Dual-Targeting CAR-NK Cells Targeting Mesothelin (MSLN) and MUC1 in Advanced Pancreatic Ductal Adenocarcinoma

* Rationale: PDAC is characterized by aggressive biology, antigen heterogeneity, and an immunosuppressive tumor microenvironment. Dual-targeting CAR designs aim to reduce antigen-escape by enabling recognition of either target antigen on tumor cells. * Investigational products: Two off-the-shelf (allogeneic) CAR-NK products are evaluated. EB-DNK101 targets MSLN and MUC1. EB-DNK102 targets CLDN18.2 and MUC1. Both products are engineered to enhance persistence (e.g., membrane-bound or secreted IL-15; example) and incorporate an inducible safety switch (e.g., iCasp9; example). * Target assessment and cohort assignment: Tumor tissue (archival or fresh biopsy) is tested centrally by immunohistochemistry (IHC) for MSLN, MUC1, and CLDN18.2. Participants are assigned to Arm A (MSLN/MUC1) or Arm B (CLDN18.2/MUC1) based on predefined positivity thresholds. If more than one cohort is eligible, assignment prioritizes the strongest antigen expression and product availability. * Conditioning and administration: Participants receive lymphodepleting chemotherapy (fludarabine + cyclophosphamide; example regimen) followed by intravenous infusion of the assigned CAR-NK product. Repeat infusions (up to 3 total) may be permitted in the absence of prohibitive toxicity and with at least stable disease. • Safety monitoring: Participants are monitored closely for cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), infusion reactions, and other adverse events. Dose-limiting toxicities (DLTs) are assessed during the first 28 days after first infusion. * Efficacy and biomarker assessments: Tumor response is assessed by imaging (RECIST v1.1) at regular intervals (e.g., every 8 weeks). Exploratory endpoints include CAR-NK expansion/persistence, cytokine profiling, and association of antigen density with response. * Target down-selection plan , After completion of Part 1 and an initial subset of Part 2 expansion participants, an internal scientific review compares antigen prevalence, manufacturability, safety, and preliminary activity across cohorts to prioritize the lead dual-target construct for subsequent confirmatory development.