ABSTRACT Pancreatic cancer (PC) is an orphan disease with a 5-year relative survival of 11.5% and relative survival for metastatic PC of only 3.1%. Although surgical resection provides the best curative option, <20% of PC patients are eligible for surgery at diagnosis. Front-line chemotherapy treatment with FOLFIRINOX results in a median overall survival (mOS) of only 11.1 months and is associated with severe toxicities that limit patient treatment. Overall, new therapies are urgently needed to fulfill this unmet medical need and extend OS beyond 11 months. Despite success in hematologic malignancies, immunotherapy has not yet significantly improved clinical outcomes in PC due to conditions surrounding solid tumors. Marker hypothesizes, based on clinical trials to date, that chemotherapy can modify the tumor microenvironment to promote T cell infiltration, T cell activation, and tumor cell killing. Marker proposes MT-601, a novel T cell therapy that simultaneously targets 6 tumor-associated antigens (TAAs) highly expressed in PC thereby minimizing tumor escape. Manufactured from the patient’s own apheresis material, MT-601 recognizes target cells via native (non-engineered) T cell receptors (TCRs), by interacting with both class I and II MHCs (CD4+ and CD8+ T cells), leading to killing of cells expressing TAAs, as well as the activation of other immune cells. In vitro studies show that MT-601 was far superior in controlling growth of PANC1 pancreatic cancer cells versus control conditions. More importantly, preliminary clinical data from Marker’s TACTOPS trial in pancreatic cancer patients demonstrated a signal of efficacy including 1 Complete Response (CR) and 3 Partial Responses (PRs) out of 13 PC patients treated. Epitope spreading was observed, likely leading to more durable responses than other cellular therapies. To date, multiple TAA (mTAA)- specific T cells have been shown to be safe in >200 patients with various cancer types. Therefore, Marker Therapeutics proposes to use MT-601, an improved mTAA-specific T cell product for PC in order to improve patient outcomes. Combining MT-601 with front-line FOLFIRINOX chemotherapy may overcome current limitations of immunotherapy in PC. This grant proposes a Phase 1, open-label study to evaluate safety and efficacy of MT-601 combined with front- line chemotherapy in metastatic PC patients. Specific Aim 1 assesses primary and secondary safety and efficacy outcomes in PC patients treated with front-line chemotherapy (FOLFIRINOX) in combination with MT- 601. Specific Aim 2 will correlate biological characteristics in the product profile with clinical safety and efficacy outcomes. Successful completion of this grant will provide clinical proof of concept for MT-601 as a treatment for PC patients and support future clinical trials leading to future BLA filing and commercial approval of MT-601.