Hypoxia-sensing CAR T cells provide safety and efficacy in treating solid tumors
Paris Kosti, James W. Opzoomer, Karen I. Larios-Martinez, Rhonda Henley‐Smith, Cheryl L. Scudamore, Mary Okesola, Mustafa Yassin Taher, David M. Davies, Tamara Muliaditan, Daniel Larcombe-Young, Natalie Woodman, Cheryl Gillett, Selvam Thavaraj, John Maher, James N. Arnold
Abstract
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.