Oncolytic adenovirus co-expressing IL-12 and IL-18 improves tumor-specific immunity via differentiation of T cells expressing IL-12Rβ2 or IL-18Rα

Gene Ther. 2011 Sep;18(9):898-909. doi: 10.1038/gt.2011.37. Epub 2011 Mar 31.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Cell Differentiation
  • Cell Line, Tumor
  • Genetic Therapy / methods*
  • Interleukin-12 / genetics*
  • Interleukin-12 / metabolism
  • Interleukin-18 / genetics*
  • Interleukin-18 / metabolism
  • Male
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / therapy*
  • Mice
  • Mice, Inbred C57BL
  • Oncolytic Virotherapy / methods*
  • Oncolytic Viruses
  • Receptors, Interleukin-12 / metabolism*
  • Receptors, Interleukin-18 / metabolism*
  • T-Lymphocytes / immunology*

Substances

  • IL12RB2 protein, human
  • Interleukin-18
  • Receptors, Interleukin-12
  • Receptors, Interleukin-18
  • Interleukin-12