Chimeric antigen receptors (CARs) redirect T cell cytotoxicity against cancer cells, providing a promising approach to cancer immunotherapy. CARs are genetically engineered cell surface molecules containing single chain variable fragments fused with cytoplasmic domains from co-stimulatory receptors: CD28, 4-1BB, and CD3ζ. 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.
In this webinar we will discuss:
- How CAR-T cells containing 4-1BB signaling domains have enforced in vitro persistence
- 4-1BB-enforced metabolic reprogramming enhances oxidative metabolism
- Mitochondrial biogenesis is selectively induced in 4-1BB CAR-T cells.
For Research Use Only. Not for use in diagnostic procedures.