Purpose: The CC chemokine receptor 4 (CCR4) is expressed on malignant T cells in cutaneous T-cell lymphoma (CTCL) as well as on regulatory T cells (Treg). When mogamulizumab, a defucosylated monoclonal antibody, binds to CCR4, it induces antibody-dependent cellular cytotoxicity against CCR4⁺ malignant T cells. The goal of this study was to determine the effect of mogamulizumab on CCR4⁺ Tregs in patients with CTCL. Experimental Design: Peripheral blood of 24 patients with CTCL participating in a phase I/II trial was analyzed for CCR4 expression on different T-cell subsets by flow cytometry, before and after one course of mogamulizumab. The number and function of natural killer (NK) cells were also analyzed. Lesional biopsies were examined for CCR4, Foxp3, and CD16 expression by immunohistochemistry. Results: Malignant T cells in peripheral blood were 20.8%–100% positive for CCR4 at baseline. Fourteen patients who achieved a response in blood had high baseline CCR4 expression on malignant T cells. Tregs in blood were 58.6% to 100% positive for CCR4 at baseline and showed decreased numbers and CCR4 expression after treatment. CD8⁺ T cells in blood were 3.2% to 23.2% positive for CCR4 at baseline and showed limited reduction of CCR4 expression with increased percentages of CD8⁺ T cells after treatment. Of 14 patients tested for NK cells in blood, 10 showed increased percentages after treatment. Four of 6 patients tested showed increased NK cell cytotoxicity. Sixteen of 18 patients who had CCR4⁺ lymphocytes in baseline lesions showed decreased numbers after treatment. Conclusions: Mogamulizumab reduces levels of CCR4⁺ malignant T cells and also CCR4⁺ Tregs in patients with CTCL, which may in turn improve immune profiles. Clin Cancer Res; 21(2); 274–85. ©2014 AACR.

The CC chemokine receptor 4 (CCR4) is highly expressed on type 2 helper T cells and regulatory T (Treg) cells. Mogamulizumab, an anti-CCR4 antibody, reduces the numbers of CCR4⁺ malignant T cells and CCR4⁺ Treg cells in cutaneous T-cell lymphoma. Depleting Treg cells by targeting CCR4 has great potential in cancer immunotherapies.