Phase IB trial redesign to test role of IL2 with anti-PSMA designer T cells to yield responses in advanced prostate cancer.

Abstract

70 Background: We created a chimeric antigen receptor (CAR) for prostate specific membrane antigen (PSMA). When expressed in patient T cells, these “designer T cells” specifically kill prostate cancer cells in vitro and in vivo in animal models (Ma et al. Prostate 2004:61:12-25). FDA approved a Phase I clinical trial. Methods: Patient T cells are retrovirally transduced and expanded. Patients undergo non-myeloablative (NMA) conditioning to create “hematologic space” into which designer T cells are infused for engraftment and improved in vivo efficacy. Patients are co-administered continuous infusion IL2. Patients are monitored for safety and response. Results: Five patients were treated, three at 10^9 and two at 10^10 cell dose levels with safety. Partial responses (PR) were seen in 2/5 patients (40%), with PSA suppressions of 50 and 70% over 1-2 months and PSA progression delay of 70 and 150 days. Yet these responses were observed only at the lowest T cell dose (10^9 cells) and not the higher tested dose (10^10 cells). Response correlated with plasma IL2 that was as much as 10-fold lower in non-responders vs responders. This low IL2 correlated in turn with high engrafted fractions of infused activated T cells. This prompted a hypothesis that infused activated T cells at high engrafted cell numbers absorbed out IL2 to a level too low to sustain dTc activation for effective tumor killing. A study redesign will test high dose IL2 (HDI) versus moderate dose IL2 (MDI) in Phase Ib/Pilot at 10^10 cell dose, then advancing to the maximum practical dose (MPD, 10^11 cells) of dTc under the optimal IL2 plan. Conclusions: A new approach to adoptive immune therapy in metastatic prostate cancer has been devised with encouraging early results. We postulate that adequate higher IL2 in vivo will allow the greater potency of higher dTc doses to be revealed, thereby potentially inducing PSA reductions of 100%, with durable remissions of metastatic prostate cancer that is refractory to all other treatments. Patients are being recruited. This clinical trial received funding from US Army/DOD and from Prostate Cancer Foundation for preclinical work.