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Development of new treatment for DLBCL through the analysis of microenvironment in combination with genomic alteration

Research Project

Project/Area Number 19K08818
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionKyushu University

Principal Investigator

Koji Kato  九州大学, 大学病院, 講師 (20571764)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywords悪性リンパ腫 / ゲノム変異 / 微小環境 / 遺伝子変異 / リンパ腫周囲環境 / びまん性大細胞型B細胞リンパ腫
Outline of Research at the Start

本研究では、DLBCLのリンパ腫細胞の遺伝子変化が、どのような免疫機構(サイトカインやB-T細胞相互作用など)を介して、DLBCLの悪性度と相関する特徴的な微小環境を形成するのか、そのメカニズムを明らかにする。さらに、リンパ腫細胞とその周囲微小環境から構成されるDLBCL病変を包括的に評価した新たな層別化スコアの作成を試み、治療標的となるようなシグナル伝達経路や分子を同定、リンパ腫細胞とその周囲微小環境の双方を標的としうる新規治療法の開発を目指す。

Outline of Final Research Achievements

Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell malignancy with varying prognosis. Several prognostic models have been established by focusing primarily on characteristics of lymphoma cells. However, the prognostic impact of the lymphoma microenvironment and its association with characteristics of lymphoma cells are not fully understood. The presence of normal germinal center (GC)-microenvironmental cells, including follicular T cells, macrophage/dendritic cells, and stromal cells in lymphoma tissue indicates a positive therapeutic response. Our prognostic model clearly identified patients with graded prognosis independently of existing prognostic models. We observed increased incidences of genomic alterations associated with poor prognosis in DLBCL tissues lacking GC-microenvironmental cells. These data suggest that the loss of GC-microenvironmental signature dictates clinical outcomes of DLBCL patients reflecting the accumulation of unfavorable molecular signatures.

Academic Significance and Societal Importance of the Research Achievements

現状、DLBCLのリンパ腫細胞のみを標的とする治療開発には、一定の限界があると言わざるを得ない。一方、キメラ抗原受容体T細胞(CAR-T)療法や免疫チェックポイント阻害薬などに代表される免疫治療は、この限界を克服する可能性がある治療として期待されている。今後、これら免疫治療の開発において、その効果を左右する微小環境の理解は必須であり、本研究はその入口となりうる成果と考えられる。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (29 results)

All 2022 2021 2020 2019

All Journal Article (15 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 15 results,  Open Access: 15 results) Presentation (7 results) (of which Int'l Joint Research: 1 results,  Invited: 7 results) Book (7 results)

  • [Journal Article] A Germinal Center-Associated Microenvironmental Signature Reflects Malignant Phenotype and Outcome of DLBCL.2022

    • Author(s)
      Miyawaki K, Kato K, Sugio T, Sasaki K, Miyoshi H, Semba Y, Kikushige Y, Mori Y, Kunisaki Y, Iwasaki H, Miyamoto T, Kuo FC, Aster JC, Ohshima K, Maeda T, Akashi K.
    • Journal Title

      Blood Adv.

      Volume: 6 Issue: 7 Pages: 2388-2402

    • DOI

      10.1182/bloodadvances.2021004618

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Phase 2 study of axicabtagene ciloleucel in Japanese patients with relapsed or refractory large B-cell lymphoma.2022

    • Author(s)
      Kato K, Makita S, Goto H, Kanda J, Fujii N, Shimada K, Akashi K, Izutsu K, Teshima T, Fukuda N, Sumitani T, Sumi H, Shimizu S, Kakurai Y, Yoshikawa K, Tobinai K, Usui N, Hatake K.
    • Journal Title

      Int J Clin Oncol.

      Volume: 27 Issue: 1 Pages: 213-223

    • DOI

      10.1007/s10147-021-02033-4

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma.2022

    • Author(s)
      Bishop MR, Dickinson M, Purtill D, Barba P, Santoro A, Hamad N, Kato K, et al.
    • Journal Title

      N Engl J Med.

      Volume: 386 Issue: 7 Pages: 629-639

    • DOI

      10.1056/nejmoa2116596

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial.2022

    • Author(s)
      Fowler NH, Dickinson M, Dreyling, (7名略), Kato K, et al.
    • Journal Title

      Nat Med.

      Volume: 57 Issue: 2 Pages: 323-325

    • DOI

      10.1038/s41591-021-01622-0

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Phase 2 Study of Tazemetostat for Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma with EZH2 Mutation in Japan.2021

    • Author(s)
      Izutsu K, Ando K, Nishikori M, Shibayama H, Teshima T, Kuroda J, Kato K, Imaizumi Y, Nosaka K, Sakai R, Hojo S, Nakanishi T, Rai S.
    • Journal Title

      Cancer Sci.

      Volume: 62 Issue: 7 Pages: 3627-3635

    • DOI

      10.1111/cas.14937

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Outcomes of allogeneic hematopoietic stem cell transplantation for ATL with HTLV-1 antibody positive donors: Allo-HCT for ATL from HTLV-1 antibody positive donors.2020

    • Author(s)
      Yoshimitsu M, Fuji S, Utsunomiya A, (12名略), Kato K.
    • Journal Title

      Biol Blood Marrow Transplant.

      Volume: 26 Issue: 4 Pages: 718-722

    • DOI

      10.1016/j.bbmt.2019.12.004

    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cyclophosphamide-Induced Tolerance in Allogeneic Transplantation: From Basic Studies to Clinical Application.2020

    • Author(s)
      Kato K, Takeuchi A, Akashi K, Eto M.
    • Journal Title

      Front Immunol.

      Volume: 10 Pages: 3138-3138

    • DOI

      10.3389/fimmu.2019.03138

    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Establishment of a human SIRPA knock-in xenograft mouse model to study human hematopoietic and cancer stem cells2020

    • Author(s)
      Jinnouchi Fumiaki、Yamauchi Takuji、Yurino Ayano、Nunomura Takuya、Nakano Michitaka、Iwamoto Chika、Obara Teppei、Miyawaki Kohta、Kikushige Yoshikane、Kato Koji、Maeda Takahiro、Miyamoto Toshihiro、Baba Eishi、Akashi Koichi、Takenaka Katsuto
    • Journal Title

      Blood

      Volume: - Issue: 19 Pages: 1661-1672

    • DOI

      10.1182/blood.2019002194

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Combination of CD47 and SIRPα constituting the “don't eat me signal” is a prognostic factor in diffuse large B-cell lymphoma.2020

    • Author(s)
      Kazama R, Miyoshi H, Takeuchi M, (8名略), Kato K, Takizawa J, Seto M, Akashi K, Ohshima K.
    • Journal Title

      Cancer Sci.

      Volume: 111 Issue: 7 Pages: 2608-2619

    • DOI

      10.1111/cas.14437

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Efficacy and safety of tisagenlecleucel in Japanese adult patients with relapsed/refractory diffuse large B-cell lymphoma.2020

    • Author(s)
      Goto H, Makita S, Kato K, Tokushige K, Fujita T, Akashi K, Izutsu K, Teshima T.
    • Journal Title

      Int J Clin Oncol.

      Volume: 25 Issue: 9 Pages: 1736-1743

    • DOI

      10.1007/s10147-020-01699-6

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] DA-EPOCH-R combined with high-dose methotrexate in patients with newly diagnosed stage II-IV CD5-positive diffuse large B-cell lymphoma: a single-arm, open-label, phase 2 study2020

    • Author(s)
      Miyazaki K, Asano N, Yamada T, Miyawaki K, Sakai R, Igarashi T, Nishikori M, Ohata K, Sunami K, Yoshida I, Yamamoto G, Takahashi N, Okamoto M, Yano H, Nishimura Y, Tamaru S, Nishikawa M, Izutsu K, Kinoshita T, Suzumiya J, Ohshima K, Kato K, Katayama N, Yamaguchi M
    • Journal Title

      Haematologica

      Volume: - Issue: 9 Pages: 2308-2315

    • DOI

      10.3324/haematol.2019.231076

    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Phase I study of duvelisib in Japanese patients with relapsed or refractory lymphoma.2020

    • Author(s)
      Izutsu K, Kato K, Kiyoi H, Yamamoto G, Shimada K, Akashi K.
    • Journal Title

      Int J Hematol.

      Volume: 112 Issue: 4 Pages: 504-509

    • DOI

      10.1007/s12185-020-02929-3

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A retrospective analysis of haplo-identical HLA-mismatch hematopoietic transplantation without posttransplantation cyclophosphamide for GVHD prophylaxis in patients with adult T-cell leukemia-lymphoma.2019

    • Author(s)
      Yoshimitsu M, Utsunomiya A, Fuji S, Fujiwara H, Fukuda T, Ogawa H, Takatsuka Y, Ishitsuka K, Yokota A, Okumura H, Ishii K, Nishikawa A, Eto T, Yonezawa A, Miyashita K, Tsukada J, Tanaka J, Atsuta Y, Kato K.
    • Journal Title

      Bone Marrow Transplant.

      Volume: 印刷中 Issue: 8 Pages: 1266-1274

    • DOI

      10.1038/s41409-018-0400-5

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The effectiveness of busulfan-based conditioning regimens for stem cell transplantation against lymphomas in children, adolescents, and young adults in Japan.2019

    • Author(s)
      Hori D, Kobayashi R, Fujita N, (2名略), Kato K, (11名略), Mitsui T.
    • Journal Title

      Pediatr Blood Cancer

      Volume: 66 Issue: 10

    • DOI

      10.1002/pbc.27918

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Successful outcome with reduced-intensity condition regimen followed by allogeneic hematopoietic stem cell transplantation for relapsed or refractory anaplastic large-cell lymphoma.2019

    • Author(s)
      Fukano R, Mori T, Fujita N, (2名略), Kato K, (11名略), Tabuchi K.
    • Journal Title

      Int J Hematol.

      Volume: 110 Issue: 6 Pages: 723-728

    • DOI

      10.1007/s12185-019-02748-1

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 造血器腫瘍に対するCAR-T細胞療法への期待と課題2021

    • Author(s)
      加藤 光次
    • Organizer
      第28回 日本輸血・細胞治療学会 秋季シンポジウム
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 造血器腫瘍に対するCAR-T細胞療法の現状と今後2021

    • Author(s)
      加藤 光次
    • Organizer
      第42回日本アフェレシス学会学術大会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] びまん性大細胞型B細胞リンパ腫に対する治療開発2020

    • Author(s)
      加藤 光次
    • Organizer
      第109回日本病理学会総会 (シンポジウム)
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] Treatment approach for relapse after allo-HSCT in patients with adult T-cell leukemia/lymphoma2020

    • Author(s)
      Kato K
    • Organizer
      第82回日本血液学会学術集会(シンポジウム)
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] A germinal center-associated microenvironmental signature predicts clinical outcome of diffuse large B-cell lymphoma.2019

    • Author(s)
      Kato K
    • Organizer
      The 10th JSH International Symposium 2019 (シンポジウム)
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] リンパ腫研究の将来:臨床研究法との関連 基礎研究をどのように臨床応用していくか、学会の果たす役割.2019

    • Author(s)
      加藤 光次
    • Organizer
      第59回日本リンパ網内系学会総会 (シンポジウム)
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] Cell therapyの進歩と今後の展望: 造血器腫瘍におけるCAR-T治療の現況と課題.2019

    • Author(s)
      加藤 光次
    • Organizer
      第17回日本臨床腫瘍学会総会 (シンポジウム)
    • Related Report
      2019 Research-status Report
    • Invited
  • [Book] 悪性リンパ腫治療マニュアル 改訂第5版2021

    • Author(s)
      加藤 光次
    • Total Pages
      6
    • Publisher
      南江堂
    • ISBN
      9784524226450
    • Related Report
      2021 Annual Research Report
  • [Book] 悪性リンパ腫治療マニュアル 改訂第5版 末梢性T細胞リンパ腫2021

    • Author(s)
      加藤 光次
    • Total Pages
      6
    • Publisher
      南江堂
    • ISBN
      9784524226450
    • Related Report
      2020 Research-status Report
  • [Book] 今日の治療指針 2020年版 -私はこう治療している 血液疾患 非ホジキンリンパ腫2020

    • Author(s)
      加藤 光次
    • Total Pages
      5
    • Publisher
      医学書院
    • ISBN
      9784260039390
    • Related Report
      2020 Research-status Report
  • [Book] 今日の治療指針 2020年版「今日の治療指針 2020年版 -私はこう治療している 血液疾患 非ホジキンリンパ腫」2020

    • Author(s)
      加藤 光次
    • Total Pages
      5
    • Publisher
      医学書院
    • ISBN
      9784260039390
    • Related Report
      2019 Research-status Report
  • [Book] 血液専門医テキスト 改訂第3版 「分子標的薬の作用機序と副作用」2019

    • Author(s)
      加藤 光次
    • Total Pages
      7
    • Publisher
      南江堂
    • ISBN
      9784524248827
    • Related Report
      2019 Research-status Report
  • [Book] 血液疾患最新の治療 2019-2020「造血幹細胞移植: 移植にむけたブリッジング治療に伴う注意すべき合併症」2019

    • Author(s)
      加藤 光次
    • Total Pages
      4
    • Publisher
      南江堂
    • ISBN
      9784524249787
    • Related Report
      2019 Research-status Report
  • [Book] ファーマナビゲーターDIC改訂版「造血幹細胞移植に伴う合併症に対して,抗凝固療法はどの程度期待できますか」2019

    • Author(s)
      加藤 光次
    • Total Pages
      8
    • Publisher
      メディカルレビュー社
    • ISBN
      9784779222337
    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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