Induction of ErbB-2/neu-specific protective and therapeutic antitumor immunity using genetically modified dendritic cells: enhanced efficacy by cotransduction of gene encoding IL-12.
Overexpression of ErbB-2/neu occurs in 20-30% of patients with breast cancer and indicates a poor prognosis. The presence of a detectable immune response to ErbB-2/neu in some patients suggests that this oncogene may be a useful target for vaccine therapy. We evaluated whether genetic immunization using dendritic cells (DC) transduced ex vivo with an adenovirus expressing the ErbB-2/neu gene (AdNeuTK) could induce protective and therapeutic immunity against a breast tumor cell line overexpressing ErbB-2/neu. Subcutaneous (s.c.) immunization with the DC vaccine elicited protective immunity in an average of 60% of animals. CTL analysis demonstrated specific cytotoxic activity against breast tumor cells, as well as syngeneic fibroblasts transduced with AdNeuTK. In vivo depletion studies demonstrated both CD4+ and CD8+ T cells were required. In a therapeutic setting, immunization with the DC vaccines could cure mice with pre-established tumors and efficacy was further enhanced by cotransducing DCs with a vector expressing murine IL-12 (AdmIL-12). These studies support DC vaccines as a therapeutic strategy for human breast cancer, while emphasizing the importance of optimizing an immune response by combining tumor antigen presentation with immunostimulatory cytokines.
Chen
Y
Y
Centre for Gene Therapeutics, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
Emtage
P
P
Zhu
Q
Q
Foley
R
R
Muller
W
W
Hitt
M
M
Gauldie
J
J
Wan
Y
Y
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology / Q000628:therapy*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage*; D003601:Cytotoxicity Tests, Immunologic; D003713:Dendritic Cells / Q000378:metabolism / Q000637:transplantation*; D005260:Female; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D018664:Interleukin-12 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009374:Neoplasms, Experimental / Q000628:therapy; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D014161:Transduction, Genetic / Q000379:methods
D019496:Cancer Vaccines; D018664:Interleukin-12; D018719:Erb-b2 Receptor Tyrosine Kinases