IMPS-36RNA NANOPARTICLE VACCINES RE-PROGRAM HOST-IMMUNITY AGAINST GLIOBLASTOMA INDUCING THERAPEUTIC ANTI-TUMOR ACTIVITY

Abstract

INTRODUCTION: Glioblastoma (GBM) remains invariably associated with poor patient outcomes thus necessitating development of more targeted therapeutics. To circumvent the challenges associated with cellular therapeutics, we developed a novel treatment platform, which leverages the use of commercially available and clinically translatable nanoparticles (NPs) that can be combined with tumor derived RNA to peripherally activate T cells against GBM antigens. Although cancer vaccines have suffered from weak immunogenicity, we have advanced a NP vaccine formulation that can dramatically reshape a host's regulatory immune profile through combinatorial delivery of tumor RNA encoding for GBM antigens and RNAs encoding for immunomodulatory molecules to mediate long-lived T cell persistence. OBJECTIVE: We sought to assess if vaccination with amplified tumor derived RNA encapsulated in lipophilic NPs could be assembled to target antigen presenting cells (APCs) in vivo and induce therapeutic anti-tumor immunity in pre-clinical murine GBM models. RESULTS: We identified a clinically translatable NP formulation for the delivery of RNA to APCs that induces in vivo gene expression and preserves RNA stability over time. We showed that RNA-NPs induce global changes in B7 co-stimulatory molecules and MHC class II expression on CD11c expressing APCs. RNA-NPs vaccines increase systemic levels of monocyte chemotactic protein-1 (MCP-1) and increase the percentage of CD11c+ cells at target sites. White blood cells from target organs (spleen and livers) of vaccinated mice induce de novo antigen specific immune responses in naive mice. T cell immunity elicited by RNA-NP vaccination was superior to peptide vaccines in CFA, enhanced through co-encapsulation of RNA encoding GM-CSF or viral PAMPs (pathogen associated molecular patterns) from hepatitis C, and engendered therapeutic anti-tumor efficacy against a radiation and temozolomide resistant GBM murine model. CONCLUSION: Combinatorial RNA-NPs represent a novel therapeutic platform for GBM patients that can be commercialized as an ‘off the shelf’ vaccine to re-program host-immunity.