Omkar U Kawalekar 1 , Roddy S O'Connor 2 , Joseph A Fraietta 1 , Lili Guo 3 , Shannon E McGettigan 1 , Avery D Posey 1 , Prachi R Patel 1 , Sonia Guedan 1 , John Scholler 1 , Brian Keith 1 , Nathaniel W Snyder , Nathaniel Snyder 4 , Ian A Blair , Ian Blair 3 , Michael C Milone 5 , Carl H June 6
Feb 16 2016
Chimeric antigen receptors (CARs) redirect T cell cytotoxicity against cancer cells, providing a promising approach to cancer immunotherapy. Despite extensive clinical use, the attributes of CAR co-stimulatory domains that impact persistence and resistance to exhaustion of CAR-T cells remain largely undefined. Here, we report the influence of signaling domains of coreceptors CD28 and 4-1BB on the metabolic characteristics of human CAR T cells. Inclusion of 4-1BB in the CAR architecture promoted the outgrowth of CD8(+) central memory T cells that had significantly enhanced respiratory capacity, increased fatty acid oxidation and enhanced mitochondrial biogenesis. In contrast, CAR T cells with CD28 domains yielded effector memory cells with a genetic signature consistent with enhanced glycolysis. These results provide, at least in part, a mechanistic insight into the differential persistence of CAR-T cells expressing 4-1BB or CD28 signaling domains in clinical trials and inform the design of future CAR T cell therapies.