부산대학교 도서관

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. The activity of CAR-T cells is reversibly halted with a small-molecule drug.
Author(s): Greta Giordano-Attianese [sup.1] [sup.2] , Pablo Gainza [sup.3] [sup.4] , Elise Gray-Gaillard [sup.1] [sup.2] , Elisabetta Cribioli [sup.1] [sup.2] , Sailan Shui [sup.3] [sup.4] , Seonghoon Kim [sup.5] , [...]