Overcoming resistance to immune checkpoint blockade with RNA-loaded nanoparticles.

Abstract

117 Background: While checkpoint blockade has shown promising survival benefits in patients with solid tumors, immune escape through loss of MHCI expression juxtaposed to an immunoregulatory milieu remain significant hurdles. To overcome these limitations, 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 activate systemic immunity and re-program the intratumoral microenvironment from a regulatory into an immune activated locale. Methods: Since local vaccination strategies are mired with poor immunogenicity, we assessed if i.v. delivery of tumor-derived RNA encapsulated in lipophilic NPs could activate peripheral and intratumoral antigen presenting cells (APCs) for induction of therapeutic anti-tumor immunity in pre-clinical murine melanoma models. Results: We identified a clinically translatable NP formulation that when administered intravenously, mediates release of inflammatory cytokines (i.e. CCL2, IFN-alpha) into serum, systemically activates host APCs in reticuloendothelial organs, and induces precipitous upregulation of MHCI and immune activation markers (i.e. CD86) within the tumor microenvironment. Both model-antigen encoding RNA and physiologically-relevant tumor-derived RNA, when encapsulated in NPs, could expand potent anti-tumor T-cell immunity. We demonstrated that RNA-NPs harness the anti-viral defense mechanism against tumor antigens in a type I interferon dependent manner, and can be further engineered to deliver combinatorial therapies by co-encapsulating mRNAs encoding for immunomodulatory molecules (i.e. HCV PAMPs, GM-CSF). In a pre-clinical melanoma model, RNA-NPs mediate anti-tumor efficacy and significantly enhance activity of immune checkpoint mAbs when used in combination. Conclusions: By employing a systemic RNA-NP formulation encoding for both tumor RNAs and immunomodulatory molecules, as an innovative and versatile platform for delivering combinatorial therapeutics via a single treatment modality, this platform can be harnessed to simultaneously target tumor antigens and re-program the intratumoral microenvironment