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

• Project/Area Number: 16H04713
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Iwate 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: ¥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)
• Keywords: CCR4 / 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。

Research Products

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  • DOI: 10.2169/internalmedicine.2082-18
  • NAID: 130007686833
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-08-01
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• [Journal Article] Mogamulizumab treatment elicits autoantibodies attacking the skin in patients with adult T cell leukemia-lymphoma (2019)
  • 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
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  • 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
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• [Journal Article] Cyclin-dependent kinase 9 as a potential specific molecular target in NK-cell leukemia/lymphoma (2018)
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• [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 transplantation (2018)
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• [Journal Article] PD-1 Inhibitor Therapy in Adult T-Cell Leukemia?Lymphoma (2018)
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• [Journal Article] Targeting General Transcriptional Machinery as a Therapeutic Strategy for Adult T-Cell Leukemia (2018)
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• [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 subunits (2018)
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  • Journal Title: Oncotarget Volume: 9 Issue: 11 Pages: 9975-9991
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• [Journal Article] Risk Assessment in Adult T Cell Leukemia/Lymphoma Treated with Allogeneic Hematopoietic Stem Cell Transplantation (2018)
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• [Journal Article] Cognitive dysfunction among newly diagnosed older patients with hematological malignancy: frequency, clinical indicators and predictors (2018)
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• [Journal Article] Clinical significance of tryptophan catabolism in Hodgkin lymphoma (2017)
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  • Journal Title: Cancer Science Volume: 109 Issue: 1 Pages: 74-83
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• [Journal Article] Cyclin-dependent kinase 9 is a novel specific molecular target in adult T-cell leukemia/lymphoma (2017)
  • 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
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• [Journal Article] Mogamulizumab for relapsed adult T-cell leukemia-lymphoma: Updated follow-up analysis of phase I and II studies (2017)
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  • Journal Title: Cancer Science Volume: 108 Issue: 10 Pages: 2022-2029
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• [Journal Article] Enhancer profiling identifies critical cancer genes and characterizes cell identity in adult T-cell leukemia (2017)
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• [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 Transplantation (2017)
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• [Journal Article] Epidemiological and clinical features of adult T-cell leukemia-lymphoma in Japan, 2010-2011: A nationwide survey (2017)
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  • Journal Title: Cancer Science Volume: 108 Issue: 12 Pages: 2478-2486
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• [Journal Article] Romidepsin in Japanese patients with relapsed or refractory peripheral T-cell lymphoma: a phase I/II and pharmacokinetics study. (2017)
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• [Journal Article] Novel monitoring of hepatitis B reactivation based on ultra-high sensitive hepatitis B surface antigen assay (2017)
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• [Journal Article] Multicenter Phase II Study of Lenalidomide in Relapsed or Recurrent Adult T-Cell Leukemia-Lymphoma: ATLL-002. (2016)
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• [Journal Article] Effects of first-line chemotherapy on natural killer cells in adult T-cell leukemia-lymphoma and peripheral T-cell lymphoma. (2016)
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