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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.

registernow

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.

Tuesday, May 2, 2017

10:00 EDT (New York)
15:00 GMT (London)

Available On Demand after May 2
All registrants will be notified when available

roddy oconnorPresented by:
Roddy O'Connor, PhD
University of Pennsylvania
Center for Cellular Immunotherapies

21.04.2017