41 (PB031) - CAR-T cell engineering strategies aimed at safe and effective targeting of solid tumors

Abstract

Adoptive cell therapy based on chimeric antigen receptor-engineered T (CAR-T) cells has proven to be life-saving for many cancer patients. However, its therapeutic efficacy has so far been restricted to only a few malignancies, with solid tumors proving to be especially recalcitrant to efficient therapy. Poor intra-tumor infiltration by T cells and “T cell dysfunction” due to an immunosuppressive microenvironment are key barriers against CAR-T cell success against solid tumors. Furthermore, low level expression of CAR-directed tumor-associated antigens (TAA) in normal tissues can result in “on-target off-tumor” cytotoxicity, raising potential safety concerns. Using our best-in-class TALEN®-based gene editing platform, we present here innovative T cell engineering strategies that can combat some of the challenges posed by CAR-T cell development for solid tumors. These allogeneic ‘Smart CAR-T’ cells are designed to integrate locus-specific synthetic genes that respond to cues localized to the solid tumor microenvironment. The subsequent expression of these genes increases CAR-T cell persistence and anti-tumor activity while staying restricted to the tumor milieu. Thus, our proof-of-concept study demonstrates the feasibility of developing CAR-T cell engineering strategies that can improve solid tumor targeting while mitigating potential safety risks, encouraging us to bring them to the clinic. No conflict of interest.