Photoswitchable CAR-T Cell Function In Vitro and In Vivo via a Cleavable Mediator
Photoswitchable CAR-T Cell Function In Vitro and In Vivo via a Cleavable Mediator
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通过可裂解介体实现体外和体内光切换 CAR-T 细胞功能
DOI：
10.1016/j.chembiol.2020.10.004
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发表时间：
2021
影响因子：
8.6
通讯作者：
Xuan Zhang
中科院分区：
文献类型：
--
作者：
Bo Zhang;Yan Wang;Shenlong Huang;Jiaqi Sun;Min Wang;Wenxiao Ma;Yanbo You;Ling Wu;Jin Hu;Wei Song;Xudong Liu;Shengjie Li;Hua Chen;Guisheng Zhang;Lihe Zhang;Demin Zhou;Lingjun Li;Xuan Zhang
基于嵌合抗原受体（CAR）-T的疗法是癌症治疗的一个突破;然而，它们受到组成性激活的阻碍，这导致了令人担忧的副作用。工程CAR-T细胞尽可能严格可控仍然是一个正在进行的研究课题。在这里，我们报告了一种光开关方法，该方法使用介体来随意调节CAR-T细胞。该介体携带由邻硝基苄基酯光可裂解接头连接的叶酸和异硫氰酸荧光素双基团。CAR-T细胞仅在介质存在下对靶细胞具有高度细胞毒性，并以剂量依赖性方式起作用。CAR-T细胞的毒性可以通过介体的裂解快速终止，并且CAR-T细胞的作用可以通过重新补充介体而再次激活，而不会影响肿瘤治疗。本文描述的方法为增强CAR-T细胞的可控性提供了方向，并可能应用于其他免疫疗法。
Chimeric antigen receptor (CAR)-T-based therapeutics are a breakthrough in cancer treatment; however, they are hampered by constitutive activation, which leads to worrisome side effects. Engineering CAR-T cells to be as tightly controllable as possible remains a topic of ongoing investigation. Here, we report a photoswitchable approach that uses a mediator for the at-will regulation of CAR-T cells. This mediator carries dual folate and fluorescein isothiocyanate moieties tethered by an ortho-nitrobenzyl ester photocleavable linker. CAR-T cells were shown to be highly cytotoxic to targeted cells only in the presence of the mediator and acted in a dose-dependent manner. The toxicity of CAR-T cells can be rapidly terminated by cleavage of the mediator, and the effects of CAR-T cells can be activated again by resupplementation with the mediator without compromising tumor therapy. The approach described here provides a direction for enhancing the controllability of CAR-T cells and can likely be applied in other immunotherapies.