Cancer therapy using a self-replicating RNA vaccine.
'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.
Surgery Branch, National Cancer Institute, Bethesda, Maryland 20892-1502, USA.
H
H
Ying
T Z
TZ
Zaks
R F
RF
Wang
K R
KR
Irvine
U S
US
Kammula
F M
FM
Marincola
W W
WW
Leitner
N P
NP
Restifo
D000818:Animals; D000917:Antibody Formation; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000276:immunology / Q000517:prevention & control*; D003713:Dendritic Cells / Q000276:immunology; D004742:Enhancer Elements, Genetic; D007273:Injections, Intramuscular; D051379:Mice; D008807:Mice, Inbred BALB C; D010957:Plasmids; D011401:Promoter Regions, Genetic; D012324:RNA-Dependent RNA Polymerase / Q000096:biosynthesis / Q000235:genetics* / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012672:Semliki forest virus / Q000201:enzymology / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured
D019496:Cancer Vaccines; D011994:Recombinant Proteins; D012324:RNA-Dependent RNA Polymerase