The oncolytic adenovirus (Ad) is currently being advanced as a promising antitumor remedy as it selectively replicates in
tumor cells and can transfer and amplify therapeutic genes.
Interleukin (IL)-12 induces a potent antitumor effect by promoting natural killer (NK) cell and cytotoxic T cell activities.
IL-18 also augments cytotoxicity of NK cells and proliferation of T cells. This effect further enhances the function of
IL-12 in a synergistic manner. Therefore, we investigated for the first time an effective
cancer immunogene
therapy of syngeneic
tumors via intratumoral administration of oncolytic Ad co-expressing
IL-12 and
IL-18, RdB/
IL-12/IL-18. Intratumoral administration of RdB/
IL-12/IL-18 improved antitumor effects, as well as increased survival, in B16-F10 murine
melanoma model. The ratio of T-helper type 1/2
cytokine as well as the levels of
IL-12,
IL-18,
interferon-γ and
granulocyte-macrophage colony-stimulating factor was markedly elevated in RdB/
IL-12/IL-18-treated
tumors. Mice injected with RdB/
IL-12/IL-18 also showed enhanced cytotoxicity of
tumor-specific immune cells. Consistent with these results, immense
necrosis and infiltration of NK cells, as well as CD4+ and CD8+ T cells, were observed in RdB/
IL-12/IL-18-treated
tumor tissues. Importantly,
tumors treated with RdB/
IL-12/IL-18 showed an elevated number of T cells expressing IL-12Rβ2 or IL-18Rα. These results provide a new insight into therapeutic mechanisms of
IL-12 plus
IL-18 and provide a potential clinical
cancer immunotherapeutic agent for improved antitumor immunity.