An effective immunization and cancer treatment with activated dendritic cells transduced with full-length wild-type p53.
P53-based immunization is an attractive approach to cancer immunotherapy due to the accumulation of p53 protein in tumor, but not in normal cells. However, it was not known whether immune response against self-protein (p53) could be generated in vivo. Mouse dendritic cells (DCs) were transduced with adenoviral construct containing murine full-length wild-type p53 (Ad-p53). Repeated immunizations with these cells protected 60% of mice against challenge with MethA sarcoma cells bearing point mutations in p53 gene. Activation of DCs via ligation of CD40 significantly improved the results of immunization: all mice were protected against MethA sarcoma. The treatment of MethA tumor-bearing mice with activated Ad-p53-transduced DCs showed complete tumor rejection in four out of six mice. The specificity of antitumor immune response was confirmed by CTL assay. The analysis of phenotype and function of DCs demonstrated that the effect of CD40 ligation on these cells was enhanced by their infection with Ad-p53. The level of neutralizing anti-adenovirus antibody was moderately elevated in these mice. No signs of autoimmune reaction were evident during detailed pathological evaluation of treated mice. These data demonstrate that activated Ad-p53-infected DCs are able to break tolerance to this protein and can be used in immunotherapy of cancer.
Nikitina
E Y
EY
H Lee Moffitt Cancer Center, University of South Florida, Tampa, FL 33612, USA.
Chada
S
S
Muro-Cacho
C
C
Fang
B
B
Zhang
R
R
Roth
J A
JA
Gabrilovich
D I
DI
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage*; D003601:Cytotoxicity Tests, Immunologic; D003713:Dendritic Cells / Q000378:metabolism*; D005260:Female; D016158:Genes, p53; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012513:Sarcoma, Experimental / Q000276:immunology / Q000628:therapy*; D014161:Transduction, Genetic
D019496:Cancer Vaccines