Augmenting the Effectiveness of CAR-T Cells by Enhanced Self-Delivery of PD-1-Neutralizing scFv

• Main Authors: Yu Ping, Feng Li, Shufeng Nan, Daiqun Zhang, Xiaojuan Shi, Jiqi Shan, Yi Zhang
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2020-08-01
• Series: Frontiers in Cell and Developmental Biology
• Subjects: chimeric antigen receptor T cell; anti-PD-1; single-chain variable fragment; tumor microenvironment; T cell function
• Online Access: https://www.frontiersin.org/article/10.3389/fcell.2020.00803/full

Chimeric antigen receptor T (CAR-T) cell therapy is not satisfying in solid tumors. PD-1-mediated suppression greatly hinders CAR-T cells in the microenvironment. It has been shown that PD-1 blockade improves the effectiveness of CAR-T cells. Herein, we designed CAR-T cells than could secret α-PD-1 scFv by themselves. To obtain optimal secretions of scFv, we screened several signal peptides. And the segment from human increased the extracellular production of PD-1-neutralizing proteins. The secreted neutralizing scFv efficiently blocked PD-1 and enhanced T cell activation when PD-L1 was present. Further analysis showed that CAR-T cells themselves could secret α-PD-1 scFv with bioactivity. In contrast to the prototype, the scFv-producing CAR-T cells demonstrated decreased PD-1 but increases expansion and toxicity against solid tumor cells. In the subcutaneous and orthotopic xenograft models, the self-delivered α-PD-1 scFv increased CAR-T cell functionalities and tumor-suppressions. Our work suggested that engineering T cells to co-express antigen-responsive receptors and checkpoint inhibitors is effective to optimize CAR-T cell therapy for solid tumors.