Hypoxia Sensing CAR T Cells Provide Safety and Efficacy in Treating Solid Tumors
Paris Kosti, James Opzoomer, Karen Larios Martinez, Rhonda Henley-Smith, Cheryl Scudamore, Mary Okesola, Mustafa Taher, David Davies, Tamara Muliaditan, Daniel Larcombe-Young, Natalie Woodman, Cheryl Gillett, Selvam Thavaraj, John Maher, James Arnold
Received Date: 5th May 20
There has been significant interest in the prospects of chimeric antigen receptor (CAR) T-cell therapy in the treatment of solid malignancies, and multiple clinical trials are in progress. However, the scope of these trials has been restricted by the lack of availability of tumor-specific targets to direct CAR binding. Tumor specificity is crucial as on-target off-tumor activation of CAR T-cells in healthy tissues can result in potentially lethal toxicities due to uncontrolled cytokine release syndrome. Here we engineer a stringent hypoxia-sensing CAR T-cell system which achieves selective expression of a pan-ErbB-targeted CAR within a solid tumor, a microenvironment characterized by an 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 the unlimited expansion of the CAR T-cell target repertoire for treating solid malignancies.
Read in full at bioRxiv.
This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.