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Curr Med Chem. 2018;25(36):4785-4806. doi: 10.2174/0929867324666170712160621.

Immunotherapeutic Interleukin-6 or Interleukin-6 Receptor Blockade in Cancer: Challenges and Opportunities.

Author information

1
Department of Immunology & Pathology, Monash University, Level 6, The Alfred, Commercial Road, Melbourne 3181, VIC, Australia.
2
Gynae-oncology Unit, Royal Women's Hospital, 20 Flemington Road, Parkville, Melbourne, Victoria 3052, Australia.
3
Department of Obstetrics and Gynaecology, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
4
Epworth Research Institute, Epworth Healthcare, Richmond, Australia.
5
Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Australia.
6
Department of Molecular and Translational Sciences, Monash University, Clayton, Australia.
7
Monash Institute of Medical Engineering, Monash University, Melbourne, Australia.

Abstract

Interleukin 6 (IL-6), a well-known pro-inflammatory cytokine with pleiotropic activity is a central player in chronic inflammatory diseases including cancers. Therefore, blockade of the IL-6 signalling pathway has become a target for the therapy of diverse cancers such as multicentric Castleman's disease (CD), multiple myeloma and solid tumours including renal, prostate, lung, colorectal and ovarian cancers. Monoclonal antibodies against IL-6 (Siltuximab) and the IL-6 receptor (IL-6R) (Tocilizumab) have emerged as potential immunotherapies, alone or in combination with conventional chemotherapy. Human trials have demonstrated the ability to block IL-6 activity and in multicentric CD lead to durable clinical response and longer disease stabilisation. However, the efficacy of these treatments is still debatable for other cancers. New generation therapeutics in development such as Clazakizumab, Sarilumab, and soluble gp130-Fc have the additional features of improved binding affinity, better specificity with reduced adverse effects. A deeper understanding of the immunological basis of these agents, as well as of the challenges that are faced by immunotherapy-based products in clinical trials, will help select the most promising anti-IL-6/IL-6R therapies for large scale use. Concurrently, current research efforts to personalize treatments may help in the treatment of patients that would greatly benefit from IL-6 blocking therapies.

KEYWORDS:

IL-6; IL-6 receptor; JAK-STAT signalling pathway; STAT-3; cancer; immunotherapy; monoclonal antibodies; pro-inflammatory cytokine.

[Indexed for MEDLINE]

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