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 Y M Taher, David M Davies, Tamara Muliaditan, Daniel Larcombe-Young, Natalie Woodman, Cheryl E Gillett, Selvam Thavaraj, John Maher, James N Arnold

Research output: Contribution to journalArticleAcademicpeer-review

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
Pages (from-to)1-9
JournalCell reports. Medicine
Volume2
Issue number4
DOIs
Publication statusPublished - 20 Apr 2021

Keywords

  • chimeric antigen receptor
  • T cell
  • hypoxia
  • HIF1α
  • cytokine release syndrome
  • toxicity
  • cancer
  • immunotherapy
  • CAR T cells
  • HypoxiCAR

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