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Immunotherapy with Chimeric NKG2D Receptors Leads to Long-Term Tumor-Free Survival and Development of Host Antitumor Immunity in Murine Ovarian Cancer^1,2

Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756

Ovarian cancer is one of the leading causes of cancer death in women and the development of novel therapies is needed to complement the standard treatment options such as chemotherapy and radiation. In this study, we show that treatment with T cells expressing a chimeric NKG2D receptor (chNKG2D) was able to lead to long-term, tumor-free survival in mice bearing established ovarian tumors. Tumor-free mice were able to reject a rechallenge with ovarian tumor cells 225 days after original tumor injection. In addition, chNKG2D T cell treatment induced specific host immune responses to ovarian tumor cells, including the development of both CD8⁺ and CD4⁺ T cell tumor-specific memory responses. The chNKG2D T cells reduced the ovarian tumor burden using both cytotoxic and cytokine-dependent pathways. Specifically, chNKG2D T cell expression of perforin, GM-CSF, and IFN- were essential for complete antitumor efficacy.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by grants from The Hitchcock Foundation, the Department of Microbiology and Immunology, Dartmouth Medical School, National Institutes of Health (AI 07363), and a Leukemia and Lymphoma Society Special Fellowship (to T.Z.).

² The contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health or the Leukemia and Lymphoma Society.

³ Address correspondence and reprint requests to Dr. Charles L. Sentman, Department of Microbiology and Immunology, Dartmouth Medical School, 6W Borwell Building, One Medical Center Drive, Lebanon, NH 03756. E-mail address: charles.sentman{at}dartmouth.edu

⁴ Abbreviations used in this paper: chNKG2D, chimeric NKG2D; wtNKG2D, wild-type NKG2D.

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