Abstract
Anti-tumor efficacy of Tcells engineered to express chimeric antigen receptors (CARs) is dependent on their specificity, survival, and invivo expansion following adoptive transfer. Toll-like receptor (TLR) and CD40 signaling in Tcells can improve persistence and drive proliferation of antigen-specific CD4+ and CD8+ Tcells following pathogen challenge or in graft-versus-host disease (GvHD) settings, suggesting that these costimulatory pathways may be co-opted to improve CAR-T cell persistence and function. Here, we present a novel strategy to activate TLR and CD40 signaling in human Tcells using inducible MyD88/CD40 (iMC), which can be triggered invivo via the synthetic dimerizing ligand, rimiducid, to provide potent costimulation to CAR-modified Tcells. Importantly, the concurrent activation of iMC (with rimiducid) and CAR (by antigen recognition) is required for interleukin (IL)-2 production androbust CAR-T cell expansion and may provide a user-controlled mechanism to amplify CAR-T cell levels invivo and augment anti-tumor efficacy.
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