title: IL-6 Inhibition With MEDI5117 Decreases The Fraction of Head and Neck Cancer Stem Cells and Prevents Tumor Recurrence.
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. ALDH(high)CD44(high) 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 ALDH(high)CD44(high) 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.
authors.affiliation: *Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA.
authors.forename: Kelsey A
authors.initials: KA
authors.lastname: Finkel
authors.affiliation: *Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA.
authors.forename: Kristy A
authors.initials: KA
authors.lastname: Warner
authors.affiliation: *Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Kerk
authors.affiliation: Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, MI, USA; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
authors.forename: Carol R
authors.initials: CR
authors.lastname: Bradford
authors.affiliation: Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, MI, USA; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: McLean
authors.affiliation: Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, MI, USA; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Prince
authors.affiliation: MedImmune LLC, Gaithersburg, MD, USA.
authors.forename: Haihong
authors.initials: H
authors.lastname: Zhong
authors.affiliation: MedImmune LLC, Gaithersburg, MD, USA.
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Hurt
authors.affiliation: MedImmune LLC, Gaithersburg, MD, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hollingsworth
authors.affiliation: Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
authors.forename: Max S
authors.initials: MS
authors.lastname: Wicha
authors.affiliation: MedImmune LLC, Gaithersburg, MD, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Tice
authors.affiliation: *Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA; Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, MI, USA; Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI, USA; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA. Electronic address: jenor@umich.edu.
authors.forename: Jacques E
authors.initials: JE
authors.lastname: Nör
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015415:Biomarkers; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D012008:Recurrence; D000077195:Squamous Cell Carcinoma of Head and Neck; D023041:Xenograft Model Antitumor Assays; D000093242:Interleukin-6 Inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D015415:Biomarkers; D015850:Interleukin-6; D000093242:Interleukin-6 Inhibitors