Abstract
BACKGROUND: High-grade gliomas are an aggressive subset of CNS tumors in need of novel treatment strategies. However, tumor heterogeneity, the immunosuppressive tumor microenvironment (TME) and the lack of immunogenic tumor specific targets have limited the translational power of many immunotherapies for high-grade gliomas. The promising application of mRNA vaccines has the potential to restore immunosurveillance through peripheral and intratumoral reprograming of the TME. METHODS: Our lab has developed a lipid particle multilamellar aggregate (RNA-LPA) vaccine that encapsulates tumor specific RNA and delivers the payload to the immune system in a highly immunogenic fashion, similar to that of a virus. We sought to assess anti-tumor activity across preclinical murine models and investigate the mechanisms for response. RESULTS: We demonstrated the immune activation potential of RNA-LPAs encoding for glioma associated antigens (i.e., pp65 and H3K27M) in preclinical murine models. We also showed activity of personalized RNA-LPA in canine and human studies (NCT04573140) for patients with high-grade gliomas. Exogenous RNA is recognized by pathogen recognition receptors (PRRs) which trigger a type I interferon (IFN) response and proinflammatory cytokine production. While most RNA based vaccines activate an innate immune response primarily through toll-like receptor 7 (TLR7), we reveal that RNA-LPAs activate the innate immune system through retinoic acid-inducible gene 1 protein (RIG-I). As a result of PRR signaling, the type I IFN and cytokine/chemokine response (IL-6, G-CSF, TNF-alpha, CXCL9, CXCL10, CCL2, CCL4) mediates massive recruitment of activated dendritic cell and activated T cell in lymphoreticular organs where antigen presenting cells and cytolytic T cell colocalize to initiate an adaptive immune response against glioma specific antigens. CONCLUSION: RNA-LPAs are a novel platform immunotherapy that initiate anti-tumor immunity against malignant brain tumors through noncanonical activation of intracellular PRRs and widespread recruitment of peripheral blood mononuclear cells to sites of RNA-LPA localization.