Details

Autor(en) / Beteiligte

• Labanieh, Louai
• Majzner, Robbie G.
• Klysz, Dorota
• Sotillo, Elena
• Fisher, Chris J.
• Vilches-Moure, José G.
• Pacheco, Kaithlen Zen B.
• Malipatlolla, Meena
• Xu, Peng
• Hui, Jessica H.
• Murty, Tara
• Theruvath, Johanna
• Mehta, Nishant
• Yamada-Hunter, Sean A.
• Weber, Evan W.
• Heitzeneder, Sabine
• Parker, Kevin R.
• Satpathy, Ansuman T.
• Chang, Howard Y.
• Lin, Michael Z.
• Cochran, Jennifer R.
• Mackall, Crystal L.

Titel

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

Ist Teil von

• Cell, 2022-05, Vol.185 (10), p.1745-1763.e22

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •SNIP CARs are tightly regulated by an FDA-approved protease inhibitor•SNIP CARs provide a safety switch and are more potent than constitutive CARs•PK modulation of drug levels enhances CAR potency through cyclic rest•Reduced drug dosing can prevent on-target off-tumor toxicity SNIP is a drug-regulated CAR platform that utilizes an FDA-approved small molecule to enable remote control and a generalizable molecular architecture that does not perturb CAR function.