Cancer therapy using a self-replicating RNA vaccine

'Naked' nucleic acid Vaccines are potentially useful candidates for the tre atment of patients with cancer(1-3), but their clinical efficacy has yet to be demonstrated. We sought to enhance the immunogenicity of a nucleic acid Vaccine by making it 'self-replicating'. We accomplished this by using a g ene encoding an RNA replicase polyprotein derived from the Semliki forest v irus, in combination with a model antigen. A single intramuscular injection of a self-replicating RNA immunogen elicited antigen-specific antibody and CD8(+) T-cell responses at doses as low as 0.1 mu g. Pre-immunization with a self-replicating RNA vector protected mice from tumor challenge, and the rapeutic immunization prolonged the survival of mice with established tumor s. The self-replicating RNA vectors did not mediate the production of subst antially more model antigen than a conventional DNA vaccine did in vitro. H owever, the enhanced efficacy in vivo correlated with a caspase-dependent a poptotic death in transfected cells. This death facilitated the uptake of a poptotic cells by dendritic cells, providing a potential mechanism for enha nced immunogenicity. Naked, non-infectious, self-replicating RNA may be an excellent candidate for the development of new cancer vaccines.