TY - JOUR
T1 - The CC chemokine receptor 4 as a novel specific molecular target for immunotherapy in adult T-cell leukemia/lymphoma
AU - Ishida, Takashi
AU - Iida, Shinsuke
AU - Akatsuka, Yoshiki
AU - Ishii, Toshihiko
AU - Miyazaki, Mikinori
AU - Komatsu, Hirokazu
AU - Inagaki, Hiroshi
AU - Okada, Noriko
AU - Fujita, Teizo
AU - Shitara, Kenya
AU - Akinaga, Shiro
AU - Takahashi, Toshitada
AU - Utsunomiya, Atae
AU - Ueda, Ryuzo
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2004/12/15
Y1 - 2004/12/15
N2 - 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 CCM4+ 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.
AB - 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 CCM4+ 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.
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U2 - 10.1158/1078-0432.CCR-04-0983
DO - 10.1158/1078-0432.CCR-04-0983
M3 - Article
C2 - 15569983
AN - SCOPUS:9344251670
VL - 10
SP - 7529
EP - 7539
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 22
ER -