title: CD137 Stimulation Enhances Cetuximab-Induced Natural Killer: Dendritic Cell Priming of Antitumor T-Cell Immunity in Patients with Head and Neck Cancer.
abstract: OBJECTIVE
  Cetuximab, an EGFR-specific antibody (mAb), modestly improves clinical outcome in patients with head and neck cancer (HNC). Cetuximab mediates natural killer (NK) cell:dendritic cell (DC) cross-talk by cross-linking FcγRIIIa, which is important for inducing antitumor cellular immunity. Cetuximab-activated NK cells upregulate the costimulatory receptor CD137 (4-1BB), which, when triggered by agonistic mAb urelumab, might enhance NK-cell functions, to promote T-cell-based immunity.
  
  
  METHODS
  CD137 expression on tumor-infiltrating lymphocytes was evaluated in a prospective cetuximab neoadjuvant trial, and CD137 stimulation was evaluated in a phase Ib trial, in combining agonistic urelumab with cetuximab. Flow cytometry and cytokine release assays using NK cells and DC were used in vitro, testing the addition of urelumab to cetuximab-activated NK, DC, and cross presentation to T cells.
  
  
  RESULTS
  CD137 agonist mAb urelumab enhanced cetuximab-activated NK-cell survival, DC maturation, and tumor antigen cross-presentation. Urelumab boosted DC maturation markers, CD86 and HLA DR, and antigen-processing machinery (APM) components TAP1/2, leading to increased tumor antigen cross-presentation. In neoadjuvant cetuximab-treated patients with HNC, upregulation of CD137 by intratumoral, cetuximab-activated NK cells correlated with FcγRIIIa V/F polymorphism and predicted clinical response. Moreover, immune biomarker modulation was observed in an open label, phase Ib clinical trial, of patients with HNC treated with cetuximab plus urelumab.
  
  
  CONCLUSIONS
  These results suggest a beneficial effect of combination immunotherapy using cetuximab and CD137 agonist in HNC. Clin Cancer Res; 23(3); 707-16. ©2016 AACR.
authors: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Raghvendra M
authors: RM
authors: Srivastava
authors: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Sumita
authors: S
authors: Trivedi
authors: Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Fernando
authors: F
authors: Concha-Benavente
authors: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Sandra P
authors: SP
authors: Gibson
authors: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Carly
authors: C
authors: Reeder
authors: Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors: Soldano
authors: S
authors: Ferrone
authors: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania. ferrisrl@upmc.edu.|Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.|Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors: Robert L
authors: RL
authors: Ferris
mesh_terms: D053330:4-1BB Ligand / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology*; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005838:Genotype; D006258:Head and Neck Neoplasms / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects* / Q000276:immunology; D011110:Polymorphism, Genetic; D020239:Receptor Cross-Talk / Q000187:drug effects; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000819:agonists / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D053330:4-1BB Ligand; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000074322:Antineoplastic Agents, Immunological; D016207:Cytokines; C496124:FCGR3A protein, human; D017452:Receptors, IgG; C505974:TNFSF9 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; C000620833:urelumab; D000068818:Cetuximab