NOT-gated CAR T Cells to Ameliorate On-target, Off-tumor Toxicity of CAR T Therapy

Stanford scientists have developed novel, inhibitory chimeric antigen receptor T cells (iCARs) based on immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing signaling domains that can inhibit standard activating CAR (aCARs) activity (see figure* below).

Chimeric antigen receptor (CAR) T cells are a promising therapeutic option, especially for cancers like acute myeloid leukemia (AML) with high mortality and relapse rates. However, the phenomenon of "on-target, off-tumor" toxicity is a barrier to clinical translation of many CAR T cells, including CD123 CAR T cells targeting AML. Combinatorial CAR T cells based on logic gating, including NOT-gated CAR T cells, can address this problem. NOT-gated CAR T cells have a tissue or antigen-specific inhibitory mechanism that limits CAR T cell killing of healthy tissues that may share expression of the main CAR target antigen while maintaining their ability to kill on-target tumor cells. Stanford researchers have developed inhibitory CARs (iCARs) based NOT-gated CAR T cells to circumvent CAR–mediated endothelial cell toxicity. This approach could allow CAR T therapy to safely target new antigens and new cancers.

*Figure:

Stage of Development
Research – in vitro