Abstract
BACKGROUND: While recurrent medulloblastoma (MB) remains almost uniformly fatal, our group has shown a trend (p=0.07) toward improved survival in patients receiving autologous tumor RNA pulsed dendritic cells (DCs) coupled with ex vivo expanded total RNA activated T-cells. However, the advancement of autologous cellular therapeutics through the commercialization pipeline has been encumbered by significant cost, complexity and time to generation. To circumvent these challenges, 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 MB antigens. OBJECTIVE: 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 MB 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. When administered intravenously, RNA-NPs lead to systemic activation (i.e. MHCI/II, CD40, CCR7 and CD86) of host APCs within reticuloendothelial organs and within the intratumoral microenvironment. 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 targeting an anaplastic murine MB, RNA NPs supersede DCs in mediating anti-tumor activity. CONCLUSION: 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 by providing near-immediate immune induction for patients with recurrent MBs.