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: 2.29). 04/2012; 7(3):235-40. DOI: 10.1007/s11899-012-0124-3
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Kensei Tobinai, Aug 11, 2015
  • Source
    • " 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 ) ."
    [Show abstract] [Hide abstract]
    ABSTRACT: The chemokine superfamily consists of a large number of ligands and receptors. At first glance, this family appears redundant and their ligand-receptor relationships promiscuous, making its study challenging. However, analyzing this family from the evolutionary perspective greatly simplifies understanding both the organization and function of this apparently complex system. In particular, the functions of a subgroup of chemokines (designated homeostatic chemokines) have played pivotal roles in advancing our understanding of the organization and function of the cellular networks that shape the immune system. Here, we update the full scope of the human and mouse chemokine superfamilies and their relationships and summarize several important roles that homeostatic chemokines play in the immune system.
    Immunity 05/2012; 36(5):705-16. DOI:10.1016/j.immuni.2012.05.008 · 19.75 Impact Factor
  • [Show abstract] [Hide abstract]
    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.
    Drugs of today (Barcelona, Spain: 1998) 10/2012; 48(10):655-60. DOI:10.1358/dot.2012.48.10.1885878 · 1.00 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The use of therapeutic monoclonal antibodies in the treatment of malignant diseases has evolved into a promising approach over the past decade. The treatment of non-Hodgkin lymphoma has changed dramatically since the introduction of rituximab, a monoclonal antibody that binds to the B-cell transmembrane protein CD20 and causes lysis of the lymphoma cells. Since then, a number of additional antibodies have been tested against other B-cell targets, resulting in variable efficacies. The goal of these newer agents is to achieve similar or better response rates as seen with rituximab and perhaps demonstrate activity in rituximabrefractory disease. The success of anti-CD20 therapy in B-cell lymphoma is prompting investigators to search for a similarly efficacious monoclonal antibody in T-cell lymphoma and clinical trials with a new anti-CD30 agent are hopeful in anaplastic CD30 positive T-NHL. Among new agents, proteasome inhibitors and immunomodulatory drugs seem to play a pivotal role in the regulation of several cell pathways involved in the development of lymphomas and the antitumor activity of these agents may improve complete remission rates with less toxic regimens.
Show more