title: Anti-EGFR Targeted Monoclonal Antibody Isotype Influences Antitumor Cellular Immunity in Head and Neck Cancer Patients.
abstract: OBJECTIVE
  EGF receptor (EGFR) is highly overexpressed on several cancers and two targeted anti-EGFR antibodies which differ by isotype are FDA-approved for clinical use. Cetuximab (IgG1 isotype) inhibits downstream signaling of EGFR and activates antitumor, cellular immune mechanisms. As panitumumab (IgG2 isotype) may inhibit downstream EGFR signaling similar to cetuximab, it might also induce adaptive immunity.
  
  
  METHODS
  We measured in vitro activation of cellular components of the innate and adaptive immune systems. We also studied the in vivo activation of components of the adaptive immune system in patient specimens from two recent clinical trials using cetuximab or panitumumab.
  
  
  RESULTS
  Both monoclonal antibodies (mAb) primarily activate natural killer (NK) cells, although cetuximab is significantly more potent than panitumumab. Cetuximab-activated neutrophils mediate antibody-dependent cellular cytotoxicity (ADCC) against head and neck squamous cell carcinomas (HNSCC) tumor cells, and interestingly, this effect was FcγRIIa- and FcγRIIIa genotype-dependent. Panitumumab may activate monocytes through CD32 (FcγRIIa); however, monocytes activated by either mAb are not able to mediate ADCC. Cetuximab enhanced dendritic cell (DC) maturation to a greater extent than panitumumab, which was associated with improved tumor antigen cross-presentation by cetuximab compared with panitumumab. This correlated with increased EGFR-specific cytotoxic CD8+T cells in patients treated with cetuximab compared with those treated with panitumumab.
  
  
  CONCLUSIONS
  Although panitumumab effectively inhibits EGFR signaling to a similar extent as cetuximab, it is less effective at triggering antitumor, cellular immune mechanisms which may be crucial for effective therapy of HNSCC. Clin Cancer Res; 22(21); 5229-37. ©2016 AACR.
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Sumita
authors.initials: S
authors.lastname: Trivedi
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Raghvendra M
authors.initials: RM
authors.lastname: Srivastava
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Fernando
authors.initials: F
authors.lastname: Concha-Benavente
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Soldano
authors.initials: S
authors.lastname: Ferrone
authors.affiliation: Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Garcia-Bates
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania. ferrrl@upmc.edu.|University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.|Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ferris
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000276:immunology; D000068818:Cetuximab / Q000276:immunology / Q000627:therapeutic use; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D000077544:Panitumumab; D017452:Receptors, IgG / Q000276:immunology; D000077195:Squamous Cell Carcinoma of Head and Neck; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; C080568:Fc gamma receptor IIA; C080572:Fc gamma receptor IIC; D007074:Immunoglobulin G; D017452:Receptors, IgG; D000077544:Panitumumab; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab