638. TGFBeta Signaling Blockade within PSMA Targeted CAR Human T Cells for the Eradication of Metastatic Prostate Cancer

The recent efficacies demonstrated using Chimeric Antigen Receptor (CAR) mediated immunotherapy to treat hematological malignancies have been met with great enthusiasm as holding great potential for the eradication of hematological malignancies. Unfortunately, the ability to target metastatic solid tumors like prostate cancer with CAR T cells has been less successful. The major parameter to achieve in using CAR T cells to treat prostate cancer is overcoming the immunosuppression that is created by the tumors to inhibit CAR T cells. Our efforts have aimed to create PSMA specific CAR T cells that are resistant to the TGFBeta induced suppression extensively demonstrated to exist in prostate cancer. Upon binding PSMA, our second-generation CAR supplies 4-1BB and CD3zeta signaling previously demonstrated to allow for long-term T cell persistence and eradication of leukemia when targeted to CD19. We therefore created anti-PSMA CAR T Cells that coexpress the dominant negative TGFBeta receptor II (dnTGFRBetaII).Having focused on safety and efficacy of these anti-PSMABBz CAR T cells that express dnTGFRBetaII (dnTGFRBetaII-T2A-PBBZ), we demonstrate evidence of dnTGFRBetaII functionality. The dnTGFRBetaII functions to prevent SMAD signaling induced by TGFBeta, therefore resisting upregulation of CD25 and CTLA-4 by T cells. When co-cultured with tumor cells in vitro, efficient antigen specific lysis is induced by the PBBZ CAR and the dnTGFRBetaII-T2A-PBBZ CAR T cells exhibit up to 15 fold overall proliferation than PBBZ alone CAR T cells over 42 days. This allows for superior levels of T cell persistence in the peripheral blood of NSG mice after 3-4 weeks post infusion when compared to T cells expressing the anti-PSMA CAR alone. Most importantly, these CAR T cells are very effective at eradicating systemic PSMA+ PC3 prostate cancer cells in vivo demonstrated in two animal experiments at three different doses of CAR T cells. These studies suggest proper resistance to TGFBeta by CAR modified T cells that show great promise to eradicate metastatic prostate cancer in the clinic.Disclosure of Conflict of Interest:C.C.K. reports having ownership interest in patents owned by Memorial Sloan-Kettering Cancer Center and licensed to Juno Therapeutics and is a consultant for 121 Bio, LLC. J.L. reports no conflicts. C.H.J. reports receiving commercial research grants from Novartis and has ownership interest in patents owned by University of Pennsylvania and licensed to Novartis.Funding Acknowledgments:This study was supported by the Prostate Cancer Foundation All-Star Killer T-Cell Special Challenge Award 2014 - 2016.