Background: PDA has a low tumor mutational burden and an immunosuppressive microenvironment. Targeting overexpressed self-antigens with adoptive, genetically engineered, high affinity T cells may overcome immunosuppression (Stromnes I, Immunol Rev 2014). We previously engineered murine CD8⁺ T cells to express a high affinity MSLN-specific TCR in the Kras^LSL-G12D/+; Trp53^LSL-R172H/+; p48^Cre/+ (KPC) mouse model, with highest efficacy observed following serial infusions (Stromnes I, Cancer Cell 2015). We developed an autologous TCR-T cell therapy targeting MSLN, which is overexpressed by 80% of PDAs. In this first-in-human phase I trial, we seek to determine the safety, preliminary efficacy, as well as the persistence, activation, localization, and functional capacity of FH-TCR T_MSLN in chemotherapy refractory, MSLN⁺ mPDA. Methods: Eligible pts have ECOG PS 0-1, ≥ 1 prior therapy for mPDA, life expectancy ≥ 12 wks, able/willing to undergo biopsies (at baseline, and after 3 and 6 wks of treatment), MSLN 2+ expression in ≥ 30% tumor cells by IHC, HLA-A*02:01, no HLA-B*13:02. Patients undergo leukapheresis, and approximately 3-4 weeks later, receive the first TCR-T_MSLN cell infusion. Three TCR-T_MSLN cell infusions given q21 days (d) are planned to be administered to each patient. Patients are enrolled in 4 cohorts by dose level (cohort 1: 1 x 10⁹; cohort 2: 3.3 x 10⁹; cohorts 3 and 4: 10 x 10⁹ T cells), with a 3+3 design. Dose limiting toxicities (DLTs) are assessed during 21d after each TCR-T_MSLN cells infusion. Lymphodepleting chemotherapy with fludarabine/cyclophosphamide is administered prior to the third TCR-T_MSLN infusion (cohorts 1-3) or prior to the first TCR-T_MSLN infusion (cohort 4). Primary endpoint is safety and DLTs. Secondary endpoints are ORR, PFS, OS. Exploratory endpoints are translational tumor and blood TCR-T_MSLN cells biomarkers. Safety is assessed by CTCAE v5.0, with a goal of grade ≥ 3 TCR-T_MSLN cells unexpected toxicity rate <35%; stopping rate if toxicity is ≥20% is 0.06. Response is assessed by RECIST 1.1. Enrollment of 15 patients allows >80% power to observe a statistically significant (one-sided alpha level 0.05), meaningful efficacy signal of ORR 20%. Secondary and exploratory endpoints will be descriptive and hypothesis generating. The study was activated in December 2021 and is open to accrual; 4 patients have been enrolled as of 24 Sept 2022. Clinical trial information: NCT04809766.