Anti-EGFR antibody cetuximab enhances the cytolytic activity of natural killer cells toward osteosarcoma

Clin Cancer Res. 2012 Jan 15;18(2):432-41. doi: 10.1158/1078-0432.CCR-11-2277. Epub 2011 Nov 16.

Abstract

Purpose: Osteosarcoma and Ewing's sarcoma are the most common bone tumors in children and adolescents. Despite intensive chemotherapy, patients with advanced disease have a poor prognosis, illustrating the need for alternative therapies. Sarcoma cells are susceptible to the cytolytic activity of resting natural killer (NK) cells which can be improved by interleukin (IL)-15 stimulation. In this study, we explored whether the cytolytic function of resting NK cells can be augmented and specifically directed toward sarcoma cells by antibody-dependent cellular cytotoxicity (ADCC).

Experimental design: Epidermal growth factor receptor (EGFR) expression was examined on osteosarcoma and Ewing's sarcoma cell lines by flow cytometry and in osteosarcoma biopsy and resection specimens by immunohistochemistry. Cetuximab-mediated ADCC by NK cells from osteosarcoma patients and healthy controls was measured with 4-hour (51)Cr release assays.

Results: EGFR surface expression was shown on chemotherapy-sensitive and chemotherapy-resistant osteosarcoma cells (12/12), most primary osteosarcoma cultures (4/5), and few Ewing's sarcoma cell lines (2/7). In the presence of cetuximab, the cytolytic activity of resting NK cells against all EGFR-expressing sarcoma cells was substantially increased and comparable with that of IL-15-activated NK cells. Surface EGFR expression on primary osteosarcoma cultures correlated with EGFR expression in the original tumor. The cytolytic activity of osteosarcoma patient-derived NK cells against autologous tumor cells was as efficient as that of NK cells from healthy donors.

Conclusion: Our data show that the cytolytic potential of resting NK cells can be potentiated and directed toward osteosarcoma cells with cetuximab. Therefore, cetuximab-mediated immunotherapy may be considered a novel treatment modality in the management of advanced osteosarcoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal, Humanized
  • Antibody-Dependent Cell Cytotoxicity
  • Antigens, CD / metabolism
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • Antineoplastic Agents / pharmacology*
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / immunology
  • Bone Neoplasms / metabolism
  • Cetuximab
  • Child
  • Coculture Techniques
  • Drug Screening Assays, Antitumor
  • ErbB Receptors / immunology*
  • ErbB Receptors / metabolism
  • Female
  • Humans
  • Killer Cells, Natural / drug effects*
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism
  • Lectins, C-Type / metabolism
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / immunology
  • Male
  • Middle Aged
  • Osteosarcoma / drug therapy*
  • Osteosarcoma / immunology
  • Osteosarcoma / metabolism
  • Sarcoma, Ewing / metabolism
  • Tumor Cells, Cultured

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • Antineoplastic Agents
  • CD69 antigen
  • Lectins, C-Type
  • EGFR protein, human
  • ErbB Receptors
  • Cetuximab