Drug-controlled CAR-T cells through the regulation of cell-cell interactions

Scheller, L.; Attianese, G. M. P. G.; Castellanos-Rueda, R.; Di Roberto, R. B.; Barden, M.; Riboulet, M.; Shui, S.; Cribioli, E.; Marchand, A.; Georgeon, S.; Abken, H.; Reddy, S.; Correia, B.; Irving, M.

doi:10.1101/2024.08.06.606454

bioRxiv · 10.1101/2024.08.06.606454

Drug-controlled CAR-T cells through the regulation of cell-cell interactions

Scheller, L.·Attianese, G. M. P. G.·Castellanos-Rueda, R.·Di Roberto, R. B.·Barden, M.·Riboulet, M.·Shui, S.·Cribioli, E.·Marchand, A.·Georgeon, S.·Abken, H.·Reddy, S.·Correia, B.·Irving, M.

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Abstract

CAR T-cell therapy is constrained by on-target, off-tumor toxicities as well as cellular exhaustion due to chronic antigen exposure. CARs comprising small-molecule controlled switches can enhance both safety and therapeutic efficacy but are limited by the scarcity of non-immunogenic protein elements responsive to non-immunosuppressive, clinically approved drugs with favorable pharmacodynamics. Here, we combine rational design and library-based optimization of a protein-protein interaction (PPI) of human origin to develop venetoclax-controlled Drug-Regulated Off-switch PPI (DROP)-CARs. DROP-CARs enable dose-dependent release of the tumor-targeting scFv and consequent T-cell dissociation from the target tumor cell. Additionally, we present proof-of-concept for a dual DROP-CAR controlled by different small molecules, as well as for logic-gated synthetic receptors enabling STAT3 signaling. We demonstrate in vitro and in vivo function of DROP-CAR T cells and conclude that the approach holds promise for clinical application.

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Scheller, L., Attianese, G. M. P. G., Castellanos-Rueda, R., Di Roberto, R. B., Barden, M., Riboulet, M., Shui, S., Cribioli, E., Marchand, A., Georgeon, S., Abken, H., Reddy, S., Correia, B., Irving, M.. 2024-08-06. Drug-controlled CAR-T cells through the regulation of cell-cell interactions. https://doi.org/10.1101/2024.08.06.606454

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