Why not treat human cancer with interleukin-1 blockade?
- Charles A. DinarelloAffiliated withDepartment of Medicine, University of ColoradoDepartment of Medicine, Radboud University, Nijmegen Medical Center Email author
The clinical successes of targeting angiogenesis provide a basis for trials of interleukin-1 (IL-1) blockade and particularly anti-IL-1β as an add-on therapy in human metastatic disease. In animal studies for over 20 years, IL-1 has been demonstrated to increase adherence of tumor cells to the endothelium in vitro, and administration of IL-1 to mice increases the number of metastatic colonies and tumor growth. Importantly, reducing endogenous IL-1 activity, particularly IL-1β, with the naturally occurring IL-1 receptor antagonist (IL-1Ra) reduces both metastasis as well as tumor burden. Inhibition of IL-1 activity prevents in vivo blood vessel formation induced by products released from hypoxic macrophages or vascular endothelial cell growth factor itself. Mice deficient in IL-1β do not form blood vessels in matrigels embedded with vascular endothelial cell growth factor or containing products of macrophages. Recombinant IL-1Ra (anakinra) has been administered to over 1,000 patients with septic shock resulting in a consistent reduction in all-cause 28-day mortality. Approved for treatment of rheumatoid arthritis, anakinra has a remarkable safety record. Anakinra resulted in decreased blood vessels in the pannus of affected joints in patients with rheumatoid arthritis. Neutralizing monoclonal antibodies to IL-1β and a soluble receptor to IL-1 are approved for treating chronic inflammatory diseases. Given the availability of three therapeutic agents for limiting IL-1 activity, the safety of blocking IL-1, and the clear benefit of blocking IL-1 activity in animal models of metastasis and angiogenesis, clinical trials of IL-1 blockade should be initiated, particularly as an add-on therapy of patients receiving antiangiogenesis-based therapies.
KeywordsCytokines Inflammation Angiogenesis Inflammasome Necrosis Endothelium Innate immune response
- Why not treat human cancer with interleukin-1 blockade?
- Open Access
- Available under Open Access This content is freely available online to anyone, anywhere at any time.
Cancer and Metastasis Reviews
Volume 29, Issue 2 , pp 317-329
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- Springer US
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- Innate immune response
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- Charles A. Dinarello (1) (2)
- Author Affiliations
- 1. Department of Medicine, University of Colorado, 12700 East 19th Ave., B168, Aurora, CO, 80045, USA
- 2. Department of Medicine, Radboud University, Nijmegen Medical Center, Nijmegen, The Netherlands