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

被引:25
作者
Wang, Q
Yu, H
Ju, DW
He, L
Pan, JP
Xia, DJ
Zhang, LH
Cao, X
机构
[1] Zhejiang Univ, Inst Immunol, Hangzhou 310031, Peoples R China
[2] Zhejiang Univ, Inst Canc, Hangzhou 310009, Peoples R China
[3] Second Mil Med Univ, Dept Immunol, Shanghai, Peoples R China
基金
中国国家自然科学基金;
关键词
antibody-targeted superantigen; interleukin-18; adenovirus; gene therapy; antitumor effect; melanoma;
D O I
10.1038/sj.gt.3301428
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:542 / 550
页数:9
相关论文
共 49 条
[31]   TUMOR-SELECTIVE CYTO-TOXIC EFFECTS OF MURINE TUMOR NECROSIS FACTOR (TNF) AND INTERFERON-GAMMA (IFN-GAMMA) IN ORGAN-CULTURE OF B-16 MELANOMA-CELLS AND HEART-TISSUE [J].
MAREEL, M ;
DRAGONETTI, C ;
TAVERNIER, J ;
FIERS, W .
INTERNATIONAL JOURNAL OF CANCER, 1988, 42 (03) :470-473
[32]  
MASAYUKI U, 2000, J VIROL, V74, P8226
[33]   In vivo antitumor effects of murine interferon-gamma-inducing factor/interleukin-18 in mice bearing syngeneic Meth A sarcoma malignant ascites [J].
Micallef, MJ ;
Yoshida, K ;
Kawai, S ;
Hanaya, T ;
Kohno, K ;
Arai, S ;
Tanimoto, T ;
Torigoe, K ;
Fujii, M ;
Ikeda, M ;
Kurimoto, M .
CANCER IMMUNOLOGY IMMUNOTHERAPY, 1997, 43 (06) :361-367
[34]   Interferon-gamma-inducing factor enhances T helper 1 cytokine production by stimulated human T cells: Synergism with interleukin-12 for interferon-gamma production [J].
Micallef, MJ ;
Ohtsuki, T ;
Kohno, K ;
Tanabe, F ;
Ushio, S ;
Namba, M ;
Tanimoto, T ;
Torigoe, K ;
Fuji, M ;
Ikeda, M ;
Fukuda, S ;
Kurimoto, M .
EUROPEAN JOURNAL OF IMMUNOLOGY, 1996, 26 (07) :1647-1651
[35]  
Micallef MJ, 1997, CANCER RES, V57, P4557
[36]   Antitumor effects on mouse melanoma elicited by local secretion of interleukin-12 and their enhancement by treatment with interleukin-18 [J].
Nagai, H ;
Hara, I ;
Horikawa, T ;
Fujii, M ;
Kurimoto, M ;
Kamidono, S ;
Ichihashi, M .
CANCER INVESTIGATION, 2000, 18 (03) :206-213
[37]   Phase I study of single, escalating doses of a superantigen-antibody fusion protein (PNU-214565) in patients with advanced colorectal or pancreatic carcinoma [J].
Nielsen, SE ;
Zeuthen, J ;
Lund, B ;
Persson, B ;
Alenfall, J ;
Hansen, HH .
JOURNAL OF IMMUNOTHERAPY, 2000, 23 (01) :146-153
[38]   CLONING OF A NEW CYTOKINE THAT INDUCES IFN-GAMMA PRODUCTION BY T-CELLS [J].
OKAMURA, H ;
TSUTSUI, H ;
KOMATSU, T ;
YUTSUDO, M ;
HAKURA, A ;
TANIMOTO, T ;
TORIGOE, K ;
OKURA, T ;
NUKADA, Y ;
HATTORI, K ;
AKITA, K ;
NAMBA, M ;
TANABE, F ;
KONISHI, K ;
FUKUDA, S ;
KURIMOTO, M .
NATURE, 1995, 378 (6552) :88-91
[39]  
OSWALD IP, 1992, J IMMUNOL, V148, P3578
[40]   Cancer vaccines [J].
Pardoll, DM .
NATURE MEDICINE, 1998, 4 (05) :525-531