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

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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 - 2015 Oct 1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    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, 21(19), 4327-4336. https://doi.org/10.1158/1078-0432.CCR-15-0357