Photoswitchable CAR-T Cell Function In Vitro and In Vivo via a Cleavable Mediator. Issue 1 (21st January 2021)

• Record Type: Journal Article
• Authors: Zhang, Bo; Wang, Yan; Huang, Shenlong; Sun, Jiaqi; Wang, Min; Ma, Wenxiao; You, Yanbo; Wu, Ling; Hu, Jin; Song, Wei; Liu, Xudong; Li, Shengjie; Chen, Hua; Zhang, Guisheng; Zhang, Lihe; Zhou, Demin; Li, Lingjun; Zhang, Xuan
• Is Part Of: Cell chemical biology. Volume 28:Issue 1(2021)
• Page Start: 60
• Page End: 69.e7
• Publication Date: 2021-01-21
• Subjects: CAR-T cytotoxicity -- photoswitchable -- cleavable mediator -- fluorescein isothiocyanate; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2020.10.004
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical Abstract: Highlights: Folate-O-FITC switch CAR-T cells to an activated state in a dose-dependent manner CAR-T-induced cytotoxicity can be rapidly terminated by the cleavage of folate-O-FITC CAR-T can be turned on/off on demand by supplementation/cleavage of folate-O-FITC Such switchable regulated manner would not compromise antitumor effects of CAR-T cells Abstract : CAR-T is a powerful technology for cancer therapy, but is largely limited by inherent controllability issues. Zhang et al. developed an accurate controllable approach based on the bond-cleavage chemistry combined with universal anti-FITC CAR-T cells, allowing the regulation of CAR-T cells in a switchable manner.