Chimeric antigen receptor T cells engineered to secrete CD40 agonist antibodies enhance antitumor efficacy

Journal of Translational Medicine

Tengjiao Wang¹  Yongmei Ding²  Yajun Zhang²  Qijun Qian³  Pei Wang⁴  Yuan Fang⁵ 

[1] Department of Bioinformatics, Institute of Translational Medicine, Navy Medical University, 201805, Shanghai, China;Department of Biotherapy, Eastern Hepatobiliary Surgery Hospital, Navy Medical University, 201805, Shanghai, China;Department of Biotherapy, Eastern Hepatobiliary Surgery Hospital, Navy Medical University, 201805, Shanghai, China;Shanghai Engineering Research Center for Cell Therapy, 201805, Shanghai, China;Department of Medical Oncology, Shanghai Mengchao Cancer Hospital, 201805, Shanghai, China;Shanghai University Cell Therapy Innovation Research Institute, 201805, Shanghai, China;Shanghai Engineering Research Center for Cell Therapy, 201805, Shanghai, China;Shanghai Engineering Research Center for Cell Therapy, 201805, Shanghai, China;College of Life Sciences and Medicine, Zhejiang Sci-Tech University, 310018, Hangzhou, Zhejiang, China;

关键词: Chimeric antigen receptor;    Anti-CD40 antibody;    Costimulatory signal;    piggyBac transposon;    Solid tumor;   

DOI  :  10.1186/s12967-021-02750-4

来源: Springer

【 摘 要 】

BackgroundAlthough chimeric antigen receptor (CAR)-T cell therapy has been remarkably successful for haematological malignancies, its efficacy against solid tumors is limited. The combination of CAR-T cell therapy with immune checkpoint inhibitors (CPIs), such as PD-1, PD-L1, and CTLA-4 antibodies, is a promising strategy for enhancing the antitumor efficacy of CAR-T cells. However, because most patients acquire resistance to CPIs, investigating other strategies is necessary to further improve the antitumor efficacy of CAR-T cell therapy for solid tumors. Recently, CD40 agonist antibodies showed potential antitumor efficacy by activating the CD40 pathway.ResultsBased on the piggyBac transposon system, rather than the widely used viral vectors, we constructed a meso3-CD40 CAR-T targeting region III of mesothelin (MSLN) that possessed the ability to secrete anti-CD40 antibodies. Compared with meso3 CAR-T cells, which did not secrete the anti-CD40 antibody, meso3-CD40 CAR-T cells secreted more cytokines and had a relatively higher proportion of central memory T (TCM) cells after stimulation by the target antigen. In addition, compared with meso3 CAR-T cells, meso3-CD40 CAR-T cells had a more powerful cytotoxic effect on target cells at a relatively low effector-to-target ratio. More importantly, we demonstrated that the antitumor activity of meso3-CD40 CAR-T cells was enhanced in a human ovarian cancer xenograft model in vivo.ConclusionsIn conclusion, these results highlight anti-CD40-secreting CAR-T cells generated by nonviral vectors as a potential clinical strategy for improving the efficacy of CAR-T cell therapies.

【 授权许可】

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