title: Enhanced antitumoral activity of oncolytic herpes simplex virus with gemcitabine using colorectal tumor models.
abstract: To enhance the oncolytic activity of herpes simplex viruses (HSVs) control of immune-suppression and immune-resistance by cancer cells is important. Myeloid-derived suppressor cells (MDSCs), which interfere with tumor-suppressive environments, are inhibited by gemcitabine (GEM) treatment. We investigated the oncolytic activity and systemic antitumor immunity induced by oncolytic HSVs in combination with GEM treatment. A mouse model with subcutaneous tumors on both sides of the lateral flanks was used. A highly attenuated HSV type 1, strain HF10, was inoculated into one side of each tumor three times following intraperitoneal injection of GEM. Histopathological changes and IFN-γ secretion of the tumor and leukocytes in the spleen were analyzed. These treatments were repeated to enhance oncolytic activity. HF10 inoculation reduced tumor growth only on the HF10-treated side. HF10 inoculation following GEM treatment resulted in greater reduction of tumor growth on the HF10-treated tumor; furthermore, reduction of tumors on the contralateral untreated side was also observed. Necrosis of the tumor was observed in areas where HSV-infected cells were detected. F4/80(+)  macrophages around the tumor were eliminated, and CD4(+)  T and CD8(+)  T cells increased in the spleen. A single injection of GEM decreased CD11b(+) /Gr-1(+)  MDSCs while retaining CD4(+)  T cells and CD8(+)  T cells. Repetition of this treatment regimen resulted in even greater reduction of tumor growth on both sides and complete rejection in some of the mice. Intratumoral injection of oncolytic HSVs following GEM injection reduced MDSCs. Repeated treatment with oncolytic HSVs following GEM resulted in enhanced oncolytic activity.
authors.affiliation: Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Esaki
authors.forename: Fumi
authors.initials: F
authors.lastname: Goshima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kimura
authors.forename: Shingo
authors.initials: S
authors.lastname: Murakami
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Nishiyama
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D002522:Chlorocebus aethiops; D015179:Colorectal Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D006561:Herpes Simplex / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D015552:Injections, Intralesional; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D050130:Oncolytic Virotherapy; D018139:Simplexvirus / Q000502:physiology*; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000821:virology; D014709:Vero Cells; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D007371:Interferon-gamma; D000093542:Gemcitabine