Interleukin-6 as a Therapeutic Target

Abstract

Human IL6 is a cytokine produced by many cell types that has pleiotropic effects. In agreement, anti-IL6 therapy reduces inflammation, hepatic acute phase proteins, and anemia and has antiangiogenic effects. Blocking IL6 has demonstrated therapeutic efficacy with drug registration in Castleman disease and inflammatory diseases (rheumatoid arthritis) without major toxicity. Interestingly, the inhibition of C-reactive protein (CRP) production is a trustworthy surrogate marker of anti-IL6 therapy efficacy. Clinically registered IL6 inhibitors include siltuximab, an anti-IL6 mAb, and tocilizumab, an anti-IL6R mAb. In various cancers, in particular plasma cell cancers, large randomized trials showed no efficacy of IL6 inhibitors, despite a full inhibition of CRP production in treated patients in vivo, the numerous data showing an involvement of IL6 in these diseases, and initial short-term treatments demonstrating a dramatic inhibition of cancer cell proliferation in vivo. A likely explanation is the plasticity of cancer cells, with the presence of various subclones, making the outgrowth of cancer subclones possible using growth factors other than IL6. In addition, current therapeutic strategies used in these cancers already target IL6 activity. Thus, anti-IL6 therapeutics are able to neutralize IL6 production in vivo and are safe and useful in inflammatory diseases and Castleman disease.

A Randomized Phase II/III Study of Naptumomab Estafenatox + IFNα versus IFNα in Renal Cell Carcinoma: Final Analysis with Baseline Biomarker Subgroup and Trend Analysis

“…IL6 is a pleiotropic cytokine (16)(17)(18). Healthy individuals have low and rather stable systemic daytime levels of IL6 although that there are some diurnal variation (19)(20)(21).…”

Prognostic Significance of Preoperative Thrombocytosis in Patients with Endometrial Carcinoma: Our Experience and Review of the Literature

“…It is not unlikely that other malignant tumors also boost platelet production via IL-6 synthesis. If this hypothesis holds true, IL-6 production emerges as a potential therapeutic target for antitumor agents [21]. Indeed, this concept is already being tested in clinical trials with IL-6 blocking agents like siltuximab (http:// www.cancer.gov/cancertopics/treatment/drugs/fda-siltuximab).…”

Castleman's Disease

“…Son yıllarda biyolojik ajanlar, IL-6 ve reseptörleri ile yapılan çalışmalar sürmektedir. 9,10 Yakınması ve sistemik bulguları olmayan olgumuzda cerrahi ile kür sağ-lanmış ve olgu izlem altına alınmıştır.…”