Vaccination by genetically modified dendritic cells expressing a truncated neu oncogene prevents development of breast cancer in transgenic mice.
Dendritic cells (DCs) are powerful antigen-presenting cells that process antigens and present peptide epitopes in the context of the major histocompatibility complex molecules to generate immune responses. DCs are being studied as potential anticancer vaccines because of their ability to present antigens to naive T cells and to stimulate the expansion of antigen-specific T-cell populations. We investigated an antitumor vaccination using DCs modified by transfer of a nonsignaling neu oncogene, a homologue of human HER-2/neu, in a transgenic model of breast cancer. BALB-neuT mice develop breast cancers as a consequence of mammary gland-specific expression of an activated neu oncogene. We vaccinated BALB-neuT mice with bone marrow-derived DCs transduced with Ad.Neu, a recombinant adenovirus expressing a truncated neu oncoprotein. The vaccine stimulated the production of specific anti-neu antibodies, enhanced interferon-gamma expression by T cells, and prevented or delayed the onset of mammary carcinomas in the mice. Over 65% of vaccinated mice remained tumor free at 28 weeks of age, whereas all of the mice in the control groups developed tumors. When challenged with a neu-expressing breast cancer cell line, vaccinated tumor-free animals had delayed tumor growth compared with controls. The antitumor effect of the vaccine was specific for expression of neu. Studies showed that CD4+ T cells were required in order to generate antitumor immunity. Importantly, the effectiveness of the vaccine was not diminished by preexisting immunity to adenovirus, whereas the protection afforded by vaccination that used direct injection of Ad.Neu was markedly reduced in mice with anti-adenovirus antibody titers. DCs modified by recombinant adenoviruses expressing tumor-associated antigens may provide an effective antitumor vaccination strategy.
Sakai
Yoshio
Y
Cancer Gene Therapy Section, Metabolism Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-1374, USA.
Morrison
Brian J
BJ
Burke
J Douglas
JD
Park
Jong-Myun
JM
Terabe
Masaki
M
Janik
John E
JE
Forni
Guido
G
Berzofsky
Jay A
JA
Morris
John C
JC
D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D018734:Genes, erbB-2; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D014161:Transduction, Genetic; D014611:Vaccination
D007371:Interferon-gamma; D018719:Erb-b2 Receptor Tyrosine Kinases