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 rimiducid; however, IL-2 was only produced when both iMC and CAR were activated simultaneously by rimiducid and tumor antigen. Treatment of NSG mice bearing large (> 200 mm³) HPAC tumors with a single i.v. dose of 1x10⁷ iMC-PSCA.ζ cells resulted in complete tumor elimination in 10/10 mice including both rimiducid-treated and untreated animals, compared to mice receiving non-transduced T cells (p = 0.0003). Weekly rimiducid administration dramatically increased CAR-T cell numbers, resulting in a 23-fold expansion of iMC-PSCA.ζ-modified T cells in the spleen compared to mice not receiving rimiducid four weeks after infusion (p = 0.02). In a dose-titration study, rimiducid administration was required for tumor control, and led to 565- and 948-fold T cell expansion at the tumor site, respectively, when lower numbers (1.25x10⁶ or 6.25x10⁵, respectively) of iMC-PSCA.ζ-modified T cells were given. Conclusions: GoCAR-T cells targeting PSCA, which contain an inducible MyD88/CD40 activation switch, may be an effective adoptive cell therapy for patients with pancreatic, prostate, bladder, and other cancers that overexpress PSCA.