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Clinical Trial
. 2023 Sep 20;18(9):e0291772.
doi: 10.1371/journal.pone.0291772. eCollection 2023.

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

Kaoru Fujikawa  1 , Takuro Saito  1 , Koji Kurose  2 , Takashi Kojima  3 , Takeru Funakoshi  4 , Eiichi Sato  5 , Kazuhiro Kakimi  6 , Shinsuke Iida  7 , Yuichiro Doki  1 , Mikio Oka  8 , Ryuzo Ueda  9 , Hisashi Wada  10
Affiliations
Clinical Trial

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

Kaoru Fujikawa et al. PLoS One. .

Abstract

Introduction: 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.

Methods: 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.

Results: Grade 3-4 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.

Conclusions: 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.

Trial registration: ClinicalTrials.gov NCT01929486.

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Conflict of interest statement

T.K. received honoraria and research funding from Ono Pharmaceutical, MSD, Shionogi, Bristol-Myers Squibb, Chugai Pharmaceutical, Amgen, Astellas Pharmaceutical, Oncolys BioPharma, Parexel, BeiGene Ltd, EPS Corporation., TAIHO PHARMACEUTICAL CO., LTD., Covidien Japan, Inc., Nippon Boehringer Ingelheim Co., Ltd., Kyowa Kirin Co., Ltd., EA Pharma Co., Ltd. and Merck Serono outside of this study. T.F. received research funding from Ono Pharmaceutical outside of this study. K.K. received research funding from TAKARA BIO outside of this study. The Department of Immunotherapeutics, The University of Tokyo Hospital is endowed by TAKARA BIO. S.I. received honoraria and research funding from Ono Pharmaceutical, Takeda, Sanofi, Bristol-Myers Squibb, and Janssen and research funding from Daichi-Sankyo, Pfizer, Abbvie, Chugai Pharmaceutical, Daichi-Sankyo, Glaxo SmithKlein, Novartis, Celgene, Amgen, Alexion and Otsuka outside of this study. Y.D. received honoraria and research funding from Ono Pharmaceutical, Taiho Pharmaceutical, and research funding from Chugai Pharmaceutical, Covidien Japan, Johnson & Johnson, and honoraria from Otsuka Pharmaceutical outside of this study. M.O. received research funding from Sysmex outside of this study. The Department of Immuno-Oncology, Kawasaki Medical School is endowed by Pole Star Co., Ltd. R.U. received research funding from Ono Pharmaceutical, Chugai Pharmaceutical, and Kyowa Kirin outside of this study, and other support from Sustainable Cell Therapeutics. H.W. received research funding from Ono Pharmaceutical and Kyowa Kirin, and honoraria from Ono Pharmaceutical, Chugai Pharmaceutical, MSD, and Bristol-Myers Squibb outside of this study. The Department of Clinical Research in Tumor Immunology, Osaka University Graduate School of Medicine is a joint research laboratory with Shionogi & Co., Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. CONSORT diagram for trial.
Phase Ia (a) and Phase Ib (b) studies.
Fig 2
Fig 2. Characteristics of clinical responses.
(a) A Waterfall plot for the best percentage change from baseline. A positive change in the tumor burden indicates tumor growth, while a negative change reflects a tumor reduction. The tumor type, presence or absence of adverse events, and presence or absence of NY-ESO-1 and XAGE1 antibody responses are annotated for each patient. (b) A Spaghetti plot for the percentage change in the target lesion tumor burden from baseline over time. Tumor burden was measured as the sum of the longest diameters of the target lesions by patients over time. The black triangle indicates the first occurrence of a new lesion. Horizontal dotted lines denote a 30% decrease and a 20% increase. 0.1 mg/ml (n = 23), blue bar; 0.5 mg/ml (n = 3), green bar; 1.0 mg/ml (n = 23), orange bar.
Fig 3
Fig 3. Representative CT imaging in patients with a durable clinical response.
(a) Esophageal cancer patient B-09. Pleural metastasis (yellow arrow) was observed on CT and FDG-PET at baseline. The pleural tumor was decreased in size by the KW-0761 treatment, which was also confirmed by a reduction in standardized uptake value-max (SUV-max) on FDG-PET. Although pleural metastasis shrank, abdominal lymph node metastasis (orange arrow) developed after 23 infusions, which was evaluated as a new lesion, leading to the discontinuation of treatment. (b) Esophageal cancer patient B-39. Multiple liver metastases (yellow arrow) were observed on CT at baseline. Disease progression and a new lesion in the liver (red arrow) were confirmed after the first 8 infusions; however, all lesions subsequently decreased in size. The objective feasible response was sustained until 36 weeks after the first treatment when abdominal lymph node metastasis developed (orange arrow).
Fig 4
Fig 4. Changes in blood laboratory data and correlations for overall survival.
(a) The lymphocyte count (/μl), percent lymphocytes in leukocytes (% lymphocytes), NLR, MLR, and PLR were assessed by blood laboratory tests at baseline and weekly after the first KW-0761 treatment until 8 infusions. Kaplan-Meier curves of OS were analyzed between high and low groups divided by the median values of calculated parameters at baseline (b) and 2 weeks after the initiation of KW-0761 (c). Bar, median; *, p<0.05.
See this image and copyright information in PMC

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