CCR4 in cutaneous T-cell lymphoma: Therapeutic targeting of a pathogenic driver
Jan P Nicolay1,2,3, Jana D Albrecht1,2,3, Silvia Alberti-Violetti4
1Department of Dermatology, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany.
Abstract:
New treatments are needed for patients with cutaneous T-cell lymphoma (CTCL), particularly for advanced mycosis fungoides (MF) and Sezary syndrome (SS). The immunopathology of MF and SS is complex, but recent advances in tumor microenvironment understanding have identified CCR4 as a promising therapeutic target. CCR4 is widely expressed on malignant T cells and Tregs in the skin and peripheral blood of patients with MF and SS. The interaction of CCR4 with its dominant ligands CCL17 and CCL22 plays a critical role in the development and progression of CTCL, facilitating the movement into, and accumulation of, CCR4-expressing T cells in the skin, and recruiting CCR4-expressing Tregs into the tumor microenvironment. Expression of CCR4 is upregulated at all stages of MF and in SS, increasing with advancing disease. Several CCR4-targeted therapies are being evaluated, including "chemotoxins" targeting CCR4 via CCL17, CCR4-directed chimeric antigen receptor-modified T-cell therapies, small-molecule CCR4 antagonists, and anti-CCR4 monoclonal antibodies. Only one is currently approved: mogamulizumab, a defucosylated, fully humanized, anti-CCR4, monoclonal antibody for the treatment of relapsed/refractory MF and SS. Clinical trial da1ta confirm that mogamulizumab is an effective and well-tolerated treatment for relapsed/refractory MF or SS, demonstrating the clinical value of targeting CCR4.
Insights
New treatments targeting CCR4 show promise for cutaneous T-cell lymphoma (CTCL), including advanced mycosis fungoides (MF) and Sezary syndrome (SS). Mogamulizumab, an anti-CCR4 antibody, is effective for relapsed/refractory MF and SS.
Area of Science:
- Oncology
- Immunology
- Dermatology
Background:
- Cutaneous T-cell lymphoma (CTCL), particularly advanced mycosis fungoides (MF) and Sezary syndrome (SS), requires novel therapeutic strategies.
- Understanding the tumor microenvironment in MF and SS has highlighted chemokine receptor 4 (CCR4) as a key therapeutic target.
- CCR4 is expressed on malignant T cells and regulatory T cells (Tregs) in MF and SS, and its ligands CCL17 and CCL22 drive disease progression.
Purpose of the Study:
- To evaluate the role of CCR4 in the immunopathology of MF and SS.
- To review current and emerging CCR4-targeted therapies for CTCL.
- To assess the clinical efficacy and tolerability of mogamulizumab in relapsed/refractory MF and SS.
Main Methods:
- Review of literature on CCR4 expression and function in CTCL.
- Analysis of clinical trial data for CCR4-targeted therapies.
- Focus on mogamulizumab, a CCR4-directed monoclonal antibody.
Main Results:
- CCR4 expression is upregulated in MF and SS, increasing with disease severity.
- Several therapeutic approaches targeting CCR4 are under investigation.
- Mogamulizumab demonstrated significant efficacy and good tolerability in patients with relapsed/refractory MF or SS.
Conclusions:
- Targeting CCR4 represents a clinically valuable strategy for treating advanced CTCL.
- Mogamulizumab is an effective treatment option for patients with relapsed/refractory MF and SS.
- Further development of CCR4-targeted therapies holds promise for improving outcomes in CTCL.
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