Abstract B100: Targeting orthotopic and metastatic pancreatic cancer with allogeneic stem cell–engineered mesothelin-redirected CAR-engineered invariant natural killer T cells

Abstract

Pancreatic cancer (PC) remains one of the leading causes of cancer-related mortality worldwide, with most patients diagnosed at advanced stages and more than half presenting with metastatic disease at diagnosis. Although chimeric antigen receptor (CAR)-T cell therapy has shown promise for the treatment of PC, its clinical efficacy remains limited by several major challenges, including tumor antigen heterogeneity, antigen escape, immunosuppressive tumor microenvironments, and progressive T-cell exhaustion. In addition, autologous CAR-T cell approaches are constrained by high manufacturing costs, prolonged production timelines, and limited scalability. To overcome these barriers, we developed an allogeneic, IL-15–enhanced, mesothelin-specific CAR-engineered invariant natural killer T-cell platform (Allo15MCAR-NKT) through genetic engineering of human hematopoietic stem and progenitor cells (HSPCs) using a clinically translatable culture and differentiation strategy. The resulting Allo15MCAR-NKT cells exhibited robust and multifaceted antitumor activity against PC through both CAR-dependent targeting and natural killer receptor–mediated cytotoxicity. In multiple orthotopic and metastatic human PC xenograft models, Allo15MCAR-NKT cells demonstrated potent tumor control and significantly prolonged survival. Mechanistically, these engineered cells showed enhanced trafficking and infiltration into tumor tissues, sustained effector and cytotoxic phenotypes, and reduced expression of exhaustion-associated markers within the tumor microenvironment. Furthermore, IL-15 enhancement promoted improved cellular persistence and functional activity in vivo. Importantly, Allo15MCAR-NKT cells displayed a favorable safety profile, with no evidence of graft-versus-host disease and minimal cytokine release syndrome observed in treated animals. Collectively, these findings establish Allo15MCAR-NKT cells as a promising next-generation, off-the-shelf immunotherapeutic strategy for pancreatic cancer. This platform has the potential to overcome critical limitations associated with current CAR-T cell therapies, including tumor heterogeneity, immune suppression, and manufacturing constraints, and supports further translational development toward clinical application in patients with advanced pancreatic cancer.