Abstract

<div>Abstract<p><b>Purpose:</b> Epstein–Barr virus (EBV) infects not only B cells but also T cells and natural killer (NK) cells, and T- and NK-cell lymphoproliferative diseases (T/NK-LPD) that are refractory to conventional chemotherapies may develop. To identify a molecular-targeted therapy for EBV-associated T/NK-LPDs, we investigated whether CC chemokine receptor 4 (CCR4) was expressed on EBV-infected T and/or NK cells and whether a humanized anti-CCR4 monoclonal antibody, mogamulizumab, was effective.</p><p><b>Experimental Design:</b> CCR4 expression was examined in various cell lines. <i>In vitro</i>, the effects of mogamulizumab on cell lines were evaluated in the presence of peripheral blood mononuclear cells from volunteers. <i>In vivo</i>, the effects of mogamulizumab were evaluated using a murine xenograft model. CCR4 expression was examined on EBV-infected cells from patients with EBV-associated T/NK-LPDs. <i>Ex vivo</i>, the effects of mogamulizumab were evaluated using patient lymphocytes.</p><p><b>Results:</b> CCR4 expression was confirmed in most EBV-positive T and NK cell lines. Mogamulizumab induced antibody-dependent cellular cytotoxicity (ADCC) activity against CCR4-positive cell lines, and inhibited the growth of EBV-positive NK-cell lymphomas in a murine xenograft model. Furthermore, CCR4 was expressed on EBV-infected cells in 8 of 17 patients with EBV-associated T/NK-LPDs. Interestingly, CCR4 was positive in 5 of 5 patients with hydroa vacciniforme, a photodermatosis caused by the clonal expansion of EBV-infected γδT cells. EBV-positive γδT cells were obtained from a patient with hydroa vacciniforme and subjected to an antibody-dependent cell-mediated cytotoxicity (ADCC) assay. The γδT cells that were positive for CCR4 were killed by mogamulizumab via ADCC.</p><p><b>Conclusions:</b> These results indicate that mogamulizumab may be a therapeutic option against EBV-associated T/NK-LPDs. <i>Clin Cancer Res; 20(19); 5075–84. ©2014 AACR</i>.</p></div>

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