A phase I clinical trial of autologous gamma delta T cells genetically engineered with a chimeric receptor to target the prostate stem cell antigen in patients with metastatic castration-resistant prostate cancer.

TPS287 Background: Prostate Stem Cell Antigen (PSCA) is a glycosylphosphatidyl inositol-anchored cell surface protein that is overexpressed in > 80% of prostate cancers and further enriched in prostate cancer bone metastases. Prior phase 1 studies with alpha/beta CAR-T cells targeting PSCA showed feasibility, and preliminary antitumor activities (NCT02744287 and NCT 03873805). To reduce the systemic toxicities, we designed gamma/delta enriched anti-PSCA CAR-T therapy with activation of its T cell receptor by the phosphoantigens induced by bone targeting zoledronate. Based on the anti-tumor activities and synergies with zolendronate observed in preclinical studies (PMID 37134157), we designed and conducted a phase 1 study in heavily pre-treated patients (pts) with metastatic castration resistant prostate cancer (mCRPC). Methods: This is a single center phase 1 dose-escalation trial with the Bayesian optimal interval design to identify the recommended phase 2 dose (RP2D). Safety assessment is the primary objective, and the secondary objective of preliminary efficacy is measured by best PSA response, radiographic progression free survival and conversion of circulating tumor cell count from above 5 per 7.5ml of peripheral blood to 3 months of study enrollment. After apheresis on day -14, each enrolled pt undergoes lymphodepletion chemotherapy (LDC) with cyclophosphamide at 500 mg/m2 and fludarabine at 30 mg/m2 on Days -5, -4, -3. Day 0 infusion of Fresh gamma/delta enriched CAR T cells targeting PSCA are being tested at five dose levels: 1 × 10 5 , 3 × 10 5 , 1 × 10 6 , 3 × 10 6 , and 5 x 10 6 CAR T cells/kg. Following determination of RP2D, an expansion phase will be initiated. The dose limiting toxicity (DLT) observation period starts with the administration of LDC and concludes at 28 days following the day 0 CAR T infusion. This study has completed dose level 2 with no DLT observed. The 2nd pt for dose level 3 is scheduled for apheresis. Clinical trial information: NCT06193486 .