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BackgroundHerpes simplex type I (HSV)-based vectors have been used experimentally for suicide gene therapy, immunomodulatory gene delivery, and direct oncolytic therapy. The current study utilizes the novel concept of regional delivery of an oncolytic virus in combination with or serving as the helper virus for packaging herpes-based amplicon vectors carrying a cytokine transgene, with the goal of identifying if this combination is more efficacious than either modality alone.Materials and MethodsA replication competent oncolytic HSV (G207) and a replication incompetent HSV amplicon carrying the gene for the immunomodulatory cytokine IL-2 (HSV-IL2) were tested in murine syngeneic colorectal carcinoma and in rat hepatocellular carcinoma models. Liver tumors were treated with vascular delivery of (1) phosphate-buffered saline (PBS), (2) G207, (3) HSV-IL2, (4) G207 and HSV-IL2 mixed in combination (mG207/HSV-IL2), and (5) G207 as the helper virus for packaging the construct HSV-IL2 (pG207/HSV-IL2).ResultsTumor burden was significantly reduced in all treatment groups in both rats and mice treated with highdose G207, HSV-IL2, or both (p < 0.02). When a low dose of virus was used in mice, anti-tumor efficacy was improved by use of G207 and HSV-IL2 in combination or with HSV-IL2 packaged by G207 (p < 0.001). This improvement was abolished when CD4+ and CD8+ lymphocytes were depleted, implying that the enhanced anti-tumor response to low-dose combined therapy is immune mediated.ConclusionsVascular regional delivery of oncolytic and amplicon HSV vectors can be used to induce improved anti-tumor efficacy by combining oncolytic and immunostimulatory strategies.

molecular medicine

Combination Vascular Delivery of Herpes Simplex Oncolytic Viruses and Amplicon Mediated Cytokine Gene Transfer Is Effective Therapy for Experimental Liver Cancer