Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Immunity. 2023 Oct 10;56(10):2388-2407.e9. doi: 10.1016/j.immuni.2023.09.001. Epub 2023 Sep 29.
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.
嵌合抗原受体 (CAR) T 细胞疗法针对 CD19 已在治疗 B 细胞恶性肿瘤方面取得巨大成功；然而，由于自体 T 细胞适应性差，一些患者无法应答。为了提高应答率，我们研究了是否破坏共抑制受体 CTLA4 或 PD-1 可以恢复 CART 功能。在白血病和骨髓瘤的临床前模型中，CRISPR-Cas9 介导的 CTLA4 缺失可改善 CAR T 细胞的增殖和抗肿瘤功效。重要的是，这种效应是 CTLA4 特异性的，而在 CAR T 细胞中缺失 CTLA4 和/或 PDCD1 时并未观察到这种效应。从机制上讲，CTLA4 缺失允许在高抗原负荷下，CD28 信号不受抑制，并维持 CAR 在 T 细胞表面的表达。在临床研究中，CTLA4 的缺失挽救了先前 CAR T 细胞治疗失败的白血病患者 T 细胞的功能。因此，选择性缺失 CTLA4 可使功能失调的慢性淋巴细胞白血病 (CLL) 患者 T 细胞恢复活力，为增加患者对 CAR T 细胞治疗的应答提供了一种策略。
