Abstract CT026: 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

Abstract Background: Outcomes for advanced EGC are poor, particularly in those with peritoneal disease. MSLN is overexpressed in up to 40% of EGC. Preclinical models of peritoneal carcinomatosis demonstrated superior efficacy and acceptable safety with IP versus systemic administration of M28z1XXPD1DNR, a MSLN-directed autologous CART, equipped with a modified CD3z (1XX), and a PD-1 dominant negative receptor that provides intrinsic T-cell checkpoint blockade (Cancer Discov 2021;11:2748). Methods: This phase I study evaluated the safety of IP M28z1XXPD1DNR in patients with MSLN-positive (IHC ≥25%) ECG with peritoneal carcinomatosis. Eligible patients may have extraperitoneal disease, must have received ≥1 prior line of therapy and have measurable or evaluable disease (RECIST 1.1). Between 4 and 18 patients will be treated to a maximum of 1x107 cells/kg (Table 1). Lymphodepletion with fludarabine 30mg/m2/day and cyclophosphamide 300mg/m2/day is given for 3 days prior to cell infusion. Adverse events (AEs), response rates, survival outcomes and immune correlates will be assessed. Results: Eleven patients have undergone apheresis; 6 received M28z1XXPD1DNR and were evaluable for dose-limiting toxicities (DLTs). Median age was 56.5 (range 38-66). Median lines of prior therapy was 3 (range 1-5). Dose escalation proceeded through DL2 (n=2), DL3 (n=2) and DL4 (n=2). No DLT was observed. Treatment-related AEs were predominantly low grade (G), including cytokine release syndrome (5/6; all G1), transient post-infusion abdominal pain (5/6), nausea (5/6), vomiting (4/6), anorexia (3/6; G≥3 in 1), constipation (3/6), diarrhea (3/6) and fatigue (3/6. All patients had progressive disease at 8 weeks. One patient showed improvement in peritoneal disease but developed a bladder serosal metastasis. Peripheral blood vector copy number showed CART expansion peaking in the first month and remaining detectable beyond 100 days following IP administration. Conclusions: IP M28zXXPD1DNR CART cells were well tolerated. CART persistence was noted beyond Day 100. Antitumor activity in MSLN-positive EGC was limited. Given the higher level of MSLN expression in peritoneal mesothelioma, we are amending the study to recruit such patients. Citation Format: Joan R. Choo, David Restle, Alfredo Amador Molina, Jasmeen Saini, Adrian Gonzalez Aguirre, Steven B. Maron, Samuel L. Cytryn, David Ilson, Parastoo Dahi, Laura H. Tang, Daniel Cameron, Stacy Fernstedt, Kay See Tan, Prasad Adusumilli, Geoffrey Ku. 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 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT026.