Development of new therapy for brain tumors using recombinant oncolytic viruses

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Recombinant oncolytic herpes simplex virus type 1 (HSV-1) vectors are promising therapeutic agents for brain tumors. Insertion of therapeutic transgenes into the viral genome confers desired antitumor functions in addition to oncolytic activities. Because the efficacy of oncolytic HSV-1 also depends on the extent of antitumor immunity induction, immunomodulatory genes are particularly suited for "arming" oncolytic HSV-1 vectors. In order to circumvent time-consuming processes required with conventional homologous recombination techniques for creating "armed" oncolytic HSV-1 vectors, we used innovative construction systems utilizing bacterial artificial chromosome and recombinase-mediated recombinations. Triple gene-deleted HSV-1 vectors expressing immunostimulatory genes were generated and tested in HSV-1-susceptible AM mice bearing poorly-immunogenic Neuro2a (murine neuroblastoma) tumors. Intraneoplastic administration of "armed" oncolytic HSV-1 vectors expressing immunostimulatory genes resulted in significantly greater efficacy compared with unarmed control HSV-1, and led to growth inhibition of inoculated tumors as well as remote non-inoculated tumors. The antitumor effect on remote tumors was not due to viral spread but due to induction of systemic antitumor immunity requiring T lymphocytes. "Armed" oncolytic HSV-1 vectors could also suppress the growth of subcutaneous tumors when administered intravenously, whereas unarmed HSV-1 showed minimal effect. The results demonstrate that oncolytic HSV-1 therapy is a useful strategy for brain tumors, and "arming" with immunostimulatory genes can further improve the efficacy and usefulness of oncolytic HSV-1.