IL-6 Inhibition With MEDI5117 Decreases The Fraction of Head and Neck Cancer Stem Cells and Prevents Tumor Recurrence

• Published in: Neoplasia (New York, N.Y.) Vol. 18; no. 5; pp. 273 - 281
• Main Authors: Finkel, Kelsey A, Warner, Kristy A, Kerk, Samuel, Bradford, Carol R, McLean, Scott A, Prince, Mark E, Zhong, Haihong, Hurt, Elaine M, Hollingsworth, Robert E, Wicha, Max S, Tice, David A, Nör, Jacques E
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2016; Elsevier
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Biomarkers; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Disease Models, Animal; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - mortality; Head and Neck Neoplasms - pathology; Humans; Interleukin-6 - antagonists & inhibitors; Interleukin-6 - metabolism; Mice; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Oncology; Recurrence; Squamous Cell Carcinoma of Head and Neck; Xenograft Model Antitumor Assays
• ISSN: 1476-5586; 1522-8002; 1476-5586; 1522-8002
• DOI: 10.1016/j.neo.2016.03.004

Abstract Head and neck squamous cell carcinomas (HNSCC) exhibit a small population of uniquely tumorigenic cancer stem cells (CSC) endowed with self-renewal and multipotency. We have recently shown that IL-6 enhances the survival and tumorigenic potential of head and neck cancer stem cells ( i.e. ALDHhigh CD44high cells). Here, we characterized the effect of therapeutic inhibition of IL-6 with a novel humanized anti-IL-6 antibody (MEDI5117) using three low-passage patient-derived xenograft (PDX) models of HNSCC. We observed that single agent MEDI5117 inhibited the growth of PDX-SCC-M1 tumors ( P < .05). This PDX model was generated from a previously untreated HNSCC. In contrast, MEDI5117 was not effective at reducing overall tumor volume for PDX models representing resistant disease (PDX-SCC-M0, PDX-SCC-M11). Low dose MEDI5117 (3 mg/kg) consistently decreased the fraction of cancer stem cells in PDX models of HNSCC when compared to IgG-treated controls, as follows: PDX-SCC-M0 ( P < .001), PDX-SCC-M1 ( P < .001), PDX-SCC-M11 ( P = .04). Interestingly, high dose MEDI5117 (30 mg/kg) decreased the CSC fraction in the PDX-SCC-M11 model ( P = .002), but not in PDX-SCC-M0 and PDX-SCC-M1. MEDI5117 mediated a dose-dependent decrease in the number of orospheres generated by ALDHhigh CD44high cells cultured in ultra-low attachment plates ( P < .05), supporting an inhibitory effect on head and neck cancer stem cells. Notably, single agent MEDI5117 reduced the overall recurrence rate of PDX-SCC-M0, a PDX generated from the local recurrence of human HNSCC. Collectively, these data demonstrate that therapeutic inhibition of IL-6 with low-dose MEDI5117 decreases the fraction of cancer stem cells, and that adjuvant MEDI5117 inhibits recurrence in preclinical models of HNSCC.