title: Oncolytic viral therapy with a combination of HF10, a herpes simplex virus type 1 variant and granulocyte-macrophage colony-stimulating factor for murine ovarian cancer.
abstract: Ovarian cancer is the most frequent cause of gynecological cancer-related mortality as a majority of patients are diagnosed at an advanced stage with intraperitoneal dissemination because of the absence of initial symptoms. Granulocyte-macrophage colony-stimulating factor (GM-CSF) plays an important role in the maturation of specialized antigen-presenting cells. In this study, we utilized a herpes simplex virus (HSV) amplicon expressing murine GM-CSF combined with HF10 (mGM-CSF amplicon), a highly attenuated HSV type 1 strain functioning as a helper virus to strengthen anti-tumor immune response, for the treatment of ovarian cancer with intraperitoneal dissemination. A mouse ovarian cancer cell line, OV2944-HM-1 (HM-1), was intraperitoneally injected, following which HF10 only or the mGM-CSF amplicon was injected intraperitoneally three times. HF10 injection prolonged survival and decreased intraperitoneal dissemination, but to a lesser extent than the mGM-CSF amplicon. Although HF10 replication was not observed in HM-1 cells, expression of VP5, a late gene coding the major capsid protein of HSV, was detected. Moreover, mGM-CSF production was detected in transfected HM-1 cells. Immunohistochemical staining revealed the infiltration of CD4- and CD8-positive cells into the peritoneal tumor(s). A significantly increased CD4+ T cell concentration was observed in the spleen. Murine splenic cells after each treatment were stimulated with HM-1 cells, and the strongest immune response was observed in the mice that received mGM-CSF amplicon injections. These results suggested that the mGM-CSF amplicon is a promising agent for the treatment of advanced ovarian cancer with intraperitoneal dissemination.
authors.affiliation: Department of Virology, Graduate School of Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Fumi
authors.initials: F
authors.lastname: Goshima
authors.forename: Shinichi
authors.initials: S
authors.lastname: Esaki
authors.forename: Chenhong
authors.initials: C
authors.lastname: Luo
authors.forename: Maki
authors.initials: M
authors.lastname: Kamakura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kimura
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Nishiyama
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D036022:Capsid Proteins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D002522:Chlorocebus aethiops; D005260:Female; D005822:Genetic Vectors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology*; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D050130:Oncolytic Virotherapy / Q000379:methods*; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000628:therapy*; D013534:Survival; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014709:Vero Cells
chemical_list: D036022:Capsid Proteins; D014409:Tumor Necrosis Factor-alpha; C442523:VP5 protein, Herpes simplex virus type 1; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: GM-CSF; HSV; amplicon; immunotherapy; ovarian cancer