Neutralization of IL-8 prevents the induction of dermatologic adverse events associated with the inhibition of epidermal growth factor receptor

• Published in: PloS one Vol. 7; no. 6; p. e39706
• Main Authors: Bangsgaard, Nannie, Houtkamp, Mischa, Schuurhuis, Danita H, Parren, Paul W H I, Baadsgaard, Ole, Niessen, Hans W M, Skov, Lone
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 25.06.2012; Public Library of Science (PLoS)
• Subjects: Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - pharmacology; Biology; Biopsy; Breast cancer; Cancer; Cancer therapies; Cancer treatment; Chemokines; Cytokines; Epidermal growth factor; Epidermal growth factor receptors; Epidermal growth factors; Exanthema; Fibroblasts; Hair; Health aspects; Histology; Humans; Immunoglobulins; Immunohistochemistry; Inflammation; Inhibition; Inhibitors; Injection; Injections, Subcutaneous; Interleukin 8; Interleukin-8 - immunology; Kinases; Leukocytes (neutrophilic); Lung cancer; Medicine; Monoclonal antibodies; Neutralization; Neutralization Tests; Neutrophils; Patient compliance; Patients; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Rodents; Skin; Skin Diseases - chemically induced; Skin Diseases - pathology; Skin Diseases - prevention & control; TNF inhibitors; Tumor necrosis factor-TNF; Tumorigenesis; Netherlands
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0039706

Epidermal growth factor receptor (EGFR) inhibitors are widely used in the treatment of cancer. EGFR-targeted treatment is known to be associated with a high incidence of dermatological adverse reactions, including papulopustular rash, which can be dose-limiting and may affect compliance to treatment. Currently, the pathways involved in EGFR inhibitor-induced rash are poorly understood and few treatment options for this adverse event are available. Here, we developed a model for induction of papulopustular rash in healthy human volunteers by subcutaneous injection of the anti-EGFR monoclonal antibody zalutumumab. The injection sites and surrounding skin were evaluated by a dermatologist for the presence or absence of papulopustular rash and skin biopsies were taken to confirm the macroscopical findings by immunohistochemistry. Locally injected zalutumumab induced a papulopustular rash, characterized by acute follicular neutrophil-rich hair follicle inflammation, and thus mimicked adverse events induced by systemic administration of EGFR inhibitors. In this model, we tested the hypothesis that neutrophils, attracted by IL-8, play a central role in the observed rash. Indeed, concomitant local repeat dose treatment with HuMab-10F8, a neutralizing human antibody against IL-8, reduced the rash. Inhibition of IL-8 can therefore ameliorate dermatological adverse events induced by treatment with EGFR inhibitors.