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Adoptive Transfer of Gene-Modified Primary NK Cells Can Specifically Inhibit Tumor Progression In Vivo¹

Hollie J. Pegram^*, Jacob T. Jackson^*, Mark J. Smyth^*,, Michael H. Kershaw^2,*, and Phillip K. Darcy^2,3,*,

^* Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; and Department of Pathology, University of Melbourne, Melbourne, Australia

NK cells hold great potential for improving the immunotherapy of cancer. Nevertheless, tumor cells can effectively escape NK cell-mediated apoptosis through interaction of MHC molecules with NK cell inhibitory receptors. Thus, to harness NK cell effector function against tumors, we used Amaxa gene transfer technology to gene-modify primary mouse NK cells with a chimeric single-chain variable fragment (scFv) receptor specific for the human erbB2 tumor-associated Ag. The chimeric receptor was composed of the extracellular scFv anti-erbB2 Ab linked to the transmembrane and cytoplasmic CD28 and TCR- signaling domains (scFv-CD28-). In this study we demonstrated that mouse NK cells gene-modified with this chimera could specifically mediate enhanced killing of an erbB2⁺ MHC class I⁺ lymphoma in a perforin-dependent manner. Expression of the chimera did not interfere with NK cell-mediated cytotoxicity mediated by endogenous NK receptors. Furthermore, adoptive transfer of gene-modified NK cells significantly enhanced the survival of RAG mice bearing established i.p. RMA-erbB2⁺ lymphoma. In summary, these data suggest that use of genetically modified NK cells could broaden the scope of cancer immunotherapy for patients.

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 by a National Health and Medical Research Council Program Grant and a Cancer Council of Victoria research grant. M.H.K. and P.K.D. were supported by National Health and Medical Research Council of Australia R.D. Wright Research Fellowships. M.J.S. was supported by a National Health and Medical Research Council Senior Principal Research Fellowship.

H.J.P. performed the research, analyzed the data, and wrote first draft of the paper. J.T.J. performed the research. M.J.S. analyzed the data. M.H.K. designed the research and analyzed the data. P.K.D. designed the research, analyzed the data, and wrote the manuscript.

² M.H.K. and P.K.D. contributed equally as senior authors.

³ Address correspondence and reprint requests to Dr. Phillip K. Darcy and Dr. Michael H. Kershaw, Peter MacCallum Cancer Institute, Locked Bag 1, A’Beckett Street, Victoria, 8006, Australia. E-mail addresses: phil.darcy{at}petermac.org and michael.kershaw{at}petermac.org

⁴ Abbreviations used in this paper: LAK, lymphokine killer cells; scFv, single-chain variable fragment; TAA, tumor-associated Ags; FasL, Fas ligand; WT, wild type.