美国德克萨斯农工大学Wenshe Liu团队报道了嵌合抗原受体T细胞的复发性化学遗传开关。相关研究成果于2021年11月15日发表于国际一流学术期刊《德国应用化学》。

作为一种革命性的癌症治疗方法，嵌合抗原受体（CAR）T细胞治疗存在细胞因子释放综合征和T细胞衰竭等并发症。其缓解需要CAR-T细胞的可控激活，也可以通过调节CAR的显示来实现。

通过将丙型肝炎病毒NS3蛋白酶（HCV-NS3）嵌入单链可变片段（scFv）和铰链结构域之间，研究人员发现抗CD19单链抗体在CAR-T细胞上的显示与临床HCV-NS3抑制剂asunaprevir（ASV）的存在正相关。该新颖的CAR设计允许在存在ASV的情况下显示抗CD19单链抗体，并在没有ASV的情况下将其清除，从而产生了一种实际上反复出现的化学开关。研究人员证明，在体外和体内，通过以剂量依赖性的方式控制ASV的存在，可以反复开启和关闭完整的CAR-on T细胞，从而在癌症治疗期间实现CAR-T激活的精细调节。

附：英文原文

Title: A Recurring Chemogenetic Switch for Chimeric Antigen Receptor T Cells

Author: Wenshe Liu, Wenyue Cao, Zhi Z. Geng, Na Wang, Quan Pan, Shaodong Guo, Jianfeng Zhou, Shiqing Xu

Issue&Volume: 2021-11-15

Abstract: As a revolutionary cancer treatment, the chimeric antigen receptor (CAR) T cell therapy suffers from complications such as cytokine release syndromes and T cell exhaustion. Their mitigation desires controllable activation of CAR-T cells that is achievable through regulatory display of CARs. By embedding the hepatitis C virus NS3 protease (HCV-NS3) between the single-chain variable fragment (scFv) and the hinge domain, we showed that the display of anti-CD19 scFv on CAR-T cells was positively correlated to the presence of a clinical HCV-NS3 inhibitor asunaprevir (ASV). This novel CAR design that allows the display of anti-CD19 scFv in the presence of ASV and its removal in the absence of ASV creates a practically recurring chemical switch.  We demonstrated that the intact CAR on T cells can be repeatedly turned on and off by controlling the presence of ASV in a dose dependent manner both in vitro and in vivo, which enables delicate modulation of CAR-T activation during cancer treatment.

DOI: 10.1002/anie.202109550

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202109550