Safety and preliminary efficacy of a novel armored mesothelin-targeted CAR-T therapy in advanced solid tumors.

2543 Background: UCMYM802 is an autologous mRNA-electroporated CAR-T cell therapy targeting mesothelin (MSLN), incorporating a lymphocyte-antigen-presenting cell costimulatory (LACO-Stim) molecule. This first-in-human study aimed to assess its safety, tolerability, preliminary efficacy, and pharmacokinetic/pharmacodynamic (PK/PD) profiles. Methods: This phase I study enrolled patients with metastatic or recurrent MSLN-positive solid tumors who failed standard therapies. Three dose levels were evaluated: 1×10 8 (n = 1), 5×10 8 (n = 1), and 1×10 9 CAR-T cells (n = 7). No lymphodepletion was required prior to infusion. Patients received up to 4 weekly infusions. Primary endpoints were safety and determination of the maximum tolerated dose (MTD). Secondary endpoints included objective response rate (ORR) by RECIST v1. 1, disease control rate (DCR), and PK/PD parameters. Results: As of Nov. 2025, 9 patients were enrolled and treated (median age 67, range 52-67). Tumor types included pancreatic cancer (n = 3), peritoneal malignant mesothelioma (n = 1), adenocarcinoma of unknown primary, consistent with a gynecologic or peritoneal origin (n = 1), extrahepatic cholangiocarcinoma (n = 1), cholangiocarcinoma (n = 1), ovarian cancer (n = 1), and lung cancer (n = 1). All patients received at least one infusion. The 1×10 9 dose level was defined as the MTD, with one dose-limiting toxicity (DLT) observed (grade 4 cytokine release syndrome CRS with hypotension). Treatment-related adverse events (TRAEs) occurred in all patients, most commonly CRS (88. 9%), fever (88. 9%), decreased lymphocyte count (77. 8%), anemia (77. 8%), prolonged prothrombin time (66. 7%), and hypoxia (55. 6%). Grade ≥3 CRS occurred in 25% of patients. Among seven efficacy-evaluable patients, two patients achieved partial response (PR; one each in 5×10 8 and 1×10 9 cohorts), and two had stable disease (SD; one each in 1×10 8 and 1×10 9 cohorts). The ORR was 28. 6% (2/7) and DCR was 57. 1% (4/7). Notable responses included a PR in gynecologic or peritoneal origin adenocarcinoma and a PR at 6 months (converted to SD at 7. 5 months) in extrahepatic cholangiocarcinoma. PK analysis showed peak CAR-T expansion (by copy number) at 1-hour post-infusion, with the highest and most sustained exposure after the first infusion. PD analysis indicated IFN-γ elevation correlating with CAR-T peak expansion. CAR-T exposure and activation marker expression showed a dose-dependent trend. Conclusions: UCMYM802 demonstrated a manageable safety profile consistent with expected CAR-T-related toxicities, primarily CRS. Preliminary anti-tumor activity was observed in heavily pretreated patients with MSLN-positive advanced solid tumors, with encouraging signals in gynecologic or peritoneal origin adenocarcinoma and biliary tract cancers. The recommended dose for expansion is 1×10⁹ CAR-T cells. These results support continued investigation of UCMYM802. Clinical trial information: NCT06256055.