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Mogamulizumab induced immune related adverse events; the impact of Treg depletion

Research Project

Project/Area Number 16H04713
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Tumor therapeutics
Research InstitutionIwate Medical University (2017-2018)
Nagoya City University (2016)

Principal Investigator

ISHIDA TAKASHI  岩手医科大学, 医学部, 教授 (80405183)

Co-Investigator(Kenkyū-buntansha) 上田 龍三  愛知医科大学, 医学部, 教授 (20142169)
伊藤 旭  名古屋市立大学, 大学院医学研究科, 助教 (00571762)
近藤 豊  名古屋市立大学, 大学院医学研究科, 教授 (00419897)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
Fiscal Year 2018: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2017: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2016: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
KeywordsCCR4 / 制御性T細胞 / 免疫関連有害事象 / 自己抗体 / 成人T細胞白血病 / モガムリズマブ / Treg / autoimmunity / mogamulizumab / 腫瘍治療学 / 抗体療法
Outline of Final Research Achievements

The purpose of this study was to determine the mechanisms by which mogamulizumab causes immune-related AEs in patients with ATL. As a result, autoantibodies recognizing human keratinocytes or melanocytes were found in the sera of patients suffering from mogamulizumab-induced erythema multiforme (EM). CDC mediated by autoantibodies against keratinocytes or melanocytes was proportionally related to the severity of the EM. Colocalization of autoantibodies and C1q, suggesting the activation of CDC, was observed in the biopsy specimens of mogamulizumab-induced EM. Consistent with these findings, NGS demonstrated that IgM germline genes had newly emerged and expanded, resulting in IgM repertoire skewing at the time of EM. In conclusion, mogamulizumab elicits autoantibodies playing an important role in skin-related AEs, possibly associated with Treg depletion. This is the first report demonstrating the presence of skin-directed autoantibodies after mogamulizumab treatment.

Academic Significance and Societal Importance of the Research Achievements

本研究では、モガムリズマブの制御性T細胞(Tregs)除去により、末梢性免疫寛容が破綻し、残存自己反応性B細胞が産生する自己抗体が、免疫関連有害事象の原因となることを明らかにした。現代の科学においても、B細胞の末梢性免疫寛容メカニズム、TregsがB細胞を制御するメカニズムは、明らかとなっていない。本研究成果は、ヒト免疫メカニズムの基盤的理解に貢献するものと考える。

さらには、本研究成果は、PD-1、CTLA-4に対する抗体治療で認める免疫関連有害事象のさらなる理解に貢献するものである。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (25 results)

All 2019 2018 2017 2016

All Journal Article (25 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 23 results,  Open Access: 13 results)

  • [Journal Article] <i>Exophiala dermatitidis</i> Fungemia Diagnosed Using Time-of-flight Mass Spectrometry during Chemotherapy for Malignant Lymphoma and Successful Treatment with Voriconazole2019

    • Author(s)
      Yoshida Takashi、Tachita Takuto、Fujinami Haruna、Oshima Yoshiko、Sasaki Hirokazu、Marumo Yoshiaki、Narita Tomoko、Ito Asahi、Ri Masaki、Kusumoto Shigeru、Ishida Takashi、Komatsu Hirokazu、Iida Shinsuke
    • Journal Title

      Internal Medicine

      Volume: 58 Issue: 15 Pages: 2219-2224

    • DOI

      10.2169/internalmedicine.2082-18

    • NAID

      130007686833

    • ISSN
      0918-2918, 1349-7235
    • Year and Date
      2019-08-01
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Revised Adult T-Cell Leukemia-Lymphoma International Consensus Meeting Report2019

    • Author(s)
      2.Cook LB, Fuji S, Hermine O, Bazarbachi A, Ramos JC, Ratner L, Horwitz S, Fields P, Tanase A, Bumbea H, Cwynarski K, Taylor G, Waldmann TA, Bittencourt A, Marcais A, Suarez F, Sibon D, Phillips A, Lunning M, Farid R, Imaizumi Y, Choi I, Ishida T, et al
    • Journal Title

      Journal of Clinical Oncology

      Volume: 37 Issue: 8 Pages: 677-687

    • DOI

      10.1200/jco.18.00501

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mogamulizumab treatment elicits autoantibodies attacking the skin in patients with adult T cell leukemia-lymphoma2019

    • Author(s)
      Suzuki Yui、Saito Masato、Ishii Toshihiko、Urakawa Itaru、Matsumoto Asuka、Masaki Ayako、Ito Asahi、Kusumoto Shigeru、Suzuki Susumu、Hiura Masanori、Takahashi Takeshi、Morita Akimichi、Inagaki Hiroshi、Iida Shinsuke、Ishida Takashi
    • Journal Title

      Clinical Cancer Research

      Volume: 印刷中 Issue: 14 Pages: 4388-4399

    • DOI

      10.1158/1078-0432.ccr-18-2575

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Pre- and post-transplant ponatinib for a patient with acute megakaryoblastic blast phase chronic myeloid leukemia with T315I mutation who underwent allogeneic hematopoietic stem cell transplantation2019

    • Author(s)
      Sasaki Hirokazu、Mitani Sachiko、Kusumoto Shigeru、Marumo Yoshiaki、Asano Arisa、Yoshida Takashi、Narita Tomoko、Ito Asahi、Yano Hiroki、Ri Masaki、Ishida Takashi、Komatsu Hirokazu、Iida Shinsuke
    • Journal Title

      International Journal of Hematology

      Volume: Mar Issue: 1 Pages: 12185-12185

    • DOI

      10.1007/s12185-019-02628-8

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] CCR4 mutations associated with superior outcome of adult T-cell leukemia/lymphoma under mogamulizumab treatment2018

    • Author(s)
      Sakamoto Yuma、Ishida Takashi、Masaki Ayako、Murase Takayuki、Yonekura Kentaro、Tashiro Yukie、Tokunaga Masahito、Utsunomiya Atae、Ito Asahi、Kusumoto Shigeru、Iida Shinsuke、Ueda Ryuzo、Inagaki Hiroshi
    • Journal Title

      Blood

      Volume: 132 Issue: 7 Pages: 758-761

    • DOI

      10.1182/blood-2018-02-835991

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cyclin-dependent kinase 9 as a potential specific molecular target in NK-cell leukemia/lymphoma2018

    • Author(s)
      Kinoshita Shiori、Ishida Takashi、Ito Asahi、Narita Tomoko、Masaki Ayako、Suzuki Susumu、Yoshida Takashi、Ri Masaki、Kusumoto Shigeru、Komatsu Hirokazu、Shimizu Norio、Inagaki Hiroshi、Kuroda Taruho、Scholz Arne、Ueda Ryuzo、Sanda Takaomi、Iida Shinsuke
    • Journal Title

      Haematologica

      Volume: 103 Issue: 12 Pages: 2059-2068

    • DOI

      10.3324/haematol.2018.191395

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Human T-cell lymphotropic/leukemia virus type 1 (HTLV-1) Tax-specific T-cell exhaustion in HTLV-1-infected individuals.2018

    • Author(s)
      Masaki A, Ishida T, Suzuki S, Ito A, Narita T, Kinoshita S, Ri M, Kusumoto S, Komatsu H, Inagaki H, Ueda R, Iida S.
    • Journal Title

      Cancer Sci

      Volume: 109 Issue: 8 Pages: 2383-2390

    • DOI

      10.1111/cas.13654

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Follow-up of a randomised phase II study of chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: impact on allogeneic haematopoietic stem cell transplantation2018

    • Author(s)
      Ishida T、Jo T、Takemoto S、Suzushima H、Suehiro Y、Choi I、Yoshimitsu M、Saburi Y、Nosaka K、Utsunomiya A、Kobayashi Y、Yamamoto K、Fujiwara H、Ishitsuka K、Yoshida S、Taira N、Imada K、Kato K、Moriuchi Y、Yoshimura K、Takahashi T、Tobinai K、Ueda R
    • Journal Title

      British Journal of Haematology

      Volume: 印刷中 Issue: 3 Pages: 479-483

    • DOI

      10.1111/bjh.15123

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] PD-1 Inhibitor Therapy in Adult T-Cell Leukemia?Lymphoma2018

    • Author(s)
      Ishitsuka K, Utsunomiya A, Ishida T.
    • Journal Title

      New England Journal of Medicine

      Volume: 379 Issue: 7 Pages: 695-697

    • DOI

      10.1056/nejmc1807852

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Targeting General Transcriptional Machinery as a Therapeutic Strategy for Adult T-Cell Leukemia2018

    • Author(s)
      Wong Regina、Ishida Takashi、Sanda Takaomi
    • Journal Title

      Molecules

      Volume: 23 Issue: 5 Pages: 1057-1057

    • DOI

      10.3390/molecules23051057

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Potent anti-tumor activity of a syringolin analog in multiple myeloma: a dual inhibitor of proteasome activity targeting &#x3B2;2 and &#x3B2;5 subunits2018

    • Author(s)
      Yoshida Takashi、Ri Masaki、Kanamori Takashi、Aoki Sho、Ashour Reham、Kinoshita Shiori、Narita Tomoko、Totani Haruhito、Masaki Ayako、Ito Asahi、Kusumoto Shigeru、Ishida Takashi、Komatsu Hirokazu、Kitahata Shun、Chiba Takuya、Ichikawa Satoshi、Iida Shinsuke
    • Journal Title

      Oncotarget

      Volume: 9 Issue: 11 Pages: 9975-9991

    • DOI

      10.18632/oncotarget.24160

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Low expression of neural adhesion molecule, CD56, is associated with poor efficacy of bortezomib plus dexamethasone therapy in multiple myeloma.2018

    • Author(s)
      Yoshida T, Ri M, Kinoshita S, Narita T, Totani H, Ashour R, Ito A, Kusumoto S, Ishida T, Komatsu H, Iida S
    • Journal Title

      PLos One

      Volume: 13 Issue: 5 Pages: e0196780-e0196780

    • DOI

      10.1371/journal.pone.0196780

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Potent antitumor effect of combination therapy with sub?optimal doses of Akt inhibitors and pomalidomide plus dexamethasone in multiple myeloma2018

    • Author(s)
      Kinoshita Shiori、Ri Masaki、Kanamori Takashi、Aoki Sho、Yoshida Takashi、Narita Tomoko、Totani Haruhito、Ito Asahi、Kusumoto Shigeru、Ishida Takashi、Komatsu Hirokazu、Iida Shinsuke
    • Journal Title

      Oncology Letters

      Volume: 15 Pages: 9450-9450

    • DOI

      10.3892/ol.2018.8501

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Risk Assessment in Adult T Cell Leukemia/Lymphoma Treated with Allogeneic Hematopoietic Stem Cell Transplantation2018

    • Author(s)
      Yoshimitsu Makoto、Tanosaki Ryuji、Kato Koji、Ishida Takashi、et al.
    • Journal Title

      Biology of Blood and Marrow Transplantation

      Volume: 24 Issue: 4 Pages: 832-839

    • DOI

      10.1016/j.bbmt.2017.11.005

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cognitive dysfunction among newly diagnosed older patients with hematological malignancy: frequency, clinical indicators and predictors2018

    • Author(s)
      Aiki Sayo、Okuyama Toru、Sugano Koji、Kubota Yosuke、Imai Fuminobu、Nishioka Masahiro、Ito Yoshinori、Iida Shinsuke、Komatsu Hirokazu、Ishida Takashi、Kusumoto Shigeru、Akechi Tatsuo
    • Journal Title

      Japanese Journal of Clinical Oncology

      Volume: 48 Issue: 1 Pages: 61-67

    • DOI

      10.1093/jjco/hyx159

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Clinical significance of tryptophan catabolism in Hodgkin lymphoma2017

    • Author(s)
      Masaki Ayako、Ishida Takashi、Maeda Yasuhiro、Ito Asahi、Suzuki Susumu、Narita Tomoko、Kinoshita Shiori、Takino Hisashi、Yoshida Takashi、Ri Masaki、Kusumoto Shigeru、Komatsu Hirokazu、Inagaki Hiroshi、Ueda Ryuzo、Choi Ilseung、Suehiro Youko、Iida Shinsuke
    • Journal Title

      Cancer Science

      Volume: 109 Issue: 1 Pages: 74-83

    • DOI

      10.1111/cas.13432

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cyclin-dependent kinase 9 is a novel specific molecular target in adult T-cell leukemia/lymphoma2017

    • Author(s)
      Narita Tomoko、Ishida Takashi、Ito Asahi、Masaki Ayako、Kinoshita Shiori、Suzuki Susumu、Takino Hisashi、Yoshida Takashi、Ri Masaki、Kusumoto Shigeru、Komatsu Hirokazu、Imada Kazunori、Tanaka Yuetsu、Takaori-Kondo Akifumi、Inagaki Hiroshi、Scholz Arne、Lienau Philip、Kuroda Taruho、Ueda Ryuzo、Iida Shinsuke
    • Journal Title

      Blood

      Volume: 130 Issue: 9 Pages: 1114-1124

    • DOI

      10.1182/blood-2016-09-741983

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mogamulizumab for relapsed adult T-cell leukemia-lymphoma: Updated follow-up analysis of phase I and II studies2017

    • Author(s)
      Ishida Takashi、Utsunomiya Atae、Jo Tatsuro、Yamamoto Kazuhito、Kato Koji、Yoshida Shinichiro、Takemoto Shigeki、Suzushima Hitoshi、Kobayashi Yukio、Imaizumi Yoshitaka、Yoshimura Kenichi、Kawamura Kouichi、Takahashi Takeshi、Tobinai Kensei、Ueda Ryuzo
    • Journal Title

      Cancer Science

      Volume: 108 Issue: 10 Pages: 2022-2029

    • DOI

      10.1111/cas.13343

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Enhancer profiling identifies critical cancer genes and characterizes cell identity in adult T-cell leukemia2017

    • Author(s)
      Wong Regina Wan Ju、Ngoc Phuong Cao Thi、Leong Wei Zhong、Yam Alice Wei Yee、Zhang Tinghu、Asamitsu Kaori、Iida Shinsuke、Okamoto Takashi、Ueda Ryuzo、Gray Nathanael S.、Ishida Takashi、Sanda Takaomi
    • Journal Title

      Blood

      Volume: 130 Issue: 21 Pages: 2326-2338

    • DOI

      10.1182/blood-2017-06-792184

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Clinical Practice Recommendations on Indication and Timing of Hematopoietic Cell Transplantation in Mature T Cell and NK/T Cell Lymphomas: An International Collaborative Effort on Behalf of the Guidelines Committee of the American Society for Blood and Marrow Transplantation2017

    • Author(s)
      Kharfan-Dabaja Mohamed A.、Kumar Ambuj、Ayala Ernesto、Hamadani Mehdi、Reimer Peter、Gisselbrecht Christian、d'Amore Francesco、Jantunen Esa、Ishida Takashi、et al.
    • Journal Title

      Biology of Blood and Marrow Transplantation

      Volume: 23 Issue: 11 Pages: 1826-1838

    • DOI

      10.1016/j.bbmt.2017.07.027

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Epidemiological and clinical features of adult T-cell leukemia-lymphoma in Japan, 2010-2011: A nationwide survey2017

    • Author(s)
      Nosaka Kisato、Iwanaga Masako、Imaizumi Yoshitaka、Ishitsuka Kenji、Ishizawa Kenichi、Ishida Yoji、Amano Masahiro、Ishida Takashi、Uike Naokuni、Utsunomiya Atae、Ohshima Koichi、Kawai Kazuhiro、Tanaka Junji、Tokura Yoshiki、Tobinai Kensei、Watanabe Toshiki、Uchimaru Kaoru、Tsukasaki Kunihiro
    • Journal Title

      Cancer Science

      Volume: 108 Issue: 12 Pages: 2478-2486

    • DOI

      10.1111/cas.13398

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Romidepsin in Japanese patients with relapsed or refractory peripheral T-cell lymphoma: a phase I/II and pharmacokinetics study.2017

    • Author(s)
      Maruyama D, Tobinai K, Ogura M, Uchida T, Hatake K, Taniwaki M, Ando K, Tsukasaki K, Ishida T, Kobayashi N, Ishizawa K, Tatsumi Y, Kato K, Kiguchi T, Ikezoe T, Laille E, Ro T, Tamakoshi H, Sakurai S, Ohtsu T.
    • Journal Title

      Int J Hematol.

      Volume: 106 Issue: 5 Pages: 655-665

    • DOI

      10.1007/s12185-017-2286-1

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Novel monitoring of hepatitis B reactivation based on ultra-high sensitive hepatitis B surface antigen assay2017

    • Author(s)
      Shinkai N, Kusumoto S, Murakami S, Ogawa S, Ri M, Matsui T, Tamori A, Toyoda H, Ishida T, Iida S, Tanaka Y.
    • Journal Title

      Liver Int.

      Volume: 印刷中 Issue: 8 Pages: 1138-1147

    • DOI

      10.1111/liv.13349

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Multicenter Phase II Study of Lenalidomide in Relapsed or Recurrent Adult T-Cell Leukemia-Lymphoma: ATLL-002.2016

    • Author(s)
      Ishida T, Fujiwara H, Nosaka K, Taira N, Abe Y, Imaizumi Y, Moriuchi Y, Jo T, Ishizawa K, Tobinai K, Tsukasaki K, Ito S, Yoshimitsu M, Otsuka M, Ogura M, Midorikawa S, Ruiz W, Ohtsu T.
    • Journal Title

      J Clin Oncol.

      Volume: 34 Issue: 34 Pages: 4086-4093

    • DOI

      10.1200/jco.2016.67.7732

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effects of first-line chemotherapy on natural killer cells in adult T-cell leukemia-lymphoma and peripheral T-cell lymphoma.2016

    • Author(s)
      Ogura M, Ishida T, Tsukasaki K, Takahashi T, Utsunomiya A.
    • Journal Title

      Cancer Chemother Pharmacol. 2016;78:199-2

      Volume: 78 Issue: 1 Pages: 199-207

    • DOI

      10.1007/s00280-016-3070-2

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed

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Published: 2016-04-21   Modified: 2020-03-30  

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