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

Nature biotechnology 2020 Apr

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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.

Citation

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 Coukos, Bruno E Correia. A computationally designed chimeric antigen receptor provides a small-molecule safety switch for T-cell therapy. Nature biotechnology. 2020 Apr;38(4):426-432