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.

Original languageEnglish
Article number100227
JournalCell Reports Medicine
Volume2
Issue number4
DOIs
Publication statusPublished - 20 Apr 2021

Keywords

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

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