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Chimeric NKG2D Receptor–Bearing T Cells as Immunotherapy for Ovarian Cancer

¹ Department of Microbiology and Immunology, Dartmouth Medical School; ² Department of Obstetrics and Gynecology, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire; and ³ Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas

Requests for reprints: Charles L. Sentman, Department of Microbiology and Immunology, Dartmouth Medical School, 6W Borwell Building, One Medical Center Drive, Lebanon, NH 03756. Phone: 603-653-0611; Fax: 603-650-6223; E-mail: charles.sentman{at}dartmouth.edu.

Despite advancements in the treatment of ovarian cancer, this disease continues to be a leading cause of cancer death in women. Adoptive transfer of tumor-reactive T cells is a promising antitumor therapy for many cancers. We designed a chimeric receptor linking NKG2D, a natural killer (NK) cell–activating receptor, to the CD3 chain of the T-cell receptor to target ovarian tumor cells. Engagement of chimeric NKG2D receptors (chNKG2D) with ligands for NKG2D, which are commonly expressed on tumor cells, leads to T-cell secretion of proinflammatory cytokines and tumor cytotoxicity. In this study, we show that >80% of primary human ovarian cancer samples expressed ligands for NKG2D on the cell surface. The tumor samples expressed MHC class I–related protein A, MICB, and UL-16 binding proteins 1 and 3. ChNKG2D-expressing T cells lysed ovarian cancer cell lines. We show that T cells from ovarian cancer patients that express chNKG2D secreted proinflammatory cytokines when cultured with autologous tumor cells. In addition, we show that chNKG2D T cells can be used therapeutically in a murine model of ovarian cancer. These data indicate that treatment with chNKG2D-expressing T cells is a potential immunotherapy for ovarian cancer. [Cancer Res 2007;67(10):5003–8]

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