Conditionally replicating (oncolytic) herpes simplex viruses (HSVs) have shown clear potential as effective agents for the treatment of solid tumors such as renal cell carcinoma (RCC). To enhance the oncolytic capabilities of first-generation HSVs, we recently developed two new constructs. Synco-2D is derived from HSV-1 and contains two mechanisms to induce cell membrane fusion. FusOn-H2 is derived from HSV-2. It selectively targets the activated Ras signaling pathway in tumor cells and also has the ability to induce cell membrane fusion and apoptosis. We studied the in vitro and in vivo antitumor effects of both Synco-2D and FusOn-H2 against RCC. Both Synco-2D and FusOn-H2 lysed human RCC cells in vitro much more readily than did Baco-1. For in vivo studies, the oncolytic viruses were administered either intratumorally or intravenously to nude mice bearing xenografted human RCC, and the tumor growth rate and animal survival were monitored after treatment. In most instances, the results were compared with those for a first-generation non-fusogenic oncolytic HSV (Baco-1). A single intratumoral injection of either Synco-2D or FusOn-H2 produced a striking effect against xenografted human RCC, in contrast to Baco-1, which produced only moderate antitumor activity. Two intravenous injections of Synco-2D also inhibited the growth of human RCC xenografts, while Baco-1 injections via the same route lacked any measurable antitumor effect. These data demonstrate that the newly constructed oncolytic HSVs have potent activity against established RCC in animal models. Clinical trials to validate these results in cancer patients appear warranted.

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