Targeting Chemokine Receptor CCR4 in Adult T-Cell Leukemia-Lymphoma and Other T-Cell Lymphomas

Department of Hematology, and Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, Japan.
Current Hematologic Malignancy Reports (Impact Factor: 2.2). 04/2012; 7(3):235-40. DOI: 10.1007/s11899-012-0124-3
Source: PubMed


Peripheral T-cell lymphoma (PTCL) is a group of lymphoid malignancy that remains difficult to treat, as most PTCL becomes refractory or relapses, and thus there is an unmet medical need for novel treatment modalities. CC chemokine receptor 4 (CCR4) is expressed in various types of PTCL including adult T-cell leukemia-lymphoma (ATL), which has the worst prognosis among them. A phase II study of a defucosylated, humanized anti-CCR4 monoclonal antibody, mogamulizumab (KW-0761), yielded an overall response rate of 50 % (13/26) and a median progression-free survival of 5.2 months in relapsed patients with CCR4-positive ATL who had been previously treated with chemotherapy. Mogamulizumab also showed potential efficacy for cutaneous T-cell lymphoma in a US phase I/II study. Further preclinical and clinical investigations are needed to examine whether concomitant use of this novel agent with other agents with different mechanisms of action would be more effective for ATL and other PTCLs.

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    • "The CC-chemokine receptor 4 (CCR4) is also highly expressed on tumor cells of T-cell derived variants of non-Hodgkin’s lymphoma (NHL), such as adult T-cell leukemia/lymphoma (ATLL) [13], [14], cutaneous T-cell lymphoma (CTCL) [15], [16], and other kinds of malignancies belonging to the heterogeneous group of peripheral T-cell lymphoma (PTCL) [17]. In Western countries, PTCL accounts for 15–20% of aggressive lymphomas and 5–10% of all NHL [18]. "
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    ABSTRACT: Background CC chemokine receptor 4 (CCR4) represents a potentially important target for cancer immunotherapy due to its expression on tumor infiltrating immune cells including regulatory T cells (Tregs) and on tumor cells in several cancer types and its role in metastasis. Methodology Using phage display, human antibody library, affinity maturation and a cell-based antibody selection strategy, the antibody variants against human CCR4 were generated. These antibodies effectively competed with ligand binding, were able to block ligand-induced signaling and cell migration, and demonstrated efficient killing of CCR4-positive tumor cells via ADCC and phagocytosis. In a mouse model of human T-cell lymphoma, significant survival benefit was demonstrated for animals treated with the newly selected anti-CCR4 antibodies. Significance For the first time, successful generation of anti- G-protein coupled chemokine receptor (GPCR) antibodies using human non-immune library and phage display on GPCR-expressing cells was demonstrated. The generated anti-CCR4 antibodies possess a dual mode of action (inhibition of ligand-induced signaling and antibody-directed tumor cell killing). The data demonstrate that the anti-tumor activity in vivo is mediated, at least in part, through Fc-receptor dependent effector mechanisms, such as ADCC and phagocytosis. Anti-CC chemokine receptor 4 antibodies inhibiting receptor signaling have potential as immunomodulatory antibodies for cancer.
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    • " indications . For example , CCR9 antagonists are currently in clinical trials for inflammatory bowel diseases ( Proudfoot et al . , 2010 ) , while CXCR3 antagonists ( presumably because they target Th1 cell responses ) also show promise in other indications ( Liu et al . , 2011 ) . CCR4 may also be a target for adult T cell leukemia - lymphomas ( Tobinai et al . , 2012 ) ."
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    ABSTRACT: T-cell neoplasms, such as adult T-cell leukemia/lymphoma (ATL) and peripheral T-cell lymphoma, are particularly aggressive and, despite novel combination chemotherapy regimens, still have extremely poor prognoses. As such, there is an unmet medical need for novel therapies and the anti-chemokine CCR4 receptor antibody mogamulizumab (KW-0761) may offer such an option for the treatment of ATL. Mogamulizumab is a humanized antibody, with a defucosylated Fc region, which enhances antibody-dependent cellular cytotoxicity. As a result, mogamulizumab demonstrates potent antitumor activity at much lower doses than other therapeutic monoclonal antibodies. Clinical testing indicates that mogamulizumab is effective and well tolerated, with a predictable pharmacokinetic profile in patients with relapsed/refractory ATL. This drug was recently granted regulatory approval in Japan for this indication and continues to be evaluated in clinical trials in both the U.S. and Europe.
    No preview · Article · Oct 2012 · Drugs of today (Barcelona, Spain: 1998)
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