Abstract 5331: Interleukin-6 as a therapeutic target in advanced ovarian cancer

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC The inflammatory cytokine IL-6 is a major component of an autocrine cytokine network in human ovarian cancer that influences angiogenesis, a stromal signature and leukocyte infiltration. We have used tissue culture experiments, animal models, and data from a Phase II clinical trial in women with advanced ovarian cancer to investigate the therapeutic potential and mechanisms of action of CNTO328, an antibody that neutralises IL-6. In tissue culture, CNTO328 had no effect on growth or survival of ovarian cancer cells that expressed IL-6 receptors and constitutively secreted the ligand. However, it inhibited constitutive production of IL-6 and other inflammatory cytokines and chemokines, including TNF-alpha, IL-8, IL-1beta and CCL2 by the malignant ovarian cells. In intraperitoneal ovarian cancer xenograft models, CNTO328 reduced tumour growth and angiogenesis and decreased transcription of inflammatory cytokines in the tumour microenvironment. Of eighteen patients with advanced, platinum-resistant ovarian cancer treated with CNTO328 in a single arm Phase II trial, there was one partial response, as defined by combined RECIST/CA125 criteria, seven patients experienced periods of disease stabilisation, and in four of these this lasted at least 6 months. Baseline plasma TNF-alpha, IL-8, VEGF, beta2 microglobulin and CRP were significantly lower in patients who had stable disease or partial response. After six weeks therapy, plasma levels of several cytokines were either stable or decreased in patients who had clinical benefit from the anti-IL-6 treatment and TNF-alpha and IL-8 were significantly lower in this group than in those who progressed. Plasma TNF-alpha, IL-8, VEGF and ascites TNF-alpha, IL-8, CCL2 and IL-1beta levels showed a strong decline in the patient with a partial response. We conclude that IL-6 antagonists may have a role to play in the treatment of ovarian cancer. Their actions involve inhibiting production of inflammatory cytokines, chemokines and angiogenic factors that have tumour-promoting actions in the ovarian cancer microenvironment. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5331.