Immunotherapy of a Vaccinia Colon Oncolysate Prepared with Interleukin-2 Gene-Encoded Vaccinia Virus and Interferon-α Increases the Survival of Mice Bearing Syngeneic Colon Adenocarcinoma

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Abstract
Therapeutic effect of a vaccinia colon oncolysate prepared with interleukin-2 (IL-2) gene-encoded vaccinia virus (IL-2VCO) in combination with recombinant interferon-alpha (IFN-alpha) was studied in a syngeneic murine CC-36 colon hepatic metastasis model. Treatment with this IL-2VCO+IFN-alpha produced a higher survival rate (90% on day 60 after tumor transplantation) in mice having CC-36 hepatic metastases when compared to treatment with IFN-alpha (0%), VCO+IFN-alpha (0%), or IL-2VCO (11%). The only treatment that produced a survival rate similar to the survival rate of IL-2VCO+IFN-alpha was VCO+IL-2 + IFN-alpha (survival rate was 67%). The cause of the prolonged survival with the IL-2VCO+IFN-alpha treatment was identified as the reduction of CC-36 hepatic metastases (mean liver weight 1.31 g and mean tumor nodules 2). This reduction was significant when compared to IL-2VCO (1.58 g and 11), VCO+IFN-alpha (1.96 g and 53), and IFN-alpha (2.24 g and 91) treatments. The mechanism of the induction of antitumor response by the VCO+IL-2+IFN-alpha treatment was analyzed by measuring the direct cytotoxic activity of IFN-alpha on CC-36 tumor cells and by measuring the induction of cytolytic T-cell activity against CC-36 tumor cells. Results suggest that IFN-alpha produced minimal direct cytotoxic activity against CC-36 cells; however, the IL-2VCO+IFN-alpha combination therapy induced an enhanced cytolytic T-cell activity against CC-36 tumor cells (85.1% at E:T 100:1) when compared to other treatments (IL-2VCO 26.3%, VCO+IFN-alpha 13.4%, and IFN-alpha alone 6.3%). In addition, the role of T-cell subsets for the induction of antitumor immune response was analyzed in a survival study that used CD8-positive T cell-depleted mice. It was found that the survival rate was affected in mice depleted with CD8-positive T cells and treated with IL-2VCO+IFN-alpha when compared to control mice which had no T-cell depletion and were treated with IL-2VCO+IFN-alpha. This study suggests that the addition of IFN-alpha along with IL-2VCO increased the survival rate of mice having CC-36 hepatic metastases through the induction of CD8-positive T cells. Furthermore, this study confirms that IL-2VV can be used as a substitute for recombinant IL-2 in cytokine-augmented active specific immunotherapy.

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