The CC Chemokine Receptor 4 as a Novel Specific Molecular Target for Immunotherapy in Adult T-Cell Leukemia/Lymphoma

Abstract

Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell neoplasm with dismal prognosis, and no optimal therapy has been developed. We tested the defucosylated chimeric anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, KM2760, to develop a novel immunotherapy for this refractory tumor. In the presence of peripheral blood mononuclear cells (PBMCs) from healthy adult donors, KM2760 induced CCR4-specific antibody-dependent cellular cytotoxicity (ADCC) against CCR4-positive ATLL cell lines and primary tumor cells obtained from ATLL patients. We next examined the KM2760-induced ADCC against primary ATLL cells in an autologous setting. Antibody-dependent cellular cytotoxicity mediated by autologous effector cells was generally lower than that mediated by allogeneic control effector cells. However, a robust ADCC activity was induced in some cases, which was comparable with that mediated by allogeneic effector cells. It suggests that the ATLL patients' PBMCs retain substantial ADCC-effector function, although the optimal conditions for maximal effect have not yet been determined. In addition, we also found a high expression of FoxP3 mRNA and protein, a hallmark of regulatory T cells, in ATLL cells, indicating the possibility that ATLL cells originated from regulatory T cells. KM2760 reduced FoxP3 mRNA expression in normal PBMCs along with CCR4 mRNA by lysis of CCR4 ؉ T cells in vitro. Our data suggest not only that the CCR4 molecule could be a suitable target for the novel antibody-based therapy for patients with ATLL but also that KM2760 may induce effective tumor immunity by reducing the number of regulatory T cells.

Regulatory T‐cell function of adult T‐cell leukemia/lymphoma cells

“…We have previously reported that the level of FOXP3 mRNA in CD4 1 CCR4 1 and CD4 1 CD25 1 cells in healthy individuals is very similar. 6 Also as reported previously, 6 the level of FOXP3 expression in control CD4 1 CCR4 2 cells was low (2.6 6 0.7, Fig. 2b).…”

“…Recently, several investigators including ourselves have reported that FOXP3, which is a master control gene for the development and function of CD4 1 CD25 1 naturally occurring regulatory T (Treg) cells, [2][3][4] is expressed in the tumor cells from a subset of patients with ATLL. [5][6][7][8][9][10] Furthermore, we and other investigators have reported that ATLL cells from most patients express CCR4, 11,12 and very recently, Hirahara et al reported that virtually all peripheral blood CD4 1 CD25 high Foxp3 1 Treg cells express high levels of CCR4. 13 Collectively, because most ATLL cells express both CD4 and CD25, 1 based on their phenotypic characteristics, these tumors might originate from CD4 1 CD25 1 FOXP3 1 CCR4 1 Treg cells.…”

“…It also adds to our understanding of ATLL patients' severely immunocompromised state, which leads to frequent and severe infectious complications. The present study and the availability of therapeutic anti-CCR4 mAb, 6,22,23 with which we are currently conducting a phase I clinical trial in patients with CCR4-positive T-cell leukemia/lymphoma 11,14 (ClinicalTrials.gov Identifier: NCT00355472), should offer improved treatment strategies for patients with ATLL.…”

Autologous Tax-Specific CTL Therapy in a Primary Adult T Cell Leukemia/Lymphoma Cell–Bearing NOD/Shi-scid, IL-2Rγnull Mouse Model

“…Therefore, depletion of Treg cells in the vicinity of tumors is a potentially promising strategy for boosting tumor-associated Agspecific immunity (35)(36)(37)(38). We have shown that a therapeutic anti-CCR4 mAb does deplete Treg cells in vitro (39,40) and in vivo in humanized mice (27). Furthermore, we confirmed the CD25 + CD4 + FOXP3 + Treg depletion activity mediated by the humanized anti-CCR4 mAb mogamulizumab (KW-0761) in humans (41)(42)(43)(44).…”

Human T-Cell Lymphotropic Virus (HTLV-1) and Adult T-Cell Leukemia

“…Antibody therapy against ATL cells has advantages due to its decreased adverse effects. As described above, most ATL cells express CCR4 antigen on their surfaces, and a humanized antibody against CCR4 is being developed as an anti-ATL agent (Ishida et al 2004). Advances in the treatment of ATL were brought about by allogeneic bone marrow or stem cell transplantation (Borg et al 1996;Yamada et al 2001).…”