926 Novel hydrophilic nanoparticle (HNP) platform for mRNA cancer vaccine delivery elicits anti-tumor efficacy in preclinical models

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Background mRNA-based cancer vaccines represent a promising therapeutic approach due to their ability to encode virtually any tumor antigen and rapidly stimulate antigen-specific immune responses. We developed hydrophilic nanoparticles (HNPs) for non-hepatic, targeted delivery of mRNA to antigen-presenting cells (APCs), particularly in the spleen, with tunable immunogenicity. For this study, we selected HNPs that activate immune responses and evaluated antigen-specific T cell priming and anti-tumor efficacy.Methods An antigen-encoding mRNA payload was formulated with various IO-HNP candidates as well as lipoplex (LPX) and lipid nanoparticle (LNP) controls. Female C57BL/6 mice received intravenous (IV) injections of IO-HNP-mRNA or LPX-mRNA, or intramuscular (IM) injections of LNP-mRNA, at doses of 0.5-1.0 mg/kg. Antigen-specific T cell responses were quantified in naive mice by tetramer staining. Anti-tumor efficacy was evaluated in multiple syngeneic mouse models, including E.G7-Ova and MC-38. Therapeutic response was measured by tumor growth inhibition (TGI) and immune correlates were assessed by ELISpot, intracellular cytokine staining, and flow cytometric analysis of tumor-infiltrating lymphocytes.Results We demonstrated specific mRNA delivery via HNPs to splenic APCs in both mouse and non-human primate models, achieving over 20% delivery to dendritic cells and over 15% to macrophages in mouse spleens with minimal hepatic uptake. Delivery of Ova-mRNA, a model antigen, via HNPs in naive mice induced a potent, antigen-specific CD8+ T cell response, with many HNPs eliciting a higher frequency of ovalbumin-specific T cells in the spleen compared to the LPX control. In therapeutic tumor models, IO-HNPs with tumor-specific antigen mRNA demonstrated TGI comparable to or superior to LNP and LPX controls.Conclusions Our platform is a potent delivery system for mRNA cancer vaccines that is superior to lipid-based benchmark platforms. Ongoing studies are evaluating the addition of co-encapsulated immune-modulatory co-payloads, such as nucleic acid-based adjuvants or mRNA for immune-stimulatory genes, to enhance T cell responses and improve therapeutic efficacy.

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