The effects of anti-IL-6 therapy in advanced ovarian cancer
IL-6 is a pleiotropic cytokine that has a significant role in inflammatory processes. In relation to ovarian cancer biology there is emerging evidence that it mediates processes relating to tumour growth, invasion, angiogenesis and chemo-resistance that lead to disease with poor prognosis. The aim of this thesis was to evaluate the efficacy and mechanism of action of an anti-human IL-6 antibody, CNTO328, in ovarian cancer. These aims were achieved with a clinical trial that was conducted in parallel with pre-clinical experiments. 18 patients with advanced platinum-resistant ovarian cancer were treated with CNTO328 in a phase II clinical trial. One patient had a partial response and seven patients attained stable disease at the end of the initial 6-week study period with correlations seen between clinical benefit and baseline levels of CRP, β2- microglobulin, TNF-α, IL-8 and VEGF. Four patients completed 6 months of treatment and had significantly decreased plasma CCL2 and increased sgp130 concentrations. Furthermore, immunohistochemical analysis of diagnostic biopsies suggested that clinical benefit was related to a lower macrophage infiltrate and increased stromal expression of IL-6, IL-6 receptors and SOCS3. I have found two ovarian cancer cell lines that secreted IL-6 and expressed both components of the IL-6 receptor signalling complex. When these cells were grown on plastic, CNTO328 had no effect on cell proliferation or survival. This suggested that IL-6 was not a growth factor for ovarian cancer cells in vitro. However, CNTO328 reduced constitutive secretion of IL-6, IL-1β, TNF-α, IL-8 and CCL2 by the ovarian cancer cells. The in vivo studies with human ovarian cancer xenograft models in nude mice showed that anti-IL-6 treatment had biological activity by inhibiting cell proliferation, macrophage infiltration and angiogenesis. In conclusion, the xenograft models and cell line experiments together with the clinical trial show that IL-6 may be a therapeutic target in ovarian cancer and exhibits both autocrine and paracrine actions within the ovarian cancer microenvironment.
- Theses