Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA, USA.
Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.
Cancer Cell. 2022 Nov 14;40(11):1294-1305.e4. doi: 10.1016/j.ccell.2022.08.008. Epub 2022 Sep 8.
Chimeric antigen receptor (CAR) T cells can revolutionize cancer medicine. However, overactivation, lack of tumor-specific surface markers, and antigen escape have hampered CAR T cell development. A multi-antigen targeting CAR system regulated by clinically approved pharmaceutical agents is needed. Here, we present VIPER CARs (versatile protease regulatable CARs), a collection of inducible ON and OFF switch CAR circuits engineered with a viral protease domain. We established their controllability using FDA-approved antiviral protease inhibitors in a xenograft tumor and a cytokine release syndrome mouse model. Furthermore, we benchmarked VIPER CARs against other drug-gated systems and demonstrated best-in-class performance. We showed their orthogonality in vivo using the ON VIPER CAR and OFF lenalidomide-CAR systems. Finally, we engineered several VIPER CAR circuits by combining various CAR technologies. Our multiplexed, drug-gated CAR circuits represent the next progression in CAR design capable of advanced logic and regulation for enhancing the safety of CAR T cell therapy.
嵌合抗原受体 (CAR) T 细胞可以彻底改变癌症治疗。然而，过度激活、缺乏肿瘤特异性表面标志物和抗原逃逸限制了 CAR T 细胞的发展。需要一种由临床批准的药物制剂调节的多抗原靶向 CAR 系统。在这里，我们提出了 VIPER CAR（多功能蛋白酶可调控 CAR），这是一组带有病毒蛋白酶结构域的诱导型 ON 和 OFF 开关 CAR 回路。我们使用 FDA 批准的抗病毒蛋白酶抑制剂在异种移植肿瘤和细胞因子释放综合征小鼠模型中对其可控性进行了评估。此外，我们还将 VIPER CAR 与其他药物门控系统进行了基准测试，证明了其性能卓越。我们通过使用 ON VIPER CAR 和 OFF 来那度胺-CAR 系统在体内证明了其正交性。最后，我们通过组合各种 CAR 技术来设计了几种 VIPER CAR 回路。我们的多路复用药物门控 CAR 回路代表了 CAR 设计的下一个进展，能够为 CAR T 细胞治疗的安全性增强提供先进的逻辑和调节功能。
