Regulated Expansion and Survival of Chimeric Antigen Receptor-Modified T Cells Using Small Molecule-Dependent Inducible MyD88/CD40
The effectiveness of T cells engineered with chimeric antigen receptors (CARs) in fighting tumors relies on their specificity, survival, and expansion after being transferred into the body. Signaling through Toll-like receptors (TLRs) and CD40 in T cells can enhance their persistence and proliferation, particularly in response to pathogens or in graft-versus-host disease (GvHD). This suggests that these costimulatory pathways could be harnessed to improve the durability and performance of CAR-T cells. In this study, we introduce a new approach for activating TLR and CD40 signaling in human T cells using an inducible MyD88/CD40 (iMC) system. This system can be activated in vivo with a synthetic dimerizing ligand, rimiducid, to provide strong costimulation to CAR-modified T cells. Crucially, simultaneous activation of iMC (by rimiducid) and CAR (through antigen recognition) is necessary for producing interleukin (IL)-2 and achieving significant CAR-T cell expansion. This method could offer a controllable way to boost CAR-T cell levels in the body and enhance their anti-tumor effectiveness.