A novel RNA-LNP immunotherapy platform to drive anti-tumor efficacy in solid tumors

Nucleoside-modified RNA vaccines complexed in ionizable lipid nanoparticles (RNA-LNPs) constitute a promising immunotherapy platform for T cell-directed cancer vaccine development. A challenge in generating a proper anti-tumor CD8 T cell response with current RNA vaccine iterations remains, however, in providing optimal activation of antigen-presenting cells. Further, the presence of an immunologically cold tumor microenvironment (TME) presents an additional obstacle in designing an immunotherapeutic strategy to overcome such immunosuppression. To address these challenges, we hypothesized that an optimized RNA-LNP platform which couples an antigen-encoding RNA with a novel RNA-LNP innate immune activator will synergistically activate dendritic cells (DCs) by engaging multiple pattern recognition receptor (PRR) pathways to enhance cross-presentation and drive CD8 T cell responses. To this end, we immunized mice with our novel RNA-LNP platform and demonstrated that multiple DC subsets were activated at both local and distal secondary lymphoid organs respective to the injection site. The DCs from the immunized mice also activated and expanded antigen-specific T cells and resulted in memory T cell formation. Abrogation of these T cell responses in genetic knockout models demonstrate that such T cell activation is mediated by multiple PRRs. Systemic delivery of the novel innate immune activators activated DCs at draining lymph nodes local to the tumor site in an orthotopically implanted murine pancreatic cancer model and subsequently conferred tumor growth suppression. Collectively, these studies establish a new paradigm for RNA-LNP immunotherapy that integrates multifaceted PRR engagement to promote antigen-specific vaccination and facilitate T cell priming and reactivation at the tumor.