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

• Published in: Gene therapy Vol. 8; no. 7; pp. 542 - 550
• Main Authors: WANG, Q, YU, H, JU, D. W, HE, L, PAN, J. P, XIA, D. J, ZHANG, L. H, CAO, X
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.04.2001
• Subjects: Adenoviridae - genetics; Adenovirus; Animal models; Animals; Antigens; Antigens, Neoplasm - immunology; Antitumor activity; Biological and medical sciences; Biotechnology; Combined Modality Therapy; Cytokines; Cytokines - biosynthesis; Cytotoxicity; Cytotoxicity, Immunologic; Enterotoxins - immunology; Female; Fundamental and applied biological sciences. Psychology; Fusion protein; Gene therapy; Gene transfer; Genetic Therapy - methods; Health. Pharmaceutical industry; Immune response; Immunoglobulin Fab Fragments - immunology; Immunotherapy; Industrial applications and implications. Economical aspects; Interleukin 10; Interleukin 18; Interleukin 2; Interleukin-18 - genetics; Interleukin-18 - immunology; Killer Cells, Natural - immunology; Lymphocytes T; Male; Melanoma; Melanoma, Experimental - immunology; Melanoma, Experimental - pathology; Melanoma, Experimental - therapy; Mice; Mice, Inbred C57BL; Monoclonal antibodies; Recombinant Fusion Proteins - therapeutic use; Spleen - immunology; Staphylococcal enterotoxin A; Staphylococcus aureus - immunology; Superantigens - immunology; Superantigens - therapeutic use; Survival Rate; T-Lymphocytes, Cytotoxic - immunology; Tumor cells; γ-Interferon; Antineoplastic agent; Animal model; Adenoviridae; Immune response; Targeting; Cytokine; Rodentia; Melanoma; Interleukin 18; Genetic transfer; Virus; Vertebrata; Mammalia; Mouse; Immunotherapy; Fusion protein; Gene therapy
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/sj.gt.3301428

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.