PD-L1 chimeric costimulatory receptor improves the efficacy of CAR-T cells for PD-L1-positive solid tumors and reduces toxicity in vivo

被引:20
作者
Liao, Qibin [1 ,2 ]
Mao, Yunyu [1 ,2 ]
He, Huan [1 ,2 ]
Ding, Xiangqing [1 ,2 ]
Zhang, Xiaoyan [1 ,2 ]
Xu, Jianqing [1 ,2 ]
机构
[1] Fudan Univ, Shanghai Publ Hlth Clin Ctr, Shanghai, Peoples R China
[2] Fudan Univ, Inst Biomed Sci, Shanghai, Peoples R China
关键词
Chimeric antigen receptor; Chimeric costimulatory receptor; PD-L1; Safety; Efficacy; ANTIGEN-RECEPTOR; B-CELL; B7-H1; BLOCKADE; FAMILY; IL-2; REMISSIONS; ACTIVATION; EXPRESSION; MOLECULES;
D O I
10.1186/s40364-020-00237-w
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background On-target off-tumor toxicity impedes the clinical application of chimeric antigen receptor-modified T cells (CAR-T cells) in the treatment of solid tumors. Previous reports proved that the combinatorial antigen recognition strategy could improve the safety profile of CAR-T cells by targeting two different tumor-associated antigens (TAAs), one as a CAR-T targeted antigen and the other as a chimeric costimulatory receptor (CCR) ligand. The programmed death-ligand 1 (PD-L1, also known as B7-H1) is preferentially overexpressed on multiple tumors, it will be highly interesting to explore the potential of PD-L1 as a universal target for designing CCR. Methods A novel dual-targeted CAR, which is composed of first-generation CD19/HER2 CAR with CD3 zeta signaling domain and PD-L1 CCR containing the CD28 costimulatory domain, was constructed and delivered into T cells by pseudotyped lentivirus. The cytokine release, cytotoxicity and proliferation of dual-targeted CAR-T cells were tested in vitro, and their safety and therapeutic efficacy were evaluated using a human tumor xenograft mouse model in vivo. Results The dual-targeted CAR-T cells exerted a similar cytotoxic activity against CD19/HER2(+) tumor cells with or without PD-L1 in vitro, however, enhanced cytokine releases and improved proliferative capacity were only observed in the presence of both CD19/HER2 and PD-L1. Importantly, the dual-targeted CAR-T cells displayed no cytotoxicity against PD-L1(+) cells alone in the absence of tumor antigen CD19/HER2. In addition, the dual-targeted CAR-T cells preferably destroyed tumor xenografts bearing both CD19/HER2 and PD-L1, but spared only antigen-positive tumor xenografts without PD-L1 in vivo. Furthermore, PD-L1 CCR also improved the antitumor efficacy of the low-affinity HER2 CAR-T cells against PD-L1(+) tumors expressing high levels of HER2. Conclusion Our observations demonstrated that PD-L1 could be used as a universal target antigen for designing CCR, and the dual-targeted CAR-T cells equipped with PD-L1 CCR could be used to reduce the risk of on-target off-tumor toxicity while retaining their potent antitumor efficacy in the treatment of PD-L1(+) solid tumors.
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页数:15
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