LAUSR

Introduction: Immunotherapy is promising for patients with treatment-refractory head and neck squamous cell carcinoma (HNSCC). However, >80% of patients do not respond to checkpoint inhibitors, suggesting that the highly immunosuppressive tumor immune microenvironment of HNSCC may play a role in treatment resistance. Our group has developed a novel treatment platform utilizing clinically translatable RNA-nanoparticles (NPs) to remodel the systemic and intratumoral HNSCC microenvironment in favor of an activated immunologic milieu. Objective: The purpose of this study is to examine the feasibility, safety and immunologic activity of systemic/intratumoral administration of RNA NPs for HNSCC. Materials and Methods: RNA-NPs were prepared by complexing negatively charged mRNA with nanoliposomes. These complexes were injected into naive and B16 or MOC1/MOC2 (murine oral cavity squamous cell carcinoma cell lines) tumor bearing C57Bl/6 mice. In vitro transfection experiments were performed in human HNSCC cell lines. Results: Human HNSCC cell lines were efficiently transfected with RNA NPs in vitro. MOC1/MOC2 tumors were efficiently transfected with RNA NPs in vivo. RNA-NPs activate dendritic cells (DCs) in the peripheral and intratumoral microenviroment of naive and B16 tumor bearing mice, and mediate antitumor efficacy in a preclinical in vivo murine model for HNSCC. RNA-NPs mediate their effects through interferon-alpha released from plasmacytoid DCs. We have successfully scaled up production of RNA-NPs for translation into human clinical trials and demonstrated safety of RNA-NPs in acute/chronic murine toxicity studies based on CBCs, electrolytes, organ function tests, and end-organ HE 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B83.