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

Abstract

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.

Harnessing the immune system in the treatment of cutaneous T cell lymphomas

“…However, a real world SS cohort found that mogamulizumab, in addition to depleting benign CD4+ T cells, Tregs, and malignant T cells, also decreased CD8+ T cells and NK cells at one month of treatment. Longer-term follow-up in this cohort revealed the emergence of “immune restoration” involving expansion of naïve and stem memory CD4+ subsets with almost complete disappearance of pre-treatment exhausted lymphocytes (PD-1+ or TIGIT+ CD4+ T cells) and activated Tregs ( 205 ). In skin biopsies taken from patients with MAR, an increase in interferon-stimulated gene IFI44L and macrophages expressing CXCL11 and CXCL9 coupled with expansion of new T cell clones expressing CXCR3 (the cognate receptor for CXCL9/11) and genes important for cytotoxic effector function was observed, shedding new insight on the potential role tumor associated macrophages may play in generating prolonged remissions from mogamulizumab ( 206 ).…”

“…In skin biopsies taken from patients with MAR, an increase in interferon-stimulated gene IFI44L and macrophages expressing CXCL11 and CXCL9 coupled with expansion of new T cell clones expressing CXCR3 (the cognate receptor for CXCL9/11) and genes important for cytotoxic effector function was observed, shedding new insight on the potential role tumor associated macrophages may play in generating prolonged remissions from mogamulizumab ( 206 ). Despite favorable changes in the immune environment, disease relapse in the SS cohort appeared to be tied to the emergence of CCR4- malignant T cells ( 205 ).…”

Advances in the understanding and treatment of Cutaneous T-cell Lymphoma

“…Mogamulizumab, an anti-CCR4 monoclonal antibody has recently been approved by FDA and EMA following a phase III clinical trial which showed increased progression free survival (PFS) compared with the HDAC inhibitor, Vorinostat ( 21 ). Recently, it has emerged that Mogamulizumab also contributes to efficient immune restoration involving CD8+ as well as stem and memory CD4+ cells ( 90 ).…”

An occurrence of eosinophilic folliculitis and alopecia associated with a sustained complete response to mogamulizumab in Sézary syndrome: a case report

“… 8 This has since come to be known as mogamulizumab-associated rash (MAR); some patients experiencing MAR, particularly those with SS, had improved clinical responses compared with those without MAR. 11 - 13 One explanation for this phenomenon is the immunomodulatory effect of mogamulizumab contributing to the restoration of efficient immunity through reduction of the number of CCR4+ malignant cells and benign T cells [including exhausted lymphocytes and activated regulatory T cells (Tregs)] and subsequent emergence of cluster of differentiation (CD)8+, naïve and stem cell memory CD4+ T cells. 11 - 13 …”

“… 11 - 13 One explanation for this phenomenon is the immunomodulatory effect of mogamulizumab contributing to the restoration of efficient immunity through reduction of the number of CCR4+ malignant cells and benign T cells [including exhausted lymphocytes and activated regulatory T cells (Tregs)] and subsequent emergence of cluster of differentiation (CD)8+, naïve and stem cell memory CD4+ T cells. 11 - 13 …”