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

Gene Therapy volume 8, pages 542–550 (2001)Cite this article

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-γ 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.

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Acknowledgements

We would like to acknowledge the gifts of C215Fab-SEA, C242Fab-SEA, C215Mab, SEA, plasmid PKGE839 from Active Biotech Research AB (Sweden). This work was supported by grants from the National Natural Science Foundation of China (No. 39770837 and No. 39730420).

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Authors and Affiliations

  1. Institute of Immunology, Zhejiang University, Hangzhou, P.R. China

    Q Wang, J P Pan, D J Xia, L H Zhang & X Cao

  2. Cancer Institute, Zhejiang University, Hangzhou, P.R. China

    H Yu

  3. Department of Immunology, Second Military Medical University, Shanghai, P.R. China

    D W Ju, L He & X Cao

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  1. Q Wang
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  2. H Yu
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H Yu, Cancer Institute, Zhejiang University, 68 Jiefang Road, Hangzhou, 310009, PR China

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Wang, Q., Yu, H., Ju, D. et al. Intratumoral IL-18 gene transfer improves therapeutic efficacy of antibody-targeted superantigen in established murine melanoma. Gene Ther 8, 542–550 (2001). https://doi.org/10.1038/sj.gt.3301428

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