Phase 1 study of PSCA-targeted chimeric antigen receptor (CAR) T cell therapy for metastatic castration-resistant prostate cancer (mCRPC).

91 Background: Chimeric antigen receptor (CAR)-engineered T cell therapies are being pursued for the treatment of mCRPC. Prostate Stem Cell Antigen (PSCA) is highly expressed on the surface membrane in mCRPC and with limited expression on normal tissues. We undertook a phase 1, first-in-human study of a PSCA-targeted 4-1BB-co-stimulated CAR T cell therapy in mCRPC. Methods: CAR T cells were manufactured at City of Hope’s cGMP facility. The trial followed the Target equivalence range design with an equivalence range of.20-.35 and too toxic level of 0.51 following participants in cohorts of 3. The plan was to begin at a dose of 100 million (M) without lymphodepletion (LD) chemotherapy consisting of fludarabine and cyclophosphamide, then add LD to 100M prior to dose escalation to maximum 600M. Patients (pts) were required to have disease progression after at least 1 androgen receptor targeted therapy but there was no limit on prior chemotherapy or other treatments. Primary objective is to define the dose limiting toxicity (DLT) and recommended phase 2 dose as well as to describe preliminary bioactivity and efficacy. Correlative studies include MRI for target bone lesion response, CAR T cell persistence, circulating tumor cells, and serum cytokines. Results: 12 pts have been treated to date, median age 68 (42-72). Three pts were treated at the 100M dose with no DLTs. In the 100M plus LD dose level there 2 pts experienced DLT of grade 3 cystitis non-infective and fatigue. The protocol was amended to reduce the LD dose to 300 mg/m2 cyclophosphamide D1-3 and intensify monitoring with early intervention for cystitis. No DLT occurred in 3 pts treated in the modified LD 100M cohort. Cytokine release syndrome (CRS), DLTs and best response by RECIST are presented by dose level in the table. PSA declines (one >90%) were seen as well as radiographic improvement, though RECIST response was limited to stable disease (SD) by concurrent bone metastases. Correlative studies indicated bioactivity of PSCA-CAR T cells. Conclusions: PSCA-CAR T cell therapy is feasible in pts with mCRPC with DLT of cystitis, and shows preliminary anti-tumor effect at a dose of 100M plus LD. Dose escalation to 300M may proceed. Clinical trial information: NCT03873805. [Table: see text]