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.
J Am Chem Soc. 2020 Nov 4;142(44):18874-18885. doi: 10.1021/jacs.0c08538. Epub 2020 Oct 2.
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 and the pharmacodynamic study 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.
嵌合抗原受体 (CAR)-修饰的 T 细胞 (CAR-T) 疗法在癌症治疗方面具有出色的疗效,尤其是在血液恶性肿瘤方面的显著效果。不幸的是,由于缺乏肿瘤特异性抗原和肿瘤微环境引起的免疫抑制,其在实体瘤中的应用受到挑战。我们构建了一种可切换的双受体 CAR-T 细胞 (sdCAR-T),其活性依赖于双抗原 (间皮素和荧光素异硫氰酸酯),并由由 PD-L1 阻断肽与荧光素异硫氰酸酯偶联而成的“开关” (FPBM) 严格控制。只有当 FPBM 和表达 PD-L1 和间皮素的同源肿瘤细胞共存时,sdCAR-T 细胞才会被激活。重要的是,长期增殖实验和药效学研究表明,与第二代间皮素 CAR-T 细胞相比,该系统具有更强的抗肿瘤活性。鉴于这种新的治疗模式比传统的 CAR-T 细胞更安全、更有效,它可能成为治疗实体瘤的一种新策略。