biostudies-literatureLabanieh LNCI NIH HHS1745-1763.e22https://www.ebi.ac.uk/biostudies/studies/S-EPMC9467936biostudies-literatureUnknown185(10)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 CellEnhanced safety and efficacy of protease-regulated CAR-T cell receptors.PMC9467936DP2 CA272092U54 CA232568U01 CA260852Murty TMehta NPacheco KZBXu PParker KRChang HYVilches-Moure JGLabanieh LCochran JRWeber EWMajzner RGYamada-Hunter SASotillo ETheruvath JHeitzeneder SLin MZMalipatlolla MMackall CLSatpathy ATFisher CJKlysz DHui JHfalseEnhanced 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 2022-01-01T00:00:00Z2022 May2026-05-28T03:41:04.288Z2025-04-05T21:07:43.538ZS-EPMC94679363548337510.1016/j.cell.2022.03.041