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

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.
AuthorsI-K Choi, J-S Lee, S-N Zhang, J Park, C H Sonn, K-M Lee, C-O Yun
JournalGene therapy (Gene Ther) Vol. 18 Issue 9 Pg. 898-909 (Sep 2011) ISSN: 1476-5462 [Electronic] England
PMID21451575 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • IL12RB2 protein, human
  • Interleukin-18
  • Receptors, Interleukin-12
  • Receptors, Interleukin-18
  • Interleukin-12
Topics
  • Adenoviridae (genetics)
  • Animals
  • Cell Differentiation
  • Cell Line, Tumor
  • Genetic Therapy (methods)
  • Interleukin-12 (genetics, metabolism)
  • Interleukin-18 (genetics, metabolism)
  • Male
  • Melanoma, Experimental (immunology, therapy)
  • Mice
  • Mice, Inbred C57BL
  • Oncolytic Virotherapy (methods)
  • Oncolytic Viruses
  • Receptors, Interleukin-12 (metabolism)
  • Receptors, Interleukin-18 (metabolism)
  • T-Lymphocytes (immunology)

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