Enhanced Safety and Antitumor Efficacy of Switchable Dual Chimeric Antigen Receptor-Engineered T Cells against Solid Tumors through a Synthetic Bifunctional PD-L1-Blocking Peptide
- 23 September 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 142 (44), 18874-18885
- https://doi.org/10.1021/jacs.0c08538
Abstract
Chimeric antigen receptor (CAR)-engineered T cells (CAR-Ts) therapy has excellent efficacy in cancer treatment especially its impressive results in hematological malignancies. Unfortunately, its application on solid tumors is challenged by the off-target effects caused by lacking of tumor specific antigens and the immunosuppression caused by tumor microenvironment. We constructed a switchable dual receptor CAR-T cell (sdCAR-T) whose activity was relied upon double antigens (mesothelin and fluorescein isothiocyanate) and was strictly controlled by a “switch” (FPBM) consisting of a PD-L1 blocking peptide conjugated to fluorescein isothiocyanate. SdCAR-T cells were activated only when FPBM and cognate tumor cells expressing both PD-L1 and mesothelin co-exist. Importantly, long-term proliferation experiments in vitro and pharmacodynamic study in vivo showed a stronger anti-tumor activity of this system compared to the second generation mesothelin CAR-T cells. In view of this novel treatment paradigm was safer and more effective than traditional CAR-T cells, it may become a new strategy for the treatment of solid tumors.Funding Information
- Ministry of Education of the People's Republic of China (CPU2018GY13, CPU2018PZH03)
- Ministry of Science and Technology of the People's Republic of China (2019ZX09201001, 2019ZX09301-110, 2019ZX09301124)
- State Key Laboratory of Natural Medicines (SKLNMKF202008, SKLNMZZCX201821)
- Natural Science Foundation of Jiangsu Province (BK20180569)
- Priority Academic Program Development of Jiangsu Higher Education Institutions
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