受体（CAR）T细胞疗法在B细胞恶性肿瘤治疗中取得巨大成功，但部分患者因自体T细胞适能较差而无法应答。为提高应答率，研究人员评估破坏共抑制受体CTLA-4或PD-1能否恢复CAR-T功能。在白血病和骨髓瘤临床前模型中，通过CRISPR-Cas9敲除CTLA4可增强CAR-T细胞增殖和抗肿瘤疗效。该效应具有CTLA4特异性；在CAR-T细胞中敲除CTLA4和/或PDCD1并未观察到相同效果。机制上，CTLA4缺失使CD28信号不再受抑制，并在高抗原负荷条件下维持T细胞表面CAR表达。在临床研究中，敲除CTLA4挽救了既往CAR-T治疗失败的白血病患者T细胞功能。因此，选择性敲除CTLA4可重振慢性淋巴细胞白血病（CLL）患者功能障碍的T细胞，为提高CAR-T治疗应答率提供了策略。
Chimeric antigen receptor (CAR) T cell therapy targeting CD19 has achieved tremendous success treating B cell malignancies; however, some patients fail to respond due to poor autologous T cell fitness. To improve response rates, we investigated whether disruption of the co-inhibitory receptors CTLA4 or PD-1 could restore CART function. CRISPR-Cas9-mediated deletion of CTLA4 in preclinical models of leukemia and myeloma improved CAR T cell proliferation and anti-tumor efficacy. Importantly, this effect was specific to CTLA4 and not seen upon deletion of CTLA4 and/or PDCD1 in CAR T cells. Mechanistically, CTLA4 deficiency permitted unopposed CD28 signaling and maintenance of CAR expression on the T cell surface under conditions of high antigen load. In clinical studies, deletion of CTLA4 rescued the function of T cells from patients with leukemia that previously failed CAR T cell treatment. Thus, selective deletion of CTLA4 reinvigorates dysfunctional chronic lymphocytic leukemia (CLL) patient T cells, providing a strategy for increasing patient responses to CAR T cell therapy.
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