IMST-16. TRANSLATABLE RNA NANOPARTICLES SUPPLANT DENDRITIC CELL VACCINES IN CELLULAR IMMUNOTHERAPY

Abstract

BACKGROUND: In a pilot study, dendritic cell (DC) vaccines targeting glioblastoma (GBM) were shown to engender long-term survival outcomes (Mitchell et al. Nature, 2015). While these approaches have shown considerable promise, the advancement of cellular therapeutics through the commercialization pipeline has been encumbered by significant cost, complexity and time to generation. To circumvent the challenges associated with autologous 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 systemically activate peripheral immunity against GBM antigens. OBJECTIVE(S): To overcome the limitations of poorly immunogenic local vaccination strategies, we assessed if intravenous delivery of tumor-derived RNA encapsulated in lipophilic NPs could systemically activate antigen presenting cells (APCs) for induction of therapeutic anti-tumor immunity in pre-clinical murine GBM models. RESULT(S): 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. When administered intravenously, RNANPs lead to systemic activation of host APCs in reticuloendothelial organs triggering precipitous upregulation of activation markers (MHCII, CD40, and CD86) and chemokine receptors (i.e. CCR7) on CD11c+ cells. We demonstrated that both model-antigen encoding RNA and physiologically-relevant tumor-derived RNA, when encapsulated in NPs, could expand potent anti-tumor T-cell immunity. T-cell immunity elicited by RNA-NPs was superior to peptide vaccines formulated in complete Freund's adjuvant. We enhanced the immunogenicity of this platform by simply combining mRNAs encoding for immunomodulatory molecules (i.e. HCV PAMPs, GM-CSF). In a pre-clinical cellular immunotherapy model for invasive malignant glioma, RNA NPs were shown to supersede DCs in mediating anti-tumor activity. CONCLUSION(S): Since RNA-NPs bypass cost/complexity of cellular therapeutics, are amenable to central distribution, and can be made within days of tumor-resection, these formulations supplant DCs providing near-immediate immune induction against GBM.