Phase I trial of Claudin 18.2-specific chimeric antigen receptor T cells for advanced gastric and pancreatic adenocarcinoma.

2509 Background: As a promising approach for some cancers, chimeric antigen receptor T cell therapy has limited success in solid tumors. Claudin18.2 (CLDN 18.2) is a stomach-specific isoform of Claudin-18, and highly expressed in gastric and pancreatic adenocarcinoma, the advanced form of both of which have urgent unmet medical needs. We previously developed and demonstrated ability of CLDN 18.2-specific CAR (CAR-CLDN18.2) T cells to eradicate CLDN 18.2-positive gastric cancer xenografts without obvious on-target off-tumor toxicity (Huang J. JNCI 2018). Methods: In this single-arm, open-label, first-in-human phase I pilot study (NCT03159819) to investigate the safety and explore the efficacy of the autologous CAR-CLDN18.2 T cells, patients with confirmed CLDN 18.2 positive advanced gastric or pancreatic adenocarcinoma aged 18 to 70 years received 1 or more cycles of CAR-CLDN18.2 T cell infusion(s) after lymphodepletion pretreatment (fludarabine and cyclophosphamide, with or without nab-paclitaxel) until disease progression or presence of intolerable toxicity. Adverse Event (AE) grade categorization is according to CTCAE 4.0, and tumor response was assessed per RECIST 1.1. Results: As of November 30th, 2018, 12 subjects with metastatic adenocarcinoma (7 gastric and 5 pancreatic) were treated with 1–5 cycles (total of 0.5 - 55 X 10 8 ) of CAR-positive T cells infusions. There were no serious adverse events, treatment-related death or severe neurotoxicity occurred in the study. No grade 4 AEs except for decreased lymphocytes, neutrophils and white blood cells. All cytokine release syndromes observed were grade 1 or 2. Among the 11 evaluable subjects, 1 achieved a complete response (gastric adenocarcinoma), 3 had partial responses (2 gastric adenocarcinomas and 1 pancreatic adenocarcinoma), 5 had stable disease and 2 had progression of disease. The total objective response rate was 33.3%, with median PFS of 130 days estimated using Kaplan-Meier method [95% CI (38, 230)]. Conclusions: This clinical study indicated that CAR-CLDN18.2 T cell therapy were safe and well tolerated and may have promising therapeutic efficacy in patients with advanced gastric and pancreatic adenocarcinoma. Clinical trial information: NCT03159819.