A computationally designed chimeric antigen receptor provides a small-molecule safety switch for T-cell therapy

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The activity of CAR-T cells is reversibly halted with a small-molecule drug. Approaches to increase the activity of chimeric antigen receptor (CAR)-T cells against solid tumors may also increase the risk of toxicity and other side effects. To improve the safety of CAR-T-cell therapy, we computationally designed a chemically disruptable heterodimer (CDH) based on the binding of two human proteins. The CDH self-assembles, can be disrupted by a small-molecule drug and has a high-affinity protein interface with minimal amino acid deviation from wild-type human proteins. We incorporated the CDH into a synthetic heterodimeric CAR, called STOP-CAR, that has an antigen-recognition chain and a CD3 zeta- and CD28-containing endodomain signaling chain. We tested STOP-CAR-T cells specific for two antigens in vitro and in vivo and found similar antitumor activity compared to second-generation (2G) CAR-T cells. Timed administration of the small-molecule drug dynamically inactivated the activity of STOP-CAR-T cells. Our work highlights the potential for structure-based design to add controllable elements to synthetic cellular therapies.
Publisher
NATURE PUBLISHING GROUP
Issue Date
2020-04
Language
English
Article Type
Article
Citation

NATURE BIOTECHNOLOGY, v.38, no.4, pp.426 - 432

ISSN
1087-0156
DOI
10.1038/s41587-019-0403-9
URI
http://hdl.handle.net/10203/276712
Appears in Collection
BS-Journal Papers(저널논문)
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