The CC chemokine receptor 4 as a novel specific molecular target for immunotherapy in adult T-cell leukemia/lymphoma

Takashi Ishida, Shinsuke Iida, Yoshiki Akatsuka, Toshihiko Ishii, Mikinori Miyazaki, Hirokazu Komatsu, Hiroshi Inagaki, Noriko Okada, Teizo Fujita, Kenya Shitara, Shiro Akinaga, Toshitada Takahashi, Atae Utsunomiya, Ryuzo Ueda

Research output: Contribution to journalArticle

121 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)7529-7539
Number of pages11
JournalClinical Cancer Research
Volume10
Issue number22
DOIs
Publication statusPublished - 15-12-2004

Fingerprint

CCR4 Receptors
Adult T Cell Leukemia Lymphoma
Immunotherapy
Antibodies
Regulatory T-Lymphocytes
Blood Cells
Tumor Cell Line
Messenger RNA
T-Lymphocytes
Neoplasms
Immunity
Monoclonal Antibodies
Tissue Donors

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Ishida, Takashi ; Iida, Shinsuke ; Akatsuka, Yoshiki ; Ishii, Toshihiko ; Miyazaki, Mikinori ; Komatsu, Hirokazu ; Inagaki, Hiroshi ; Okada, Noriko ; Fujita, Teizo ; Shitara, Kenya ; Akinaga, Shiro ; Takahashi, Toshitada ; Utsunomiya, Atae ; Ueda, Ryuzo. / The CC chemokine receptor 4 as a novel specific molecular target for immunotherapy in adult T-cell leukemia/lymphoma. In: Clinical Cancer Research. 2004 ; Vol. 10, No. 22. pp. 7529-7539.
@article{036f29e27f914feea2d8ad391fe55866,
title = "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 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.",
author = "Takashi Ishida and Shinsuke Iida and Yoshiki Akatsuka and Toshihiko Ishii and Mikinori Miyazaki and Hirokazu Komatsu and Hiroshi Inagaki and Noriko Okada and Teizo Fujita and Kenya Shitara and Shiro Akinaga and Toshitada Takahashi and Atae Utsunomiya and Ryuzo Ueda",
year = "2004",
month = "12",
day = "15",
doi = "10.1158/1078-0432.CCR-04-0983",
language = "English",
volume = "10",
pages = "7529--7539",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "22",

}

Ishida, T, Iida, S, Akatsuka, Y, Ishii, T, Miyazaki, M, Komatsu, H, Inagaki, H, Okada, N, Fujita, T, Shitara, K, Akinaga, S, Takahashi, T, Utsunomiya, A & Ueda, R 2004, 'The CC chemokine receptor 4 as a novel specific molecular target for immunotherapy in adult T-cell leukemia/lymphoma', Clinical Cancer Research, vol. 10, no. 22, pp. 7529-7539. https://doi.org/10.1158/1078-0432.CCR-04-0983

The CC chemokine receptor 4 as a novel specific molecular target for immunotherapy in adult T-cell leukemia/lymphoma. / Ishida, Takashi; Iida, Shinsuke; Akatsuka, Yoshiki; Ishii, Toshihiko; Miyazaki, Mikinori; Komatsu, Hirokazu; Inagaki, Hiroshi; Okada, Noriko; Fujita, Teizo; Shitara, Kenya; Akinaga, Shiro; Takahashi, Toshitada; Utsunomiya, Atae; Ueda, Ryuzo.

In: Clinical Cancer Research, Vol. 10, No. 22, 15.12.2004, p. 7529-7539.

Research output: Contribution to journalArticle

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

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.

UR - http://www.scopus.com/inward/record.url?scp=9344251670&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=9344251670&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-04-0983

DO - 10.1158/1078-0432.CCR-04-0983

M3 - Article

VL - 10

SP - 7529

EP - 7539

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 22

ER -