Augmentation of antitumor activity of a recombinant adeno-associated virus carcinoembryonic antigen vaccine with plasmid adjuvant.
Recombinant adeno-associated virus 2 (rAAV) vectors have been successfully used for sustained expression of therapeutic genes. The potential of using rAAV as a cancer vaccine vector and the impact of a bacterial plasmid adjuvant on this activity were investigated. C57BL/6 mice received a single intramuscular injection of rAAV expressing the human tumor-associated antigen, carcinoembryonic antigen (CEA). Three weeks later, when CEA expression was optimal, a bacterial plasmid containing methylated DNA motifs was injected into the same muscle. Mice were challenged 1 week later with syngeneic MC38 tumor cells stably expressing CEA. Immunization with rAAV-CEA alone resulted in sustained transgene expression and the elicitation of a humoral immune response to CEA. Cellular immune response, however, was weak, and tumor protection was not significant. In contrast, immunization with rAAV-CEA and the plasmid adjuvant resulted in stronger cellular immune response to CEA and tumor protection. The addition of plasmid adjuvant increased both myeloid dendritic cell recruitment in situ and CEA-specific T-helper-1-associated immune response. These data indicate that robust rAAV transgene expression of a tumor antigen followed by transient plasmid delivery to recruit and activate dendritic cells is an effective method of eliciting antitumor cellular immune responses.
Ponnazhagan
Selvarangan
S
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. sponnazh@path.uab.edu
Mahendra
Gandham
G
Lima
Jose
J
Aldrich
Wayne A
WA
Jenkins
Connie B
CB
Ren
Changchun
C
Kumar
Sanjay
S
Kallman
Lisa
L
Strong
Theresa V
TV
Shaw
Denise R
DR
Triozzi
Pierre L
PL
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D000912:Antibodies, Neoplasm / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D019496:Cancer Vaccines / Q000235:genetics; D002272:Carcinoembryonic Antigen / Q000235:genetics* / Q000276:immunology*; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D003131:Combined Modality Therapy; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D003587:Cytomegalovirus / Q000235:genetics; D004274:DNA, Recombinant / Q000235:genetics; D000229:Dependovirus / Q000235:genetics* / Q000276:immunology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009132:Muscles / Q000166:cytology; D009368:Neoplasm Transplantation / Q000276:immunology; D009374:Neoplasms, Experimental / Q000276:immunology / Q000517:prevention & control*; D010957:Plasmids / Q000627:therapeutic use*; D011401:Promoter Regions, Genetic; D018417:Th1 Cells / Q000276:immunology
D000276:Adjuvants, Immunologic; D000912:Antibodies, Neoplasm; D000914:Antibodies, Viral; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; D016207:Cytokines; D004274:DNA, Recombinant