{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T20:02:27Z","timestamp":1791576147957,"version":"4.3.4"},"reference-count":29,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2023,9,20]],"date-time":"2023-09-20T00:00:00Z","timestamp":1695168000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001700","name":"the Ministry of Education, Culture, Sports, Science and Technology of Japan","doi-asserted-by":"crossref","award":["19H03729"],"award-info":[{"award-number":["19H03729"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]},{"name":"the Development of Technology for Patient Stratification Biomarker Discovery grant","award":["19ae0101074s0401"],"award-info":[{"award-number":["19ae0101074s0401"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Introduction<\/jats:title>\n<jats:p>Regulatory T cells (Tregs) have attracted attention as a novel therapeutic target to augment the clinical efficacy of immunotherapy. We conducted phase Ia and Ib trials to examine the safety and efficacy of the anti-CCR4 antibody, KW-0761 (mogamulizumab), which may eliminate effector Tregs (eTregs). We herein overviewed the results of these trials, presented cases with a durable clinical response, and investigated factors associated with the clinical effects of KW-0761.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Forty-nine patients with CCR4-negative solid cancers were enrolled in the phase Ia and Ib trials on KW-0761. An integral analysis of safety, clinical responses, prognosis, blood laboratory data, and cancer testis antigen-specific immune responses was performed.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Grade 3\u20134 treatment-related adverse events were reported in 21 (42.9%) out of 49 patients, all of which were manageable. A partial response and stable disease were observed in 1 and 9 patients, respectively. A durable clinical response was noted in 2 esophageal and 2 lung cancer patients. eTreg depletion in peripheral blood was confirmed in most patients, and eTreg depletion was sustained during the KW-0761 treatment. High lymphocyte levels at baseline and 2 weeks after the initiation of KW-0761 were associated with a favorable clinical outcome.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>A durable clinical response was noted in some patients, and high lymphocyte levels before treatment initiation may be a biomarker for the efficacy of KW-0761. The synergistic effect of KW-0761 for depleting Tregs and other immunotherapies is expected in the future.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0291772","type":"journal-article","created":{"date-parts":[[2023,9,20]],"date-time":"2023-09-20T17:27:38Z","timestamp":1695230858000},"page":"e0291772","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":21,"title":["Integrated analysis of phase 1a and 1b randomized controlled trials; Treg-targeted cancer immunotherapy with the humanized anti-CCR4 antibody, KW-0761, for advanced solid tumors"],"prefix":"10.1371","volume":"18","author":[{"given":"Kaoru","family":"Fujikawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1733-5064","authenticated-orcid":true,"given":"Takuro","family":"Saito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3878-1477","authenticated-orcid":true,"given":"Koji","family":"Kurose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Kojima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeru","family":"Funakoshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiichi","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2631-3040","authenticated-orcid":true,"given":"Kazuhiro","family":"Kakimi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinsuke","family":"Iida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichiro","family":"Doki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikio","family":"Oka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryuzo","family":"Ueda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5444-6193","authenticated-orcid":true,"given":"Hisashi","family":"Wada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,9,20]]},"reference":[{"issue":"35","key":"pone.0291772.ref001","doi-asserted-by":"crossref","first-page":"4138","DOI":"10.1200\/JCO.20.01888","article-title":"Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer","volume":"38","author":"T Kojima","year":"2020","journal-title":"J Clin Oncol"},{"issue":"10111","key":"pone.0291772.ref002","doi-asserted-by":"crossref","first-page":"2461","DOI":"10.1016\/S0140-6736(17)31827-5","article-title":"Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial","volume":"390","author":"Y-K Kang","year":"2017","journal-title":"The Lancet"},{"issue":"5","key":"pone.0291772.ref003","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1056\/NEJMoa2111380","article-title":"Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma","volume":"386","author":"Y Doki","year":"2022","journal-title":"N Engl J Med"},{"issue":"3","key":"pone.0291772.ref004","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.4049\/jimmunol.155.3.1151","article-title":"Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases","volume":"155","author":"S Sakaguchi","year":"1995","journal-title":"J Immunol"},{"issue":"5609","key":"pone.0291772.ref005","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1126\/science.1079490","article-title":"Control of regulatory T cell development by the transcription factor Foxp3","volume":"299","author":"S Hori","year":"2003","journal-title":"Science"},{"issue":"44","key":"pone.0291772.ref006","doi-asserted-by":"crossref","first-page":"17945","DOI":"10.1073\/pnas.1316796110","article-title":"Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans","volume":"110","author":"D Sugiyama","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"6","key":"pone.0291772.ref007","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1016\/j.immuni.2009.03.019","article-title":"Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor","volume":"30","author":"M Miyara","year":"2009","journal-title":"Immunity"},{"issue":"11","key":"pone.0291772.ref008","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.2217\/imt.14.94","article-title":"Mogamulizumab and the treatment of CCR4-positive T-cell lymphomas","volume":"6","author":"M Remer","year":"2014","journal-title":"Immunotherapy"},{"issue":"8","key":"pone.0291772.ref009","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1200\/JCO.2011.37.3472","article-title":"Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a multicenter phase II study","volume":"30","author":"T Ishida","year":"2012","journal-title":"J Clin Oncol"},{"issue":"24","key":"pone.0291772.ref010","doi-asserted-by":"crossref","first-page":"7275","DOI":"10.1158\/1078-0432.CCR-19-2030","article-title":"FDA Approval Summary: Mogamulizumab-kpkc for Mycosis Fungoides and Sezary Syndrome","volume":"25","author":"YL Kasamon","year":"2019","journal-title":"Clin Cancer Res"},{"issue":"1","key":"pone.0291772.ref011","doi-asserted-by":"crossref","first-page":"7280","DOI":"10.1038\/s41467-021-27574-0","article-title":"Depletion of central memory CD8(+) T cells might impede the antitumor therapeutic effect of Mogamulizumab","volume":"12","author":"Y Maeda","year":"2021","journal-title":"Nat Commun"},{"issue":"19","key":"pone.0291772.ref012","doi-asserted-by":"crossref","first-page":"4327","DOI":"10.1158\/1078-0432.CCR-15-0357","article-title":"Phase Ia Study of FoxP3+ CD4 Treg Depletion by Infusion of a Humanized Anti-CCR4 Antibody, KW-0761, in Cancer Patients","volume":"21","author":"K Kurose","year":"2015","journal-title":"Clin Cancer Res"},{"issue":"4","key":"pone.0291772.ref013","first-page":"827","article-title":"Phase Ib study on the humanized anti-CCR4 antibody, KW-0761, in advanced solid tumors","volume":"83","author":"T Saito","year":"2021","journal-title":"Nagoya J Med Sci"},{"issue":"2","key":"pone.0291772.ref014","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.ejca.2008.10.026","article-title":"New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)","volume":"45","author":"EA Eisenhauer","year":"2009","journal-title":"Eur J Cancer"},{"issue":"23","key":"pone.0291772.ref015","doi-asserted-by":"crossref","first-page":"7412","DOI":"10.1158\/1078-0432.CCR-09-1624","article-title":"Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria","volume":"15","author":"JD Wolchok","year":"2009","journal-title":"Clin Cancer Res"},{"issue":"1","key":"pone.0291772.ref016","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1097\/JTO.0000000000000364","article-title":"Increase in activated Treg in TIL in lung cancer and in vitro depletion of Treg by ADCC using an antihuman CCR4 mAb (KM2760)","volume":"10","author":"K Kurose","year":"2015","journal-title":"J Thorac Oncol"},{"issue":"6","key":"pone.0291772.ref017","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1002\/ijc.1282","article-title":"Immunohistochemical analysis of NY-ESO-1 antigen expression in normal and malignant human tissues","volume":"92","author":"AA Jungbluth","year":"2001","journal-title":"Int J Cancer"},{"key":"pone.0291772.ref018","first-page":"5","article-title":"Identification of XAGE-1 isoforms: predominant expression of XAGE-1b in testis and tumors","volume":"7","author":"S Sato","year":"2007","journal-title":"Cancer Immun"},{"issue":"5","key":"pone.0291772.ref019","doi-asserted-by":"crossref","first-page":"E649","DOI":"10.1002\/ijc.27359","article-title":"Spontaneous antibody, and CD4 and CD8 T-cell responses against XAGE-1b (GAGED2a) in non-small cell lung cancer patients","volume":"131","author":"Y Ohue","year":"2012","journal-title":"Int J Cancer"},{"issue":"2","key":"pone.0291772.ref020","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1158\/1078-0432.CCR-20-1830","article-title":"OX40 Agonist BMS-986178 Alone or in Combination With Nivolumab and\/or Ipilimumab in Patients With Advanced Solid Tumors","volume":"27","author":"M Gutierrez","year":"2021","journal-title":"Clin Cancer Res"},{"issue":"5","key":"pone.0291772.ref021","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1158\/2159-8290.CD-21-1345","article-title":"Preclinical Characterization and Phase I Trial Results of a Bispecific Antibody Targeting PD-L1 and 4-1BB (GEN1046) in Patients with Advanced Refractory Solid Tumors","volume":"12","author":"A Muik","year":"2022","journal-title":"Cancer Discov"},{"issue":"9","key":"pone.0291772.ref022","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1084\/jem.20130579","article-title":"Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma","volume":"210","author":"TR Simpson","year":"2013","journal-title":"J Exp Med"},{"issue":"4","key":"pone.0291772.ref023","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.ccell.2018.02.010","article-title":"Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies","volume":"33","author":"F Arce Vargas","year":"2018","journal-title":"Cancer Cell"},{"issue":"5","key":"pone.0291772.ref024","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1158\/1078-0432.CCR-09-2697","article-title":"Defucosylated humanized anti-CCR4 monoclonal antibody KW-0761 as a novel immunotherapeutic agent for adult T-cell leukemia\/lymphoma","volume":"16","author":"T Ishii","year":"2010","journal-title":"Clin Cancer Res"},{"issue":"8","key":"pone.0291772.ref025","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1038\/nrc1669","article-title":"Cancer\/testis antigens, gametogenesis and cancer","volume":"5","author":"AJ Simpson","year":"2005","journal-title":"Nat Rev Cancer"},{"issue":"10","key":"pone.0291772.ref026","doi-asserted-by":"crossref","first-page":"2362","DOI":"10.1002\/ijc.23810","article-title":"Analysis of peripheral and local anti-tumor immune response in esophageal cancer patients after NY-ESO-1 protein vaccination","volume":"123","author":"H Wada","year":"2008","journal-title":"Int J Cancer"},{"issue":"45","key":"pone.0291772.ref027","doi-asserted-by":"crossref","first-page":"5901","DOI":"10.1016\/j.vaccine.2014.09.002","article-title":"High expression of MAGE-A4 and MHC class I antigens in tumor cells and induction of MAGE-A4 immune responses are prognostic markers of CHP-MAGE-A4 cancer vaccine","volume":"32","author":"T Saito","year":"2014","journal-title":"Vaccine"},{"issue":"2","key":"pone.0291772.ref028","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1097\/CJI.0000000000000017","article-title":"Vaccination with NY-ESO-1 overlapping peptides mixed with Picibanil OK-432 and montanide ISA-51 in patients with cancers expressing the NY-ESO-1 antigen","volume":"37","author":"H Wada","year":"2014","journal-title":"J Immunother"},{"issue":"12","key":"pone.0291772.ref029","doi-asserted-by":"crossref","first-page":"2071","DOI":"10.1016\/j.jtho.2019.08.008","article-title":"Serum Antibody Against NY-ESO-1 and XAGE1 Antigens Potentially Predicts Clinical Responses to Anti-Programmed Cell Death-1 Therapy in NSCLC","volume":"14","author":"Y Ohue","year":"2019","journal-title":"J Thorac Oncol"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0291772","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,20]],"date-time":"2023-09-20T17:28:07Z","timestamp":1695230887000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0291772"}},"subtitle":[],"editor":[{"given":"Hiroyoshi","family":"Nishikawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,9,20]]},"references-count":29,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,9,20]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0291772","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,20]]}}}