[HTML][HTML] Regulated expansion and survival of chimeric antigen receptor-modified T cells using small molecule-dependent inducible MyD88/CD40

AE Foster, A Mahendravada, NP Shinners, WC Chang… - Molecular therapy, 2017 - cell.com
AE Foster, A Mahendravada, NP Shinners, WC Chang, J Crisostomo, A Lu, M Khalil…
Molecular therapy, 2017cell.com
Anti-tumor efficacy of T cells engineered to express chimeric antigen receptors (CARs) is
dependent on their specificity, survival, and in vivo expansion following adoptive transfer.
Toll-like receptor (TLR) and CD40 signaling in T cells can improve persistence and drive
proliferation of antigen-specific CD4+ and CD8+ T cells 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 …
Anti-tumor efficacy of T cells engineered to express chimeric antigen receptors (CARs) is dependent on their specificity, survival, and in vivo expansion following adoptive transfer. Toll-like receptor (TLR) and CD40 signaling in T cells can improve persistence and drive proliferation of antigen-specific CD4+ and CD8+ T cells 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 T cells using inducible MyD88/CD40 (iMC), which can be triggered in vivo via the synthetic dimerizing ligand, rimiducid, to provide potent costimulation to CAR-modified T cells. Importantly, the concurrent activation of iMC (with rimiducid) and CAR (by antigen recognition) is required for interleukin (IL)-2 production and robust CAR-T cell expansion and may provide a user-controlled mechanism to amplify CAR-T cell levels in vivo and augment anti-tumor efficacy.
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