Mechanisms of resistance to mogamulizumab

In this issue of Blood, Beygi et al¹ expanded our understanding of resistance to mogamulizumab in cutaneous T-cell lymphoma (CTCL) from loss or decreased CC chemokine receptor type 4 (CCR4) protein expression and impaired antibody-dependent cell-mediated cytotoxicity (ADCC).

Chemokines and their receptors facilitate cell migration and homing into peripheral tissues. CCR4 has been identified as a skin-homing receptor that is preferentially expressed on memory T helper 2 (Th2) cells, cutaneous lymphocyte antigen–positive Th1 and Th2 cells, and T regulatory cells (Tregs).² In response to its chemokine ligands, CCL17 (thymus and activation-regulated chemokine) and CCL22 (macrophage-derived chemokine) produced by monocytes or macrophages and dendritic cells, CCR4 expression promotes T-cell migration to the skin.

CTCLs are a group of rare and incurable non-Hodgkin lymphomas that arise from clonal proliferation of skin-homing T lymphocytes.³ Mycosis fungoides (MF), the most common form, and Sézary syndrome (SS), the leukemic variant, make up 70% of CTCL cases worldwide.⁴ Advanced-stage CTCL remains difficult to manage because of the relatively low overall response rate (ORR) of 30% achieved with standard systemic therapies approved by the US Food and Drug Administration (FDA). The majority of patients will need an alternative therapy within 1 year of treatment initiation, and treatment will require consideration of the patient’s disease, comorbidities, and quality of life as well as the availability of treatment options and their potential toxicities.

Mogamulizumab is a humanized, defucosylated immunoglobulin G1 kappa monoclonal antibody that depletes CCR4-expressing cells by enhanced ADCC. CCR4 expression is upregulated in all stages of CTCL,⁵ and therefore it is an ideal therapeutic target for mogamulizumab. In 2018, the FDA approved mogamulizumab for treating refractory CTCL based on the MAVORIC randomized phase 3 trial of 372 enrolled patients; the trial results showed that mogamulizumab was superior to vorinostat in ORRs (28% vs 5%) and progression-free survival (7.6 vs 3.1 months).⁶ Analysis by CTCL subtype revealed a higher ORR of 37% in patients with SS. However, most patients developed resistance to mogamulizumab, and disease relapse occurred by about 14 months in responders. Notably, CCR4 is mutated in a substantial proportion of patients with MF and SS,⁷ specifically gain-of function mutations (see figure), but the mechanisms have not been elucidated.

In their study, Beygi et al investigated whether intrinsic and acquired resistance to mogamulizumab is associated with loss of CCR4 expression and genomic alterations in the CCR4 gene in CTCL. The authors identified 17 patients with evaluable archived samples from lesional skin, blood, and/or lymph nodes at time of progression; 11 patients had discontinued treatment because of lack of response (primary or intrinsic resistance), and 7 patients discontinued treatment because of loss of response (secondary or acquired resistance).

First, the authors analyzed CCR4 protein expression by immunohistochemistry and/or flow cytometry and performed targeted sequencing to identify genomic alterations in the CCR4 gene. The authors demonstrated that CCR4 protein expression was absent in 8 of 14 posttreatment specimens from patients with primary or secondary resistance. Genomic alterations were seen in 5 patients. Notably, resistance-associated CCR4 mutations were shown in 3 patients with SS and were distinct from previously identified pretreatment mutations. One variant (CCR4^L21V) involved the N-terminal mogamulizumab binding epitope, but all mutations, including the ones within the transmembrane site, were associated with loss of CCR4 protein expression. Two patients demonstrated CCR4 copy number loss, which suggests deletion of the wild-type CCR4 allele. As proof of concept, the transfection of mutated CCR4^L21V and CCR4^M116R variants into human T-cell leukemia Jurkat cells resulted in decreased CCR4 expression and markedly impaired ADCC when treated with mogamulizumab.

Although Beygi et al have identified novel genomic alterations of CCR4 and convincingly demonstrated that these alterations lead to low or loss of CCR4 protein expression and impaired mogamulizumab-mediated ADCC in CTCL, about two-thirds of patients show either intrinsic loss of CCR4 without genomic alterations or high CCR4 expression associated with an as yet undetermined mechanism of resistance. The authors therefore proposed 3 mechanistic explanations for mogamulizumab resistance: (1) detectable genomic events, (2) no detectable genomic events but low or loss of CCR4 protein expression, and (3) an undetermined mechanism with preserved CCR4 expression. However, the study size was small and included predominantly patients with SS. As suggested by the authors, additional studies are needed to explore the possibility of whether genomic alterations in MF are involved in the mechanisms of resistance to mogamulizumab, particularly in light of the differential response rates between MF and SS.⁶ 

Although the study by Beygi et al provides insights into the mechanism of resistance, the CCR4 mechanism of action is likely to be much more complex, because CCR4 targeting can have immunomodulatory effects. CCR4 mediates migration of immunosuppressive Tregs to the tumor microenvironment, and mogamulizumab can cause depletion of Tregs, thereby allowing a therapeutic antitumor immune response and an exaggerated immune response to occur.^8-10 Exploring combinatorial regimens may open avenues for overcoming resistance to mogamulizumab.