Efficacy Against Human Prostate Cancer by Prostate-specific Membrane Antigen-specific, Transforming Growth Factor-β Insensitive Genetically Targeted CD8+ T-cells Derived from Patients with Metastatic Castrate-resistant Disease

Current immunotherapy has limited efficacy on metastatic castrate-resistant prostate cancer (mCRPC). We therefore sought to improve the antitumor ability of mCRPC patient-derived CD8(+) T-cells by the endowment of specificity to prostate-specific membrane antigen (PSMA) and insensitivity to immunosuppressant molecule transforming growth factor-beta (TGF-beta) under the control of herpes simplex virus-1 thymidine kinase. CD8(+) T-cells were collected by leukapheresis and cultured in a Food and Drug Administration-approved Cell Processing Work Station. We developed a chimeric antigen receptor retroviral construct using an anti PSMA chimeric immunoglobulin T cell receptor(zeta) gene (PZ1) and dominant negative TGF-beta type II receptor (T beta RIIDN), that could induce CD8(+) T-cells to be PSMA reactive and insensitive to TGF-beta. Cr-51 release assay was performed on PC-3 and PC-3-PSMA. The further antitumor functions of PSMA-specific, TGF-beta insensitive CD8(+) T-cells was evaluated using an immunodeficient RAG-1(-/-) mouse model. We found PSMA-specific, TGF-beta insensitive CD8(+) T-cells from mCRPC were expanded with strong expression of PZ1 and thymidine kinase genes, and their growth was not suppressed by TGF-beta. The survival of these cells decreased sharply after treatment with ganciclovir. Treatment of PSMA-specific TGF-beta, insensitive CD8(+) T-cells was associated with 61.58% specific lysis on PC-3-PSMA, and significantly suppressed PC3-PSMA tumor compared with the PC3 tumor. A large amount of tumor apoptosis and CD8(+) T-cell infiltration were found only in the PC3-PSMA tumor. This study verified that PSMA-specific, TGF-beta insensitive CD8(+) T-cells derived from mCRPC patients could be successfully expanded and used to overcome the immunosuppressive effects of the tumor microenvironment to control PSMA-expressing PC in vitro and in vivo. This may provide a promising approach for men with mCRPC who fail androgen deprivation therapy. Patient summary: We investigated the role of a novel chimeric antigen receptor T-immunotherapy based on autologous metastatic castrate-resistant prostate cancer patient-derived prostate-specific membrane antigen (PSMA)-specific, transforming growth factor-beta insensitive CD8(+) T-cells on PSMA-positive prostate cancer. We found that this chimeric antigen receptor T-cells could kill PSMA-positive prostate cancer specifically. The results suggest that this novel immunotherapy treatment is a potential new approach for men with metastatic castrate-resistant prostate cancer. (C) 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.