CCR4 as a Therapeutic Target for Cancer Immunotherapy

Abstract

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.

Multifaceted Roles of Chemokines and Chemokine Receptors in Tumor Immunity

“…In this regard, mogamulizumab, an anti-CCR4 monoclonal antibody, was recently developed for the treatment of CCR4-expressing adult T-cell leukemia/lymphoma [ 93 ]. The mogamulizumab treatment was also shown to efficiently deplete CCR4-expressing Treg cells and to increase the number of tumor-specific CD8 + T cells in the blood of patients with adult T-cell leukemia/lymphoma [ 173 , 174 ]. It was further shown that a CCR4 antagonist CCR4-351 inhibited Treg cell recruitment into tumor tissues in mice bearing murine pancreatic and colon cancers, and augmented tumor-specific immune responses [ 63 ].…”

“…Although the chemokine superfamily have long been regarded as highly promising therapeutic targets for drug development, currently only three drugs are approved: Maraviroc, a small-molecule CCR5 antagonist for blocking infection by CCR5-tropic HIV-1; Plerixafor, a small-molecule CXCR4 antagonist for the mobilization of hematopoietic stem cells from the bone marrow for transplantation in patients with non-Hodgkin’s lymphoma and multiple myeloma; Mogamulizumab, a fully humanized and glyco-engineered monoclonal anti-CCR4 antibody for patients with aggressive/refractory adult T cell leukemia/lymphoma (ATLL) and cutaneous T cell lymphomas (CTCLs) [ 93 , 173 , 197 ]. However, the recent impressive therapeutic success of immune checkpoint inhibitors in cancer immunotherapy have opened the possibility of clinical application of drugs targeting chemokines and chemokine receptors as an adjunct therapeutic drug for cancer immunotherapy or chemotherapy.…”

“…In this context, several CCR4-targeted cancer immunotherapies have been performed in both animal and human studies, aiming at inhibiting Treg cell-mediated immune suppression [ 174 , 202 , 221 ]. In particular, mogamulizumab, an anti-CCR4 monoclonal antibody with a potent antibody-dependent cellular cytotoxicity (ADCC) activity, has been developed and approved for the treatment of CCR4-expressing T cell malignancies such as ATLL and CTCLs with great success [ 173 ]. Of note, mogamulizumab treatment has also shown to efficiently deplete Treg cells in patients with ATLL and CTCLs [ 173 ] and to increase tumor-specific CD8 + T cells in the blood of patients with ATLL [ 174 , 202 ].…”

“…In particular, mogamulizumab, an anti-CCR4 monoclonal antibody with a potent antibody-dependent cellular cytotoxicity (ADCC) activity, has been developed and approved for the treatment of CCR4-expressing T cell malignancies such as ATLL and CTCLs with great success [ 173 ]. Of note, mogamulizumab treatment has also shown to efficiently deplete Treg cells in patients with ATLL and CTCLs [ 173 ] and to increase tumor-specific CD8 + T cells in the blood of patients with ATLL [ 174 , 202 ]. Thus, blocking CCR4 by mogamulizumab has been regarded as a promising strategy to enhance tumor-specific immune responses by depleting Treg cells.…”

“…Accordingly, several clinical trials have been performed to test the efficacy of combination of mogamulizumab (KW-0761) and one of the immune checkpoint inhibitors in patients with solid tumors. Although it has been confirmed that Treg cells in the peripheral blood and tumor tissues are efficiently depleted in patients treated with mogamulizumab, no synergistic enhancement of the therapeutic effect of immune checkpoint inhibitors by the combination with mogamulizumab has been observed so far [ 173 ]. Importantly, CCR4 is also expressed by other T cell subsets including Th17 cells.…”