Fig. 1: SNIP CARs as a druggable platform to enhance CAR T-cell efficacy and safety against solid tumors.
From: A SNIPpet of safety: a Goldilocks approach in CAR-T therapy
Left: Many constitutively expressed CARs exhibit tonic signaling in the absence of ligand, resulting in a pre-infused product that is enriched in exhausted CAR T-cells (top). In the SNIP CAR system, the trans expression of a hepatitis C protease together with inclusion of its cleavage site upstream of the CAR intracellular signaling domain abrogates tonic signaling (SNIP OFF), thus conferring a less exhausted T-cell phenotype. Middle: Upon encounter with malignant cells expressing the target antigen, constitutive CAR T-cells are less responsive because of their exhausted state. However, optimal signaling in non-exhausted SNIP CAR T-cells can be induced by inhibiting the protease with the FDA-approved grazoprevir (GPV) drug (SNIP ON), resulting in increased anti-tumor cytotoxicity. Right: While constitutive CAR T-cells can induce severe toxicities, secondary to CRS or targeting of healthy cells, the activity of SNIP CAR T-cells can be inhibited by pausing GPV administration, resulting in a reversal of toxicities. Figure made with permission from BioRender.com.
