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Interleukin 21 Enhances Antibody-Mediated Tumor Rejection

¹ Cancer Immunology Program, Peter MacCallum Cancer Center, East Melbourne, Victoria, Australia; ² Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan; and ³ ZymoGenetics, Seattle, Washington

Requests for reprints: Mark J. Smyth, Cancer Immunology Program, Peter MacCallum Cancer Center, East Melbourne, 3002, Victoria, Australia. Phone: 61-3-9656-3728; Fax: 61-3-9656-1411; E-mail: mark.smyth{at}petermac.org.

Key Words: cytokine • antibody • established cancer • TRAIL • immunomodulation

Interleukin-21 (IL-21) is a cytokine with structural and sequence homology to IL-2 and IL-15 that has antitumor activity alone in mouse experimental tumor models and a tolerable safety profile in phase I trials in patients with metastatic melanoma and renal cell carcinoma. Several monoclonal antibodies (mAb) targeted at tumor-associated antigens also have improved antitumor activities in mice when used in combination with IL-21. Recently, we described a rational three antibody-based approach (triple mAb, TrimAb) to eradicating established mouse tumors that required the generation of tumor-reactive CD8⁺ T cells and IFN-. Herein, we show that sequentially combining TrimAb with recombinant IL-21 can significantly improve the antitumor activity of this combination against very advanced disease. These data further support the use of IL-21 in adjuvant settings where strong T cell–mediated immune responses to tumors can be generated. [Cancer Res 2008;68(8):3019–25]