Abstract LB-205: A lipoplex-based mRNA nanovaccine for cancer immunotherapy

Abstract Intracellular delivery of messenger RNA (mRNA)-based cancer vaccines have shown great potential to activate antitumor immune response for cancer prevention and therapy. In vivo delivery efficiency of mRNA has been greatly improved by various nucleotide chemical modifications and nanovector formulations, but the efficacy of mRNA vaccine remains unsatisfied. Here, we report a lipoplex-based mRNA nanovaccine that can markedly improve mRNA delivery in antigen presenting cells, activate T cell response, and induce robust antitumor immunity. The nanovaccine formulation contains three components: cationic polymer/lipid(poly(amidoamine)/alkylene oxide), DSPE-PEG2000, and epitope-encoding mRNA. With appropriate ratio, the optimized nanovaccine show effective mRNA delivery in dendritic cells, and strongly active antigen-specific immune response in vitro and in vivo. The mRNA@lipoplex nanovaccine enhanced mRNA uptake by dendritic cells, and significantly increased T cell activation reflected by IL-2 and IFN-γsecretion in an in vitro antigen presentation assay. Besides enhancing cross-presentation, nanoparticle itself can promote the expression of inflammatory cytokines such as IL-12 via stimulating NF-κB signal pathway in dendritic cells. In a tumor prevention setting, mRNA@lipoplex nanovaccine produced strong CD8+ T cell activation and great efficacy in preventing tumor development. Furthermore, treatment of established B16 and B16-OVA melanoma and MC38-OVA colon tumors with nanovaccine containing mRNA encoding cancer-associated antigen resulted in great therapeutic efficacy and prolonged survival. Re-challenge of tumor-free mice with MC38-OVA cells led to complete tumor rejection, suggesting long-term antitumor memory. In conclusion, our work presents a new means to deliver mRNA cancer vaccine, which in principle may be applied for immunotherapy for a wide range of tumor types. Citation Format: Zhang Hongxia, You Xinru, Wang Xiaojuan, Wang Zining, Xu Feifei, Wu Jun, Xia Xiaojun. A lipoplex-based mRNA nanovaccine for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-205.