title: Combined stimulation of IL-2 and 4-1BB receptors augments the antitumor activity of E7 DNA vaccines by increasing Ag-specific CTL responses.
abstract: Human papillomavirus (HPV) infection is a major cause of cervical cancer. Here, we investigate whether concurrent therapy using HPV E7 DNA vaccines (pE7) plus IL-2 vs. IL-15 cDNA and anti-4-1BB Abs might augment antitumor activity against established tumors. IL-2 cDNA was slightly better than IL-15 cDNA as a pE7 adjuvant. Co-delivery of pE7+IL-2 cDNA increased tumor cure rates from 7% to 27%, whereas co-delivery of pE7+IL-2 cDNA with anti-4-1BB Abs increased tumor cure rates from 27% to 67% and elicited long-term memory responses. This increased activity was concomitant with increased induction of Ag-specific CTL activity and IFN-γ responses, but not with Ag-specific IgG production. Moreover, the combined stimulation of IL-2 and 4-1BB receptors with rIL-2 and anti-4-1BB Abs resulted in enhanced production of IFN-γ from Ag-specific CD8+ T cells. However, this effect was abolished by treatment with anti-IL-2 Abs and 4-1BB-Fc, suggesting that the observed effect was IL-2- and anti-4-1BB Ab-specific. A similar result was also obtained for Ag-specific CTL activity. Thus, these studies demonstrate that combined stimulation through the IL-2 and 4-1BB receptors augments the Ag-specific CD8+ CTL responses induced by pE7, increasing tumor cure rates and long-term antitumor immune memory. These findings may have implications for the design of DNA-based therapeutic vaccines against cancer.
authors.affiliation: Department of Microbiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, Korea.
authors.forename: Ha
authors.initials: H
authors.lastname: Kim
authors.affiliation: School of Biological Sciences, University of Ulsan, Ulsan, Korea.
authors.forename: Byungsuk
authors.initials: B
authors.lastname: Kwon
authors.affiliation: Department of Microbiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, Korea.
authors.forename: Jeong-Im
authors.initials: JI
authors.lastname: Sin
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D019409:Interleukin-15 / Q000037:antagonists & inhibitors / Q000276:immunology; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D050725:Papillomavirus E7 Proteins / Q000276:immunology; D053918:Papillomavirus Vaccines / Q000627:therapeutic use*; D017154:Stromal Cells / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000037:antagonists & inhibitors / Q000276:immunology*; D019444:Vaccines, DNA / Q000627:therapeutic use*
chemical_list: D000911:Antibodies, Monoclonal; D019409:Interleukin-15; D007376:Interleukin-2; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D019444:Vaccines, DNA; D007371:Interferon-gamma