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The Activation of Natural Killer Cell Effector Functions by Cetuximab-Coated, Epidermal Growth Factor Receptor–Positive Tumor Cells is Enhanced By Cytokines

Authors' Affiliations: ¹ Integrated Biomedical Sciences Graduate Program, ² Department of Internal Medicine, ³ Center for Biostatistics, and ⁴ Department of Surgery, Arthur G. James Comprehensive Cancer Center and Solove Research Institute, Ohio State University, Columbus, Ohio

Requests for reprints: William E. Carson III, The Ohio State University, Department of Surgery, N924 Doan Hall, 410 West 10th Avenue, Columbus, OH 43210. Phone: 614-293-6306; Fax: 614-688-4366; E-mail: william.carson{at}osumc.edu.

Purpose: Natural killer (NK) cells express an activating Fc receptor (FcRIIIa) 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.

Experimental Design: 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- 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- production than was observed with either agent alone. NK cell–derived IFN- significantly enhanced monocyte ADCC against cetuximab-coated tumor cells. Costimulated NK cells also secreted elevated levels of chemokines (IL-8, macrophage inflammatory protein-1, 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.