Interleukin-6 as a therapeutic target in human ovarian cancer.

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.

• Authors: Jermaine Coward, Hagen Kulbe, Probir Chakravarty, David Leader, Vessela Vassileva, D Andrew Leinster, Richard Thompson, Tiziana Schioppa, Jeffery Nemeth, Jessica Vermeulen, Naveena Singh, Norbert Avril, Jeff Cummings, Elton Rexhepaj, Karin Jirström, William M Gallagher, Donal J Brennan, Iain A McNeish, Frances R Balkwill
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 18 Pg. 6083-96 (Sep 15 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21795409 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR.

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Biomarkers
• Interleukin-6
• Receptors, Interleukin-6
• siltuximab

Topics

• Animals
• Antibodies, Monoclonal (pharmacokinetics, therapeutic use)
• Antineoplastic Agents (pharmacokinetics, therapeutic use)
• Biomarkers (blood)
• Cell Line, Tumor
• Computational Biology
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Interleukin-6 (antagonists & inhibitors, metabolism)
• Kaplan-Meier Estimate
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Ovarian Neoplasms (diagnosis, drug therapy, metabolism, mortality)
• Prognosis
• Receptors, Interleukin-6 (metabolism)
• Signal Transduction
• Treatment Outcome
• Xenograft Model Antitumor Assays