RT Journal Article SR Electronic T1 Hypoxia-Sensing CAR T-Cells Provide Safety and Efficacy in Treating Solid Tumors JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.05.13.091546 DO 10.1101/2020.05.13.091546 A1 Paris Kosti A1 James W. Opzoomer A1 Karen I. Larios-Martinez A1 Rhonda Henley-Smith A1 Cheryl L. Scudamore A1 Mary Okesola A1 Mustafa Y.M. Taher A1 David M. Davies A1 Tamara Muliaditan A1 Daniel Larcombe-Young A1 Natalie Woodman A1 Cheryl E. Gillett A1 Selvam Thavaraj A1 John Maher A1 James N. Arnold YR 2020 UL http://biorxiv.org/content/early/2020/05/14/2020.05.13.091546.abstract 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.