Cancer therapy using a self-replicating RNA vaccine

Nat Med. 1999 Jul;5(7):823-7. doi: 10.1038/10548.


'Naked' nucleic acid vaccines are potentially useful candidates for the treatment of patients with cancer, 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 gene encoding an RNA replicase polyprotein derived from the Semliki forest virus, 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 microg. Pre-immunization with a self-replicating RNA vector protected mice from tumor challenge, and therapeutic immunization prolonged the survival of mice with established tumors. The self-replicating RNA vectors did not mediate the production of substantially more model antigen than a conventional DNA vaccine did in vitro. However, the enhanced efficacy in vivo correlated with a caspase-dependent apoptotic death in transfected cells. This death facilitated the uptake of apoptotic cells by dendritic cells, providing a potential mechanism for enhanced immunogenicity. Naked, non-infectious, self-replicating RNA may be an excellent candidate for the development of new cancer vaccines.

MeSH terms

  • Animals
  • Antibody Formation
  • Apoptosis
  • B-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cancer Vaccines / therapeutic use*
  • Colonic Neoplasms / immunology
  • Colonic Neoplasms / prevention & control*
  • Dendritic Cells / immunology
  • Enhancer Elements, Genetic
  • Injections, Intramuscular
  • Mice
  • Mice, Inbred BALB C
  • Plasmids
  • Promoter Regions, Genetic
  • RNA Replicase / biosynthesis
  • RNA Replicase / genetics*
  • RNA Replicase / therapeutic use*
  • Recombinant Proteins / biosynthesis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Semliki forest virus / enzymology
  • Semliki forest virus / genetics
  • Transfection
  • Tumor Cells, Cultured


  • Cancer Vaccines
  • Recombinant Proteins
  • RNA Replicase