title: The activation of natural killer cell effector functions by cetuximab-coated, epidermal growth factor receptor positive tumor cells is enhanced by cytokines.
abstract: OBJECTIVE
  Natural killer (NK) cells express an activating Fc receptor (FcgammaRIIIa) that mediates antibody-dependent cellular cytotoxicity (ADCC) and production of immune modulatory cytokines in response to antibody-coated targets. Cetuximab is a therapeutic monoclonal antibody directed against the HER1 antigen. We hypothesized that the NK cell response to cetuximab-coated tumor cells could be enhanced by the administration of NK cell-stimulatory cytokines.
  
  
  METHODS
  Human NK cells stimulated with cetuximab-coated tumor cells and interleukin-2 (IL-2), IL-12, or IL-21 were assessed for ADCC and secretion of IFN-gamma and T cell-recruiting chemokines. IL-21 and cetuximab were given to nude mice bearing HER1-positive xenografts.
  
  
  RESULTS
  Stimulation of human NK cells with cetuximab-coated tumor cells and IL-2, IL-12, or IL-21 resulted in 3-fold to 10-fold higher IFN-gamma production than was observed with either agent alone. NK cell-derived IFN-gamma significantly enhanced monocyte ADCC against cetuximab-coated tumor cells. Costimulated NK cells also secreted elevated levels of chemokines (IL-8, macrophage inflammatory protein-1alpha, and RANTES) that could direct the migration of naive and activated T cells. IL-2, IL-12, and IL-21 enhanced NK cell ADCC against tumor cells treated with cetuximab. The combination of cetuximab, trastuzumab (an anti-HER2 monoclonal antibody), and IL-21 mediated greater NK cell cytokine secretion and ADCC than any agent alone. Furthermore, administration of IL-21 enhanced the effects of cetuximab in a murine tumor model.
  
  
  CONCLUSIONS
  These results show that cetuximab-mediated NK cell activity can be significantly enhanced in the presence of NK cell-stimulatory cytokines. These factors, therefore, may be effective adjuvants to administer, in combination with cetuximab, to patients with HER1-positive malignancies.
authors.affiliation: Integrated Biomedical Sciences Graduate Program, Arthur G. James Comprehensive Cancer Center and Solove Research Institute, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Roda
authors.forename: Trupti
authors.initials: T
authors.lastname: Joshi
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Butchar
authors.forename: Jaclyn W
authors.initials: JW
authors.lastname: McAlees
authors.forename: Amy
authors.initials: A
authors.lastname: Lehman
authors.forename: Susheela
authors.initials: S
authors.lastname: Tridandapani
authors.forename: William E
authors.initials: WE
authors.lastname: Carson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage; D045744:Cell Line, Tumor; D000068818:Cetuximab; D016207:Cytokines / Q000378:metabolism*; D004357:Drug Synergism; D066246:ErbB Receptors / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D007107:Immune System; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D007694:Killer Cells, Natural / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects; D008495:Medical Oncology / Q000379:methods; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D000098546:Interleukin-21
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D016207:Cytokines; D007376:Interleukin-2; D007378:Interleukins; D018664:Interleukin-12; D007371:Interferon-gamma; C512478:EGFR protein, human; D066246:ErbB Receptors; D000098546:Interleukin-21; D000068818:Cetuximab