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

Cell Rep Med. 2021 Apr 9;2(4):100227. doi: 10.1016/j.xcrm.2021.100227. eCollection 2021 Apr 20.


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.

Keywords: CAR T cells; HIF1α; HypoxiCAR; T cell; cancer; chimeric antigen receptor; cytokine release syndrome; hypoxia; immunotherapy; toxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor / metabolism
  • Disease Models, Animal
  • Genes, erbB / genetics
  • Humans
  • Hypoxia / genetics
  • Hypoxia / metabolism*
  • Immunotherapy, Adoptive* / methods
  • Mice, Transgenic
  • Receptors, Chimeric Antigen / genetics*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*
  • Tumor Microenvironment / immunology*
  • Xenograft Model Antitumor Assays / methods


  • Receptors, Chimeric Antigen