Inducible Myd88/Cd40 To Allow Rimiducid-Dependent Activation For Control Of Proliferation And Survival Of Chimeric Antigen Receptor (Car) T Cells Targeting Prostate Stem Cell Antigen (Psca).

206 Background: PSCA is a cell surface antigen that is overexpressed in a majority of metastatic prostate, transitional cell and pancreatic carcinomas. We describe a novel T cell costimulation switch, inducible MyD88/CD40 (iMC), activated by a small molecule, rimiducid, to enhance survival, proliferation and anti-tumor activity of CAR-T cells targeting PSCA. Methods: T cells were transduced with a retrovirus encoding tandem rimiducid-binding domains,cloned in-frame with MyD88 and CD40 signaling elements and first generation CARs (CAR.ζ) targeting PSCA (SFG-iMC-2A-PSCA.ζ). iMC activation was assessed with and without rimiducid treatment of T cells. Coactivation via iMC and CAR was tested in coculture assays with or without rimiducid using various PSCA+tumor cells, e.g. Capan-1 and HPAC pancreatic adenocarcinoma. Efficacy of iMC-modified CAR-T cells in vivo was assessed using an NSG mouse tumor model. Results: T cells transduced with iMC-PSCA.ζ produced cytokines (e.g., IFN-γ and IL-6) in response to rimidu...