Abstract A093: Multiplexed cytokine and antigen mRNA administration generates durable anti-tumor immunity against pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains a devastating malignancy characterized by limited therapeutic options for advanced disease. Immunotherapy in particular has had dismal success rates in the PDAC due to a tumor microenvironment (TME) that contributes to immune exclusion and poor drug delivery. Many cytokines necessary for Natural Killer (NK) and T cell chemotaxis, activation, and cytotoxicity are absent in the PDAC TME. Despite their early success, cytokine therapies have largely failed in the treatment of solid tumors as a result of the lack of efficacy of single cytokine administration and toxicities from systemic delivery. To overcome these limitations, we designed multiplexed mRNA cocktails encoding diverse interleukins, chemokines, and interferons for intratumoral delivery. Administration of a cytokine-encoding mRNA mixture into mice with orthotopically transplanted PDAC tumors could achieve robust yet transient cytokine expression locally in the PDAC TME, leading to NK cell and CD8+ T cell immunity and reduced tumor growth and fibrosis in multiple mouse models. Combining cytokine mRNAs with those encoding tumor-associated antigens could further activate CD8+ T cell-mediated tumor control and enhanced survival after just a single dose in PDAC-bearing mice. Remarkably, lipid-based nanoparticle (NP) encapsulation of an all-in-one cytokine and antigen mRNA cocktail allowed safe systemic administration and local delivery of these immunogenic signals to autochthonous PDAC tumors in genetically engineered mouse models, culminating in complete tumor responses in 50% of animals. These results suggest that multiplexed mRNA approaches to delivering cytokine signals and antigens generally absent in the TME could pave the way for an effective immunotherapy for PDAC. Citation Format: Chaitanya Naimesh Parikh, Kelly De Marco, Griffin Kane, Nikita Bhalerao, Ronnie Dinnell, Hadiya Giwa, Zhao Zhen, Lin Zhou, Katherine Murphy, Loretah Chibaya, Youwei Qiao, Wen Xue, Haruka Mori, Brian Lewis, Jason Pitarresi, Prabhani Atukorale, Marcus Ruscetti. Multiplexed cytokine and antigen mRNA administration generates durable anti-tumor immunity against pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A093.