Evaluation of combined vaccinia virus-mediated antitumor gene therapy with p53, IL-2, and IL-12 in a glioma model

Our previous studies have shown that vaccinia virus (VV) expressing p53, interleukin-2 (IL-2), and interleukin-12 (IL-12) results in an effective inhibition of subcutaneous glioma growth in mice. We propose that combination therapy of tumors with virus-mediated p53 and cytokine genes offers the prospect of synergistic antitumor response. In this work, the antitumor efficacy of VV-mediated combination of p53, IL-2, and IL-12 genes was evaluated in a nude mouse model. To minimize cytokine-associated toxicity, a virus dose as low as 10 plaque-forming units of VV expressing IL-2 and IL-12 per animal was used alone and together with 2 x 10(7) plaque-forming units of VV expressing p53. Intratumoral treatment of established C6 glioma with recombinant viruses rVV-p53, rVV-mIL2, rVV-mIL12, and rVV-2-12 induced the prolonged expression of p53, IL-2, IL-12, and both cytokines simultaneously. The combination of rVV-p53/rVV-mIL 2 or rVV-p53/rVV-2-12 resulted in significant tumor inhibition compared to single modality treatment (P<.05). rVV-p53/rVV-2-12 therapy was associated with significant elevation of natural killer, Mac-1+, and NKT cells in blood and interferon-gamma, and tumor necrosis factor-alpha expression in tumors. The difference in the inhibition of tumor growth between the rVV-p53/rVV-mIL2 combination and rVV-p53 was statistically insignificant. These data demonstrate that gene therapy based on VV-mediated combination of p53, IL-2, and IL-12 treatment may be a promising adjunctive strategy for glioma treatment.