Enhanced safety and efficacy of protease-regulated CAR-T cell receptors
Louai Labanieh, Robbie G. Majzner, Dorota D. Klysz, Elena Sotillo, Chris Fisher, José G. Vilches-Moure, Kaithlen Zen B Pacheco, Meena Malipatlolla, Peng Xu, Jessica H. Hui, Tara Murty, Johanna Theruvath, Nishant A. Mehta, Sean A. Yamada‐Hunter, Evan W. Weber, Sabine Heitzeneder, Kevin R. Parker, Ansuman T. Satpathy, Howard Y. Chang, Michael Z. Lin, Jennifer R. Cochran, Crystal L. Mackall
Abstract
Regulatable CAR platforms could circumvent toxicities associated with CAR-T therapy, but existing systems have shortcomings including leakiness and attenuated activity. Here, we present SNIP CARs, a protease-based platform for regulating CAR activity using an FDA-approved small molecule. Design iterations yielded CAR-T cells that manifest full functional capacity with drug and no leaky activity in the absence of drug. In numerous models, SNIP CAR-T cells were more potent than constitutive CAR-T cells and showed diminished T cell exhaustion and greater stemness. In a ROR1-based CAR lethality model, drug cessation following toxicity onset reversed toxicity, thereby credentialing the platform as a safety switch. In the same model, reduced drug dosing opened a therapeutic window that resulted in tumor eradication in the absence of toxicity. SNIP CARs enable remote tuning of CAR activity, which provides solutions to safety and efficacy barriers that are currently limiting progress in using CAR-T cells to treat solid tumors.