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Intratumoral IL-18 gene transfer improves therapeutic efficacy of antibody-targeted superantigen in established murine melanoma.

Abstract
Antibody-targeted superantigen C215Fab-SEA is a fusion protein of staphylococcal enterotoxin A (SEA) and the Fab region of the tumor-reactive C215 mAb. It can trigger CTL against C215 antigen-positive tumor cells and induce tumor-suppressive cytokines. However, the antitumor effect of C215Fab-SEA is not satisfactory because of suboptimal production of Th1 cytokines after repeated administration. Interleukin 18 (IL-18) is a novel cytokine with profound effects on Th1 cellular response. In this study, we showed that adenovirus-mediated intratumoral IL-18 gene transfer strongly improved the therapeutic efficacy of C215Fab-SEA in the pre-established C215 antigen-expressing B16 melanoma murine model. More significant tumor inhibition and prolonged survival time were observed in tumor-bearing mice received combined therapy of C215Fab-SEA and Ad IL-18 than those of mice treated with C215Fab-SEA or AdIL-18 alone. Combination therapy augmented NK and CTL activities of tumor-bearing mice more markedly. The production of IL-2 and IFN-gamma also increased more significantly. More potent antitumor effect of combined therapy was observed in IL-10 KO mice with enhanced Th1 response. Our data demonstrated that the antitumor effect of C215Fab-SEA immunotherapy could be potentiated significantly by combination with intratumoral IL-18 gene transfer through more efficient activation of Th1 immune responses.
AuthorsQ Wang, H Yu, D W Ju, L He, J P Pan, D J Xia, L H Zhang, X Cao
JournalGene therapy (Gene Ther) Vol. 8 Issue 7 Pg. 542-50 (Apr 2001) ISSN: 0969-7128 [Print] England
PMID11319621 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antigens, Neoplasm
  • Cytokines
  • Enterotoxins
  • Immunoglobulin Fab Fragments
  • Interleukin-18
  • Recombinant Fusion Proteins
  • Superantigens
  • enterotoxin A, Staphylococcal
Topics
  • Adenoviridae (genetics)
  • Animals
  • Antigens, Neoplasm (immunology)
  • Combined Modality Therapy
  • Cytokines (biosynthesis)
  • Cytotoxicity, Immunologic
  • Enterotoxins (immunology)
  • Female
  • Genetic Therapy (methods)
  • Immunoglobulin Fab Fragments (immunology)
  • Interleukin-18 (genetics, immunology)
  • Killer Cells, Natural (immunology)
  • Male
  • Melanoma, Experimental (immunology, pathology, therapy)
  • Mice
  • Mice, Inbred C57BL
  • Recombinant Fusion Proteins (therapeutic use)
  • Spleen (immunology)
  • Staphylococcus aureus (immunology)
  • Superantigens (immunology, therapeutic use)
  • Survival Rate
  • T-Lymphocytes, Cytotoxic (immunology)

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