2. Academic Validation
  3. 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

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

  • J Am Chem Soc. 2020 Nov 4;142(44):18874-18885. doi: 10.1021/jacs.0c08538.
Peiwei Yang 1,  Ying Wang 1,  Zheng Yao 1,  Xinmei Gao 1,  Chen Liu 1,  Xinmin Wang 1,  Heming Wu 1,  Xu Ding 1,  Jialiang Hu 1,  Bingjing Lin 1,  Qian Li 1,  Mengwei Li 1,  Xin Li 1,  Xiangying Chen 1,  Weiyan Qi 1,  Weiguang Li 1,  Jianpeng Xue 1,  Hanmei Xu 1
Affiliations

Affiliation

  • 1 The Engineering Research Center of Synthetic Polypeptide Drug Discovery and Evaluation, Jiangsu Province and State Key Laboratory of Natural Medicines, Ministry of Education, China Pharmaceutical University, Nanjing 210009, P. R. China.
PMID: 32966054 DOI: 10.1021/jacs.0c08538
Abstract

Chimeric antigen receptor (CAR)-engineered T cells (CAR-Ts) therapy has an 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 the tumor microenvironment. We constructed a switchable dual receptor CAR-T cell (sdCAR-T) whose activity 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 coexist. Importantly, long-term proliferation experiments in vitro and the pharmacodynamic study in vivo showed a stronger antitumor activity of this system compared to the second generation Mesothelin CAR-T cells. In view of this novel treatment paradigm being safer and more effective than traditional CAR-T cells, it may become a new strategy for the treatment of solid tumors.

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