Antitumor efficacy of tumor-antigen-encoding recombinant poxvirus immunization in Dunning rat prostate cancer: implications for clinical genetic vaccine development.
One potential use for prostate-cancer-associated genes discovered through ongoing genetics studies entails the construction of virus- or plasmid-based recombinant vector vaccines encoding these new tumor-associated antigens (TAA) to induce TAA-specific immune responses for the prevention or therapy of prostate cancer. Clinical trials evaluating prototypes of such recombinant vaccines are under way. TAA-encoding recombinant vector vaccines, however, have not previously been evaluated in a prostate-cancer animal model. For assessment of the potential susceptibility of prostate cancer to genetic immunization strategies using TAA-encoding recombinant vectors, the antitumor efficacy of a model recombinant viral vector encoding a TAA was evaluated in rat Dunning prostate cancer. Recombinant vaccinia was chosen as a prototype virus vector encoding a TAA for these studies, and beta-galactosidase was chosen as a model target TAA. Dunning AT-2 cells were transduced with a retroviral vector to express beta-galactosidase, and the susceptibility of tumorigenic AT-2-lacZ cells to immunization with vaccinia-lacZ was measured using protection studies in Copenhagen and nu/nu rats. Stably transduced AT-2-lacZ cells expressing beta-galactosidase as measured by enzymatic substrate-based assays were found to retain their tumorigenicity in vivo despite abundant expression of rat major histocompatibility complex (MHC) class I. Immunization with model TAA-encoding recombinant vaccinia-lacZ conferred significant protection against subsequent growth of AT-2-lacZ cells in vivo (P = 0.01); however, the efficacy of such immunization was markedly dependent on the volume of tumor challenge. The antitumor efficacy of TAA-encoding recombinant vaccinia immunization was abrogated in nu/nu rats, suggesting a T-cell-dependent mechanism of activity. These studies suggest that prostate cancer may be a suitable target for immunization strategies using TAA-encoding recombinant vectors. Such immunization strategies may be more effective in settings of minimal cancer burden.
Charles
L G
LG
Department of Surgery/Urology, University of Michigan School of Medicine, Ann Arbor 48109-0330, USA.
Xie
Y C
YC
Restifo
N P
NP
Roessler
B
B
Sanda
M G
MG
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000276:immunology; D019496:Cancer Vaccines; D002455:Cell Division / Q000276:immunology; D015967:Gene Expression Regulation, Viral; D007121:Immunocompetence; D007763:Lac Operon; D008297:Male; D011212:Poxviridae / Q000235:genetics* / Q000276:immunology; D011471:Prostatic Neoplasms / Q000276:immunology / Q000628:therapy*; D051381:Rats; D011919:Rats, Inbred Strains; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000276:immunology; D014615:Vaccinia; D014765:Viral Vaccines
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D011993:Recombinant Fusion Proteins; D014765:Viral Vaccines