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Interleukin-6 as a Therapeutic Target in Human Ovarian Cancer

Coward, Jermaine; Kulbe, Hagen; Chakravarty, Probir; Leader, David; Vassileva, Vessela; Leinster, D. Andrew; Thompson, Richard; Schioppa, Tiziana; Nemeth, Jeffery and Vermeulen, Jessica, et al. (2011) In Clinical Cancer Research 17(18). p.6083-6096
Abstract
Purpose: We investigated whether inhibition of interleukin 6 (IL-6) has therapeutic activity in ovarian cancer via abrogation of a tumor-promoting cytokine network. Experimental Design: We combined preclinical and in silico experiments with a phase 2 clinical trial of the anti-IL-6 antibody siltuximab in patients with platinum-resistant ovarian cancer. Results: Automated immunohistochemistry on tissue microarrays from 221 ovarian cancer cases showed that intensity of IL-6 staining in malignant cells significantly associated with poor prognosis. Treatment of ovarian cancer cells with siltuximab reduced constitutive cytokine and chemokine production and also inhibited IL-6 signaling, tumor growth, the tumor-associated macrophage infiltrate... (More)
Purpose: We investigated whether inhibition of interleukin 6 (IL-6) has therapeutic activity in ovarian cancer via abrogation of a tumor-promoting cytokine network. Experimental Design: We combined preclinical and in silico experiments with a phase 2 clinical trial of the anti-IL-6 antibody siltuximab in patients with platinum-resistant ovarian cancer. Results: Automated immunohistochemistry on tissue microarrays from 221 ovarian cancer cases showed that intensity of IL-6 staining in malignant cells significantly associated with poor prognosis. Treatment of ovarian cancer cells with siltuximab reduced constitutive cytokine and chemokine production and also inhibited IL-6 signaling, tumor growth, the tumor-associated macrophage infiltrate and angiogenesis in IL-6-producing intraperitoneal ovarian cancer xenografts. In the clinical trial, the primary endpoint was response rate as assessed by combined RECIST and CA125 criteria. One patient of eighteen evaluable had a partial response, while seven others had periods of disease stabilization. In patients treated for 6 months, there was a significant decline in plasma levels of IL-6-regulated CCL2, CXCL12, and VEGF. Gene expression levels of factors that were reduced by siltuximab treatment in the patients significantly correlated with high IL-6 pathway gene expression and macrophage markers in microarray analyses of ovarian cancer biopsies. Conclusion: IL-6 stimulates inflammatory cytokine production, tumor angiogenesis, and the tumor macrophage infiltrate in ovarian cancer and these actions can be inhibited by a neutralizing anti-IL-6 antibody in preclinical and clinical studies. Clin Cancer Res; 17(18); 6083-96. (C) 2011 AACR. (Less)
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Clinical Cancer Research
volume
17
issue
18
pages
6083 - 6096
publisher
American Association for Cancer Research
external identifiers
  • wos:000294952400026
  • scopus:80052855899
ISSN
1078-0432
DOI
10.1158/1078-0432.CCR-11-0945
language
English
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yes
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dea1154f-9549-4848-b101-8728b1edebae (old id 2183561)
date added to LUP
2011-10-24 15:29:20
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2017-11-19 03:10:48
@article{dea1154f-9549-4848-b101-8728b1edebae,
  abstract     = {Purpose: We investigated whether inhibition of interleukin 6 (IL-6) has therapeutic activity in ovarian cancer via abrogation of a tumor-promoting cytokine network. Experimental Design: We combined preclinical and in silico experiments with a phase 2 clinical trial of the anti-IL-6 antibody siltuximab in patients with platinum-resistant ovarian cancer. Results: Automated immunohistochemistry on tissue microarrays from 221 ovarian cancer cases showed that intensity of IL-6 staining in malignant cells significantly associated with poor prognosis. Treatment of ovarian cancer cells with siltuximab reduced constitutive cytokine and chemokine production and also inhibited IL-6 signaling, tumor growth, the tumor-associated macrophage infiltrate and angiogenesis in IL-6-producing intraperitoneal ovarian cancer xenografts. In the clinical trial, the primary endpoint was response rate as assessed by combined RECIST and CA125 criteria. One patient of eighteen evaluable had a partial response, while seven others had periods of disease stabilization. In patients treated for 6 months, there was a significant decline in plasma levels of IL-6-regulated CCL2, CXCL12, and VEGF. Gene expression levels of factors that were reduced by siltuximab treatment in the patients significantly correlated with high IL-6 pathway gene expression and macrophage markers in microarray analyses of ovarian cancer biopsies. Conclusion: IL-6 stimulates inflammatory cytokine production, tumor angiogenesis, and the tumor macrophage infiltrate in ovarian cancer and these actions can be inhibited by a neutralizing anti-IL-6 antibody in preclinical and clinical studies. Clin Cancer Res; 17(18); 6083-96. (C) 2011 AACR.},
  author       = {Coward, Jermaine and Kulbe, Hagen and Chakravarty, Probir and Leader, David and Vassileva, Vessela and Leinster, D. Andrew and Thompson, Richard and Schioppa, Tiziana and Nemeth, Jeffery and Vermeulen, Jessica and Singh, Naveena and Avril, Norbert and Cummings, Jeff and Rexhepaj, Elton and Jirström, Karin and Gallagher, William M. and Brennan, Donal J. and McNeish, Iain A. and Balkwill, Frances R.},
  issn         = {1078-0432},
  language     = {eng},
  number       = {18},
  pages        = {6083--6096},
  publisher    = {American Association for Cancer Research},
  series       = {Clinical Cancer Research},
  title        = {Interleukin-6 as a Therapeutic Target in Human Ovarian Cancer},
  url          = {http://dx.doi.org/10.1158/1078-0432.CCR-11-0945},
  volume       = {17},
  year         = {2011},
}