Targeting castration resistant prostate cancer (CRPC) with autologous PSMA-directed CAR+ T cells.

TPS4700 Background: Based on our preclinical animal models, we initiated a phase I dose-escalating study to assess safety, dose requirement and targeting efficiency of genetically directed autologous human T cells targeted to Prostate Specific Membrane Antigen (PSMA). Our approach is based on the infusion of autologous PSMA-targeted T cells utilizing the P28z second generation chimeric antigen receptor (CAR) in patients (pts) with metastatic CRPC, following iv cyclophosphamide (Cy) (trial NCT01140373). For safety, the herpes simplex virus-1 thymidine kinase (hsvtk) gene is co-expressed with the P28z receptor, and renders T cells sensitive to ganciclovir for immediate T cell elimination if needed. The expression of hsvtk enables PET imaging using radiolabeled FIAU to localize adoptively transferred T cells. The aims of the trial are to assess: (1) safety of PSMA-targeted T cells; (2) biologic and anti-tumor effects; (3) T cell persistence at tumor site; and (4) immune response. Methods: Autologous T cells are activated from a leukapheresis product using anti-CD3/CD28 Dynabeads. Release criteria include mean vector copy number by Q-PCR and vector identity by Southern blot, absence of Replication Competent Retrovirus and residual Dynabeads. Pts will be treated at 3 dose levels from 107 to 108 CAR+ T cells/kg. Four patients have been enrolled; 3 have been treated with 300mg/m2 of Cy one day before infusion of 107 CAR+ T cells/kg. Pts underwent baseline and post treatment CT, bone and PET scans. Pts are followed weekly, then monthly with blood work including immune and vector sequence monitoring. Results: The first 3 pts within the first cohort were successfully treated without toxicity. Two had stable disease for greater than 6 months with the third patient having disease progression. There were no acute adverse events. Conclusion: We have established an ex vivo transduction, expansion and therapeutic protocol for the generation and testing of safe, clinical-grade, PSMA targeted T cells. Pts enrolled at the next dose level of 3 x 107 CAR+ T cells/kg will be assessed as described and by imaging the transduced T cell population using 18F-FIAU as a radiotracer. The data pertaining to the planned T cell imaging will be presented as well.