RNA nanoparticle vaccines: combining cytokine activation with antigen and CTL peptide delivery to improve vaccine efficacy (131.4)

Abstract

We have used an RNA nanoparticle system to test the hypothesis that co-expression of a tumor antigen-cytokine fusion, with or without a co-delivered tumor CTL epitope, can improve anti-tumor immunity to a self antigen. Our initial studies demonstrated that a Semliki Forest Virus (SFV) bGal RNA expression vector could be modified to allow for in vitro coat protein RNA encapsidation by a distant alphavirus family member, Tobacco Mosaic Virus (TMV). Encapsidated RNA stimulated robust targeted immune cell uptake and activation, including dendritic cells. In response to vaccination, encapsidation significantly improved humoral and cellular immune responses compared to naked RNA, including IFNg activation , and protection from challenge with a lethal dose of bGal expressing tumor. More recently, our goal is to test efficacy of encapsidated RNA in a Non-hodgkin’s murine lymphoma tumor self-antigen system using the A20 expressing tumor. We have constructed a variety of SFV A20 scFv antigen-cytokine fusions, and are co-developing an A20 CTL surface antigen fusion. In vitro expression will be confirmed, and mice will be immunized and tested by ELISA and ELISpot for functional B and T cell immune activation. This nanoparticle RNA system generates vaccine compositions that are easy to customize, easy to produce, and facilitates intracellular delivery of unique nucleic acid/protein antigen combinations that should improve vaccine efficacy against a weakly immunogenic tumor.