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 1 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.Ovarian cancer is the most aggressive gynecological cancer and the foremost cause of death from gynecological malignancies in the developed world. 1 However, the lack of effective screening strategies and the absence of symptoms during early disease stages are responsible for the late detection of these tumors, resulting in metastases that primarily spread within the peritoneal cavity. Recent developments in treatment modalities, including wide resection-based surgery and new chemotherapy regimens, have resulted in marked improvement in the short-term survival of ovarian cancer patients. 2 Nevertheless, the long-term prognosis of advanced cases remains unsatisfactory, necessitating a new paradigm in the treatment strategy. Oncolytic viral therapy refers to the use of viruses that selectively replicate in cancer cells.3 It is a promising anticancer therapy because efficient transduction and cancer cellspecific viral replication can boost therapeutic efficacy. Previously, we demonstrated an increase in anti-tumor responses after injection of HF10, a highly attenuated variant of the herpes simplex virus type 1 (HSV-1).4 HF10 was also reported to effectively destroy intraperitoneal disseminated tumors such as colon carcinomas and melanoma in immunocompetent murine models. [5][6][7] The combination of oncolytic HSV with immunosti...

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