title: Phase Ia Study of FoxP3+ CD4 Treg Depletion by Infusion of a Humanized Anti-CCR4 Antibody, KW-0761, in Cancer Patients.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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, including Tregs, and induction of immune responses were analyzed.
  
  
  RESULTS
  The results showed that KW-0761 infusion in a dose range between 0.1 mg/kg and 1.0 mg/kg was safe and well tolerated. No dose-limiting toxicity was 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.
authors.affiliation: Department of Respiratory Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Kurose
authors.affiliation: Department of Respiratory Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ohue
authors.affiliation: Department of Clinical Research in Tumor Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Wada
authors.affiliation: Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Iida
authors.affiliation: Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ishida
authors.affiliation: Exploratory Oncology Research & Clinical Trial Center, Kashiwa, Chiba, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kojima
authors.affiliation: Exploratory Oncology Research & Clinical Trial Center, Kashiwa, Chiba, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Doi
authors.affiliation: Department of Tumor Immunology, Aichi Medical University, Nagakute, Aichi, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Department of Respiratory Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Isobe
authors.affiliation: Department of Dermatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Takeru
authors.initials: T
authors.lastname: Funakoshi
authors.affiliation: Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-Ku, Tokyo, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kakimi
authors.affiliation: Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Nishikawa
authors.affiliation: Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Kita-ku, Okayama, Japan.
authors.forename: Heiichiro
authors.initials: H
authors.lastname: Udono
authors.affiliation: Department of Respiratory Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan.
authors.forename: Mikio
authors.initials: M
authors.lastname: Oka
authors.affiliation: Department of Tumor Immunology, Aichi Medical University, Nagakute, Aichi, Japan. nakayama@mw.kawasaki-m.ac.jp uedaryu@aichi-med-u.ac.jp.
authors.forename: Ryuzo
authors.initials: R
authors.lastname: Ueda
authors.affiliation: Faculty of Health and Welfare, Kawasaki University of Medical Welfare, Kurashiki, Okayama, Japan. nakayama@mw.kawasaki-m.ac.jp uedaryu@aichi-med-u.ac.jp.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Nakayama
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006098:Granulocytes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D008212:Lymphocyte Depletion; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D010641:Phenotype; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D054398:Receptors, CCR4; C549035:mogamulizumab