Loss of <scp>CCR</scp>4 antigen expression after mogamulizumab therapy in a case of adult <scp>T</scp>‐cell leukaemia‐lymphoma

Ohno, Nobuhiro; Kobayashi, Seiichiro; Ishigaki, Tomohiro; Kikuchi, Yuji; Kobayashi, Masayuki; Sato, Koota; Watanabe, Nobuyuki; Tojo, Arinobu; Uchimaru, Kaoru

doi:10.1111/bjh.12555

Cited by 8 publications

(6 citation statements)

References 10 publications

(11 reference statements)

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“…34 Loss of CCR4 expression under MOGA was reported in two cases of ATLL, without an underlying mechanism. 35,36 Here, only one patient harboured a mutation targeting a CCR4 transmembrane domain, potentially altering protein folding and/or cellsurface expression. However, this previously undescribed mutation was found in a minority of SCs and may not explain the global phenotype.…”

Section: Discussionmentioning

confidence: 99%

Mogamulizumab induces long‐term immune restoration and reshapes tumour heterogeneity in Sézary syndrome*

et al. 2022

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Summary Background Mogamulizumab, an anti‐CCR4 monoclonal antibody, has been shown to increase progression‐free survival in cutaneous T‐cell lymphoma. Objectives We hypothesized that besides the targeted depletion of Sézary cells (SCs), mogamulizumab may reshape the immune tumour microenvironment. Methods Both malignant and benign compartments from 26 patients with B2 stage Sézary syndrome before mogamulizumab initiation were prospectively analysed using KIR3DL2 and TCRVβ markers, serological markers and molecular assessments of clonality. Results Prior to mogamulizumab, the benign subset of CD4+ T cells displayed exhausted phenotypes, with an increased gradient in programmed death‐1, TIGIT, DNAM‐1, CD27, CD28 and CD70 expression from age‐matched controls to patients’ benign CD4+ T cells and to SCs. All patients presented SCs with heterogeneous phenotypes, and differential expression of individual markers was found within distinct malignant subsets. Early complete blood response was observed in 17 of 26 patients and was associated with higher baseline CCR4 expression. A drastic decrease in benign T cells and activated regulatory T‐cell counts was observed during the first 4 weeks. Long‐term follow‐up revealed the emergence of an immune restoration involving CD8+ and naive and stem memory CD4+ T cells, with almost complete disappearance of exhausted lymphocytes. Development of resistance or tumour escape to mogamulizumab was associated with the emergence of CCR4− SCs in blood and skin, displaying significant changes in their heterogeneity patterns, and not explained only by mutations within CCR4 coding regions. Conclusions Mogamulizumab likely contributes to the restoration of efficient immunity and reshapes not only the malignant lymphocyte subset but also the benign subset. These results have potential implications for optimal therapeutic sequences and/or combinations. What is already known about this topic? Management of Sézary syndrome (SS) involves successive therapies that participate as cause and consequence in the emergence of resistant clones, on a background of immunodeficiency. We and others have reported the complex and dynamic heterogeneity of Sézary cells (SCs) during disease progression. Mogamulizumab therapy, by targeting the skin‐homing receptor CCR4, mainly expressed by SCs, has been shown to increase progression‐free survival in patients with SS. What does this study add? Using multicolour flow cytometry, we provide quantification of CCR4 and immune checkpoint molecules on malignant SCs and benign CD4+ T cells from patients with SS, separated using KIR3DL2 and TCRVβ expression. Mogamulizumab is not only aimed at eradicating malignant SCs but potentially contributes to the restoration of efficient immunity. Tumour escape is associated with the emergence of CCR4− SCs, not explained only by mutations within CCR4 coding regions.

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Section: Discussionmentioning

confidence: 99%

Mogamulizumab induces long‐term immune restoration and reshapes tumour heterogeneity in Sézary syndrome*

et al. 2022

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“…The disease eventually recurs and becomes refractory to Mogamulizumab. This acquired resistance appears to be mostly due to the selection against CCR4 expression in original malignant clones [ 178 , 179 ]. Thus, allo-HSCT still provides only chances for a cure in patients with aggressive ATLL and CTCLs [ 91 , 180 , 181 , 182 ].…”

Section: Mogamulizumab and Allo-hsctmentioning

confidence: 99%

CCR4 as a Therapeutic Target for Cancer Immunotherapy

Yoshie

2021

Cancers

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CCR4 is a chemokine receptor mainly expressed by T cells. It is the receptor for two CC chemokine ligands, CCL17 and CCL22. Originally, the expression of CCR4 was described as highly selective for helper T type 2 (Th2) cells. Later, its expression was extended to other T cell subsets such as regulatory T (Treg) cells and Th17 cells. CCR4 has long been regarded as a potential therapeutic target for allergic diseases such as atopic dermatitis and bronchial asthma. Furthermore, the findings showing that CCR4 is strongly expressed by T cell malignancies such as adult T cell leukemia/lymphoma (ATLL) and cutaneous T cell lymphomas (CTCLs) have led to the development and clinical application of the fully humanized and glyco-engineered monoclonal anti-CCR4 Mogamulizumab in refractory/relapsed ATLL and CTCLs with remarkable successes. However, Mogamulizumab often induces severe adverse events in the skin possibly because of its efficient depletion of Treg cells. In particular, treatment with Mogamulizumab prior to allogenic hematopoietic stem cell transplantation (allo-HSCT), the only curative option of these T cell malignancies, often leads to severe glucocorticoid-refractory graft-versus-host diseases. The efficient depletion of Treg cells by Mogamulizumab has also led to its clinical trials in advanced solid tumors singly or in combination with immune checkpoint inhibitors. The main focus of this review is CCR4; its expression on normal and malignant T cells and its significance as a therapeutic target in cancer immunotherapy.

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“…Ohno and colleagues showed a loss of CCR4 expression on the same adult TCLL clones. Loss of CCR4 expression is one mechanism; others can be mutation, or deletion within epitope coding region of mogamulizumab, increase in soluble CCR4 and reduced ADCC [Ohno et al 2013].…”

Section: Role Of Mogamulizumab In Ctclmentioning

confidence: 99%

Mogamulizumab for the treatment of cutaneous T-cell lymphoma: recent advances and clinical potential

Duvic

Evans

Wang

2016

Therapeutic Advances in Hematology

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Mogamulizumab (KW-0761) is a humanized immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that targets CC chemokine receptor 4 (CCR4). It has shown promising therapeutic potential in phase I and II clinical trials and is currently being investigated for efficacy in treating cutaneous T-cell lymphoma (CTCL). We review the mechanism of action of mogamulizumab and its role in treating CTCL. We also discuss the results of major clinical trials.

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Loss of CCR4 antigen expression after mogamulizumab therapy in a case of adult T‐cell leukaemia‐lymphoma

Cited by 8 publications

References 10 publications

Mogamulizumab induces long‐term immune restoration and reshapes tumour heterogeneity in Sézary syndrome*

Mogamulizumab induces long‐term immune restoration and reshapes tumour heterogeneity in Sézary syndrome*

CCR4 as a Therapeutic Target for Cancer Immunotherapy

Mogamulizumab for the treatment of cutaneous T-cell lymphoma: recent advances and clinical potential

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