PT  - JOURNAL ARTICLE
AU  - Paris Kosti
AU  - James W. Opzoomer
AU  - Karen I. Larios-Martinez
AU  - Rhonda Henley-Smith
AU  - Cheryl L. Scudamore
AU  - Mary Okesola
AU  - Mustafa Y.M. Taher
AU  - David M. Davies
AU  - Tamara Muliaditan
AU  - Daniel Larcombe-Young
AU  - Natalie Woodman
AU  - Cheryl E. Gillett
AU  - Selvam Thavaraj
AU  - John Maher
AU  - James N. Arnold
TI  - Hypoxia-Sensing CAR T-Cells Provide Safety and Efficacy in Treating Solid Tumors
AID  - 10.1101/2020.05.13.091546
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.05.13.091546
4099  - http://biorxiv.org/content/early/2020/05/14/2020.05.13.091546.short
4100  - http://biorxiv.org/content/early/2020/05/14/2020.05.13.091546.full
AB  - 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 1. 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 2. 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.Competing Interest StatementYes there is potential Competing Interest. J.M. is co-founder and chief scientific officer, T.M. is an employee, and D.M.D., D.L.Y. are consultants to Leucid Bio, which is a spinout company focused on development of cellular therapeutic agents. J.N.A., J.M. and P.K. are named inventors on a patent submitted in relation to this work. All other authors have declared that there are no competing financial interests or conflicts of interest in relation to this study.