Antitumor Efficacy of Oncolytic Herpes Virus Type 1 Armed with GM-CSF in Murine Uveal Melanoma Xenografts.

Abstract

BackgroundUveal melanoma (UM) is the most common primary intraocular tumor in adults with a high incidence of metastasis. Standard care therapies for UM include enucleation and radiation, which are minimally effective in prolonging patient survival. Oncolytic virus treatment has become a new trend in cancer field. Of which, oncolytic herpes simplex virus type 1 (HSV-1) therapy is one of the most effective antitumor treatments. Here, we established an oncolytic HSV-1 encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), tested its efficacy in UM therapy, and investigated the innate immune response induced by this virus.MethodsOncolytic HSV-1 expressing GM-CSF (HSV-GM-CSF) was constructed, then verified using qPCR and Western blot assays. Cell viability assays and transmission electron microscopy were conducted on three UM cell lines, MUM2B, 92.1, and MP41, to assess the cell-killing ability and virus infection of this virus. For in vivo experiments, BALB/c-nude mice in situ UM xenografts were established to testify the efficacy of the oncolytic virus, oncolytic HSV-1, and HSV-GM-CSF groups, respectively. IVIS images, ocular volumes, mice weights, and survivals were tracked to see the efficacy of the virus. Hematoxylin and eosin staining, immunohistochemistry, and flow cytometry analyses were conducted to demonstrate the immune activity after virus treatment.ResultsAll three tested UM cell lines were sensitive to infection by HSV-GM-CSF. In vivo xenograft experiments revealed that oncolytic virus HSV-1 reduced UM tumor volume and that oncolytic virus HSV-1 armed with GM-CSF enhanced the antitumor effect compared with unmodified HSV-1. The bodyweights of untreated control group mice were significantly lower than those of mice in either virus-treated group (HSV-1 or HSV-GM-CSF). Follow-up survivals were prolonged in the virus-treated groups compared with the control group and were prolonged to a greater extent in the HSV-GM-CSF group than in the HSV-1 group. Macrophage stimulation was observed following HSV-GM-CSF treatment.ConclusionOur results indicate that the recombinant oncolytic virus HSV-GM-CSF is a potential therapeutic treatment for UM.