Comparison of two cancer vaccines targeting tyrosinase: plasmid DNA and recombinant alphavirus replicon particles.
OBJECTIVE
Immunization of mice with xenogeneic DNA encoding human tyrosinase-related proteins 1 and 2 breaks tolerance to these self-antigens and leads to tumor rejection. Viral vectors used alone or in heterologous DNA prime/viral boost combinations have shown improved responses to certain infectious diseases. The purpose of this study was to compare viral and plasmid DNA in combination vaccination strategies in the context of a tumor antigen.


METHODS
Using tyrosinase as a prototypical differentiation antigen, we determined the optimal regimen for immunization with plasmid DNA. Then, using propagation-incompetent alphavirus vectors (virus-like replicon particles, VRP) encoding tyrosinase, we tested different combinations of priming with DNA or VRP followed by boosting with VRP. We subsequently followed antibody production, T-cell response, and tumor rejection.


RESULTS
T-cell responses to newly identified mouse tyrosinase epitopes were generated in mice immunized with plasmid DNA encoding human (xenogeneic) tyrosinase. In contrast, when VRP encoding either mouse or human tyrosinase were used as single agents, antibody and T-cell responses and a significant delay in tumor growth in vivo were observed. Similarly, a heterologous vaccine regimen using DNA prime and VRP boost showed a markedly stronger response than DNA vaccination alone.


CONCLUSIONS
Alphavirus replicon particle vectors encoding the melanoma antigen tyrosinase (self or xenogeneic) induce immune responses and tumor protection when administered either alone or in the heterologous DNA prime/VRP boost approaches that are superior to the use of plasmid DNA alone.
Goldberg
Stacie M
SM
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. goldber3@mskcc.org
Bartido
Shirley M
SM
Gardner
Jason P
JP
Guevara-Patiño
José A
JA
Montgomery
Stephanie C
SC
Perales
Miguel-Angel
MA
Maughan
Maureen F
MF
Dempsey
JoAnn
J
Donovan
Gerald P
GP
Olson
William C
WC
Houghton
Alan N
AN
Wolchok
Jedd D
JD
D000524:Alphavirus / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D004274:DNA, Recombinant / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D006801:Humans; D007114:Immunization / Q000379:methods; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D014442:Monophenol Monooxygenase / Q000235:genetics / Q000276:immunology*; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D012093:Replicon / Q000235:genetics; D016019:Survival Analysis
D019496:Cancer Vaccines; D004274:DNA, Recombinant; D014442:Monophenol Monooxygenase