Phase Ia Study of FoxP3+ CD4 Treg Depletion by Infusion of a Humanized Anti-CCR4 Antibody, KW-0761, in Cancer Patients

Koji Kurose, Yoshihiro Ohue, Hisashi Wada, Shinsuke Iida, Takashi Ishida, Takashi Kojima, Toshihiko Doi, Susumu Suzuki, Midori Isobe, Takeru Funakoshi, Kazuhiro Kakimi, Hiroyoshi Nishikawa, Heiichiro Udono, Mikio Oka, Ryuzo Ueda, Eiichi Nakayama

Research output: Contribution to journalArticle

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Abstract

Purpose: FoxP3+ Tregs inhibit immune responses against tumors. KW-0761 is a humanized anti-human CCR4 monoclonal antibody (mAb) that has antibody-dependent cellular cytotoxicity activity. Depletion of CCR4-expressing FoxP3+ CD4 Tregs by KW-0761 infusion was investigated in solid cancer patients. Experimental Design: We conducted a phase Ia clinical trial of KW-0761 infusion in 7 lung and 3 esophageal cancer patients. Toxicity, clinical efficacy, changes in lymphocyte subpopulations, includingTregs,andinductionofimmune responseswereanalyzed. Results: The results showed that KW-0761 infusion in a dose range between0.1mg/kg and 1.0mg/kgwas safe andwell tolerated. Nodose-limiting toxicitywas observed. Four of 10 patients showed stable disease during treatment and were long survivors. The monitoring of FoxP3+ Tregs in the peripheral blood mononuclear cells during treatment indicated efficient depletion of those cells, even at the lowest dose of 0.1 mg/kg used. The reduction in Th 1 CD4 T cells and CD8 T cells was limited, whereas a significant reduction was observed with Th 2 and Th 17 CD4 T cells. Immune responses to cancer/testis (CT) antigens and an autoantibody response to thyroid peroxidase were observed in some patients. Conclusions: The findings showed Tregs depletion and the possible occurrence of an immune response following KW-0761 infusion. Combined use of KW-0761 to deplete FoxP3+ Tregs with other immunotherapies, such as cancer vaccines or checkpoint inhibitors, is a promising approach to augment immune responses.

Original languageEnglish
Pages (from-to)4327-4336
Number of pages10
JournalClinical Cancer Research
Volume21
Issue number19
DOIs
Publication statusPublished - Oct 1 2015

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Antibodies, Monoclonal, Humanized
Anti-Idiotypic Antibodies
Neoplasms
T-Lymphocytes
Iodide Peroxidase
Cancer Vaccines
Lymphocyte Subsets
Testicular Neoplasms
Esophageal Neoplasms
Autoantibodies
Immunotherapy
Survivors
mogamulizumab
Blood Cells
Research Design
Monoclonal Antibodies
Clinical Trials
Antigens
Lung
Antibodies

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Phase Ia Study of FoxP3+ CD4 Treg Depletion by Infusion of a Humanized Anti-CCR4 Antibody, KW-0761, in Cancer Patients. / Kurose, Koji; Ohue, Yoshihiro; Wada, Hisashi; Iida, Shinsuke; Ishida, Takashi; Kojima, Takashi; Doi, Toshihiko; Suzuki, Susumu; Isobe, Midori; Funakoshi, Takeru; Kakimi, Kazuhiro; Nishikawa, Hiroyoshi; Udono, Heiichiro; Oka, Mikio; Ueda, Ryuzo; Nakayama, Eiichi.

In: Clinical Cancer Research, Vol. 21, No. 19, 01.10.2015, p. 4327-4336.

Research output: Contribution to journalArticle

Kurose, K, Ohue, Y, Wada, H, Iida, S, Ishida, T, Kojima, T, Doi, T, Suzuki, S, Isobe, M, Funakoshi, T, Kakimi, K, Nishikawa, H, Udono, H, Oka, M, Ueda, R & Nakayama, E 2015, 'Phase Ia Study of FoxP3+ CD4 Treg Depletion by Infusion of a Humanized Anti-CCR4 Antibody, KW-0761, in Cancer Patients', Clinical Cancer Research, vol. 21, no. 19, pp. 4327-4336. https://doi.org/10.1158/1078-0432.CCR-15-0357
Kurose, Koji ; Ohue, Yoshihiro ; Wada, Hisashi ; Iida, Shinsuke ; Ishida, Takashi ; Kojima, Takashi ; Doi, Toshihiko ; Suzuki, Susumu ; Isobe, Midori ; Funakoshi, Takeru ; Kakimi, Kazuhiro ; Nishikawa, Hiroyoshi ; Udono, Heiichiro ; Oka, Mikio ; Ueda, Ryuzo ; Nakayama, Eiichi. / Phase Ia Study of FoxP3+ CD4 Treg Depletion by Infusion of a Humanized Anti-CCR4 Antibody, KW-0761, in Cancer Patients. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 19. pp. 4327-4336.
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AU - Kurose, Koji

AU - Ohue, Yoshihiro

AU - Wada, Hisashi

AU - Iida, Shinsuke

AU - Ishida, Takashi

AU - Kojima, Takashi

AU - Doi, Toshihiko

AU - Suzuki, Susumu

AU - Isobe, Midori

AU - Funakoshi, Takeru

AU - Kakimi, Kazuhiro

AU - Nishikawa, Hiroyoshi

AU - Udono, Heiichiro

AU - Oka, Mikio

AU - Ueda, Ryuzo

AU - Nakayama, Eiichi

PY - 2015/10/1

Y1 - 2015/10/1

N2 - Purpose: FoxP3+ Tregs inhibit immune responses against tumors. KW-0761 is a humanized anti-human CCR4 monoclonal antibody (mAb) that has antibody-dependent cellular cytotoxicity activity. Depletion of CCR4-expressing FoxP3+ CD4 Tregs by KW-0761 infusion was investigated in solid cancer patients. Experimental Design: We conducted a phase Ia clinical trial of KW-0761 infusion in 7 lung and 3 esophageal cancer patients. Toxicity, clinical efficacy, changes in lymphocyte subpopulations, includingTregs,andinductionofimmune responseswereanalyzed. Results: The results showed that KW-0761 infusion in a dose range between0.1mg/kg and 1.0mg/kgwas safe andwell tolerated. Nodose-limiting toxicitywas observed. Four of 10 patients showed stable disease during treatment and were long survivors. The monitoring of FoxP3+ Tregs in the peripheral blood mononuclear cells during treatment indicated efficient depletion of those cells, even at the lowest dose of 0.1 mg/kg used. The reduction in Th 1 CD4 T cells and CD8 T cells was limited, whereas a significant reduction was observed with Th 2 and Th 17 CD4 T cells. Immune responses to cancer/testis (CT) antigens and an autoantibody response to thyroid peroxidase were observed in some patients. Conclusions: The findings showed Tregs depletion and the possible occurrence of an immune response following KW-0761 infusion. Combined use of KW-0761 to deplete FoxP3+ Tregs with other immunotherapies, such as cancer vaccines or checkpoint inhibitors, is a promising approach to augment immune responses.

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