Hypoxia-sensing CAR T cells provide safety and efficacy in treating solid tumors

Utilizing T cells expressing chimeric antigen receptors (CARs) to identify and attack solid tumors has proven challenging, in large part because of the lack of tumor-specific targets to direct CAR binding. Tumor selectivity is crucial because on-target, off-tumor activation of CAR T cells can result in potentially lethal toxicities. This study presents a stringent hypoxia-sensing CAR T cell system that achieves selective expression of a pan-ErbB-targeted CAR within a solid tumor, a microenvironment characterized by inadequate oxygen supply. Using murine xenograft models, we demonstrate that, despite widespread expression of ErbB receptors in healthy organs, the approach provides anti-tumor efficacy without off-tumor toxicity. This dynamic on/off oxygen-sensing safety switch has the potential to facilitate unlimited expansion of the CAR T cell target repertoire for treating solid malignancies. [Display omitted] A dual oxygen-sensing switch provides stringent hypoxia-dependent regulation of a CARHypoxiCAR T cells deliver tumor-selective CAR expression and anti-tumor efficacyHypoxiCAR T cells prevent on-target, off-tumor activation and cytokine release syndromeHypoxiCAR provides a strategy to expand the CAR repertoire for solid malignancies Utilizing CAR T cells to attack solid tumors has proven challenging because of the lack of tumor-specific CAR targets. Kosti et al. demonstrate that re-engineering CARs to stringently and selectively express in response to tumor hypoxia prevents their off-tumor activation and toxicity while delivering robust anti-tumor efficacy.