Abstract
BACKGROUND: Pediatric brain tumors are poorly immunogenic preventing current immunotherapies (i.e. checkpoint blockers) from having significant activity. Unlocking immunotherapy against these malignancies is predicated on reprogramming their immunogenicity. OBJECTIVE/METHODS: We developed a novel treatment platform, which leverages the use of clinically translatable lipid-nanoparticles (NPs) combined with tumor derived mRNA that simultaneously function as both vaccines and immunomodulating agents to reprogram the systemic/local microenvironments of pediatric brain cancers. RESULTS: Systemic tumor mRNA-NPs localize to lymphoid organs (i.e. liver, spleen lymph nodes) and to the intratumoral milieu, activating the immunologic microenvironment therein through release of type I interferon from plasmacytoid dendritic cells. This culminates in a CD4 and CD8 central memory T cell response against H3.1K27M murine gliomas. In immunologically resistant murine tumor models, RNA-NPs induce robust anti-tumor efficacy and mediate synergistic activity in settings where immune checkpoint inhibitors (i.e. anti-PD-L1 therapy) do not confer therapeutic benefit. We demonstrate safety of RNA-NPs in acute/chronic murine toxicity studies and in a client-owned canine (pet dog) diagnosed with a malignant glioma. In our first canine subject, RNA-NPs elicited activation of dendritic cells, release of type I interferon and activation of CD8+ T cells. CONCLUSION: RNA-NPs bypass MHC restriction and can be made readily available for all patients (and not only HLA specific haplotypes); they also provide a renewable antigen resource that can be used to continuously vaccinate patients for months/years after diagnosis. Through partnership with the Pacific Pediatric Neuro-Oncology Consortium (PNOC), we are in the final stages of FDA-IND submission before first-in-human trials.