Author: ["Greta Giordano-Attianese","Pablo Gainza","Elise Gray-Gaillard","Elisabetta Cribioli","Sailan Shui","Seonghoon Kim","Mi-Jeong Kwak","Sabrina Vollers","Angel De Jesus Corria Osorio","Patrick Reichenbach","Jaume Bonet","Byung-Ha Oh","Melita Irving","George
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Abstract
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 CD3ζ- 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. The activity of CAR-T cells is reversibly halted with a small-molecule drug.Cite this article
Giordano-Attianese, G., Gainza, P., Gray-Gaillard, E. et al. A computationally designed chimeric antigen receptor provides a small-molecule safety switch for T-cell therapy. Nat Biotechnol 38, 426–432 (2020). https://doi.org/10.1038/s41587-019-0403-9 