A phase I trial of intraperitoneal (IP) mesothelin (MSLN)-targeted CAR T-cell therapy in patients with MSLN-positive esophagogastric cancer (EGC) with peritoneal carcinomatosis.

TPS513 Background: Outcomes for patients with advanced EGC remain poor. The peritoneum is an immune-privileged niche and a common site of metastases occurring in up to 40% of patients with metastatic EGC; this is characterised by poor survival because of resistance to immunotherapy and a lack of measurable disease, which excludes trial participation. MSLN was selected as a target for CAR T cell therapy as it is overexpressed in up to 60% of EGC, is associated with aggressive disease biology and has low levels of expression in normal tissues. In pre-clinical in vivo models of peritoneal carcinomatosis, improved efficacy was observed with regional administration of IP CAR T cells, compared with systemic CAR T cells. No significant toxicity was observed at clinically relevant doses of IP administered CAR T-cells. M28z1XXPD1DNR CAR T-cells are a next-generation MSLN-targeted CAR, equipped with a modified CD3z (1XX), and a PD-1 dominant negative receptor (PD1DNR) that provides T-cell intrinsic checkpoint blockade. Methods: This is a single-arm phase I study assessing the safety, maximum tolerated dose (MTD) and preliminary efficacy of IP administered M28zXXPD1DNR CAR T cells in patients with MSLN-positive (IHC ≥ 25%) EGC with evidence of peritoneal carcinomatosis (imaging and/or cytology). Patients with concomitant extraperitoneal disease are eligible. Patients must have received at least one prior line of treatment for advanced or metastatic disease and have at least one measurable or evaluable lesion per RECIST 1.1. A minimum of 4 patients and maximum of 18 patients will be treated with 4 escalating doses (with 1 “fallback” dose) of CAR T cells to a maximum of 3 x 10 7 cells/kg administered via peritoneal catheter (Table). Lymphodepletion with fludarabine 30mg/m 2 /day and cyclophosphamide 300mg/m 2 /day is given for 3 days prior to the CAR T cell infusion. Adverse events, response rates (RECIST 1.1), survival outcomes and immuno-monitoring (immune cell phenotyping and serum/peritoneal fluid cytokine analysis) will be assessed. The trial is currently enrolling patients. Clinical trial information: Will be registered before ASCO GI. Dose-escalation scheme based on the continuous reassessment method. Dose Level Dose (cells/kg) 1 1 x 10 6 2 (Starting dose) 3 x 10 6 3 6 x 10 6 4 1 x 10 7 5 3 x 10 7