Safety and Efficacy of a Multi-Tumor-Associated Antigen-Specific T Cell Therapy in Pancreatic Cancer Patients

Abstract public domain (NIH RePORTER)

ABSTRACT Pancreatic cancer (PC) is an orphan disease affecting approximately 67,440 people annually in the US. With a 5-year relative survival of only 13% for all stages combined and 3.2% for metastatic disease, PC represents one of the most aggressive malignancies. Although surgical resection provides the best curative option, <20% of PC patients are eligible for surgery at diagnosis. Patients with locally advanced unresectable PC typically have a median survival of less than 1 year. Standard frontline treatment includes FOLFIRINOX (FFX) or NALIRIFOX (NLX), yet these result in median overall survival of only 11.1 months and are associated with cumulative toxicities that limit longer treatment. Patients with locally advanced unresectable PC have an urgent unmet need for treatments that extend median survival beyond 12 months. Marker Therapeutics has developed MT-601, a multi-tumor associated antigen (mTAA)-specific autologous T cell product that recognizes six target antigens expressed by pancreatic tumors: PRAME, NY-ESO-1, survivin, MAGE-A4, SSX2, and WT1. This non-engineered T cell therapy limits tumor adaptation through negative antigen selection (immune escape) while reducing on-target, off-tumor effects. MT-601 is manufactured from patient apheresis material using a simplified process that stimulates and expands polyclonal tumor-specific T cells. The product consists of CD4+ and CD8+ T cells that recognize target cells via native T cell receptors, interacting with both class I and II MHC complexes. Preliminary data from the Phase 1 TACTOPS trial of mTAA-specific T cells in pancreatic cancer demonstrated clinical benefit with 1 complete response, 2 partial responses, and 8 stable disease among 13 FFX treated patients. To date, mTAA-specific T cells have shown an excellent safety profile in >200 patients across 7 cancer indications, without cytokine release syndrome, neurotoxicity, or dose-limiting toxicities. MT-601 represents an improved product with the addition of WT1, higher dosing (400×10⁶ cells vs 20×10⁶), and enhanced manufacturing yielding 4X increased potency. Therefore, Marker proposes a Phase 1, single-center, open-label clinical trial (PANACEA, NCT# 06549751) to evaluate the safety and efficacy of MT-601 administered during maintenance capecitabine following FFX or NLX in patients with locally advanced unresectable PC. The trial includes Dose Escalation using a modified 3+3 design followed by Expansion at the recommend dose. Specific Aim 1 will assess safety and efficacy of MT-601 in combination with maintenance capecitabine, determining the maximum tolerated dose and evaluating progression-free survival and duration of response. Specific Aim 2 will correlate biological characteristics of MT- 601 with clinical outcomes, including T cell expansion, persistence, clonality, and anti-tumor immune effects. Successful completion of this trial will provide critical dosing, safety, and efficacy data necessary to advance MT- 601 to a randomized pivotal study comparing MT-601 plus maintenance chemotherapy versus maintenance chemotherapy alone, ultimately advancing this therapy toward market approval for PC patients.

Public health relevance public domain (NIH RePORTER)

NARRATIVE This application will advance a novel therapy comprised of T cells that have been trained in the laboratory to recognize six markers expressed by pancreatic tumor cells but with limited expression on healthy cells. To date, over 200 patients have been treated in clinical studies with this type of therapy with an excellent safety profile, without the severe toxicities seen with other T cell therapies. This project will advance this cell therapy for locally advanced unresectable pancreatic cancer patients receiving maintenance capecitabine following FOLFIRINOX or NALIRIFOX chemotherapy, addressing an urgent unmet need in a patient population with low survival rates.