Expression of FMS-like Tyrosine Kinase 3 Ligand by Oncolytic Herpes Simplex Virus Type I Prolongs Survival in Mice Bearing Established Syngeneic Intracranial Malignant Glioma

BACKGROUND: Glioblastoma is a fatal brain tumor in needing urgent effective therapy. Treatments with both oncolytic viruses and immunotherapy have shown preclinical efficacy and clinical promise. We sought to exploit possible synergies between oncolytic herpes simplex virus type 1 (oHSV-1) infection of intracranial gliomas and delivery of immune-stimulating fms-like tyrosine kinase 3 ligand (Flt3L) by engineering a herpes vector to express the cytokine. OBJECTIVE: To construct an oHSV-1 vector that expresses high levels of Flt3L and examine its antiglioma efficacy in an immunocompetent murine model. METHODS: G47 Delta and a bacterial artificial chromosome system were used to generate a novel oHSV-1, termed G47 Delta-Flt3L, expressing Flt3L. Cytokine expression was confirmed, and G47 Delta-Flt3L was injected intratumorally into established intracranial CT-2A gliomas in syngeneic C57/Bl6 mice. Animals were followed for survival and assessed by the Kaplan-Meier method. RESULTS: G47 Delta-Flt3L expressed high levels of Flt3L in culture. Expression of Flt3L affected neither viral replication nor had a cytotoxic effect on CT2A glioma cells. Direct inoculation into intracerebral CT2A glioma cells resulted in high levels of detectable Flt3L in mouse blood and was superior to parental G47 Delta in prolonging survival in glioma-bearing animals. CONCLUSION: Treatment with G47 Delta-Flt3L improves survival of glioma-bearing mice.