Enhanced safety and efficacy of protease-regulated CAR-T cell receptors

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.

Automated summary

SNIP CARs are a protease-based CAR platform that can regulate CAR activity using an FDA-approved small molecule. SNIP CAR-T cells exhibit higher potency and show reduced T cell exhaustion and enhanced stemness compared to constitutive CAR-T cells in various models. In a ROR1-based CAR lethality model, toxicity can be reversed by stopping the drug, and tumor eradication without toxicity can be achieved by reducing the drug dosage. SNIP CARs provide a solution to the safety and efficacy barriers currently limiting the use of CAR-T cells in treating solid tumors by enabling remote tuning of CAR activity.