Abstract B106: Multiplexed cytokine and tumor-associated antigen mRNA immunotherapy for pancreatic ductal adenocarcinoma: Expanding antigenic breadth and tumor-targeted delivery toward clinical translation

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains largely unresponsive to immunotherapy because its dense, immune-excluded tumor microenvironment (TME) restricts therapeutic delivery and lacks the coordinated signals required to recruit and activate natural killer (NK) and T cells. We previously developed a multiplexed mRNA platform that transiently expresses complementary interleukins, chemokines, and interferons within the TME. Intratumoral administration of mRNAs encoding IL-12, IL-18, CCL5, CXCL10, and IFNβ promoted NK- and CD8+ T-cell activation and reduced tumor growth and fibrosis across immunologically distinct PDAC transplant models. Incorporating mRNAs encoding tumor-associated antigens (TAAs) further enhanced dendritic cell antigen presentation and both local and systemic CD8+ T-cell priming, thereby prolonging survival even after a single dose. Encapsulation of the complete cytokine-antigen mRNA cocktail in lipid nanoparticles (LNPs) enabled systemic administration and delivery to autochthonous PDAC tumors, producing curative responses in 50% of treated animals and durable persistence of antigen-reactive T cells. Building on these findings, we are expanding the antigen repertoire to address PDAC heterogeneity and reduce the likelihood of antigen-loss escape. Preliminary analysis of single-cell RNA-sequencing data from human pancreatic cancer specimens confirmed strong tumor-associated expression of MUC1 and MSLN, two components of our current antigen cocktail, and further identified TROP2, CEACAM5, CEACAM6, and CLDN18 as promising candidates for an expanded multi-antigen formulation. Ongoing studies are evaluating whether rationally selected antigen combinations broaden tumor-reactive T-cell responses, promote epitope spreading, and improve efficacy across heterogeneous PDAC models. In parallel, through a planned collaboration, we are assessing pancreatic tumor-directed formulations identified from an mRNA-LNP library and prioritizing candidates that enhance functional mRNA expression in pancreatic tumors while limiting off-target liver exposure. Lead formulations are currently being integrated with our multiplexed payload and evaluated for biodistribution, intratumoral expression, immune activation, antitumor efficacy, and tolerability in orthotopic, autochthonous, and humanized mouse models of PDAC. To translate these findings into a clinical therapy for patients, we founded ImmunoScript, a biotechnology company focused on advancing this platform through targeted-delivery optimization, IND-enabling development, and first-in-human clinical trials. Together, this work lays the foundation for a tumor-directed mRNA immunotherapy capable of overcoming immune exclusion, broadening T-cell recognition of PDAC-associated antigens, and inducing durable antitumor immunity.