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Clinical research on cancer immunotherapy combining the evasion of tumor immunosuppression and active immunity for advanced lung cancer

Research Project

Project/Area Number 18K15928
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 53030:Respiratory medicine-related
Research InstitutionKumamoto University

Principal Investigator

Tomita Yusuke  熊本大学, 病院, 講師 (90648619)

Project Period (FY) 2018-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2021: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000)
Fiscal Year 2020: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords腫瘍免疫 / 腸内細菌叢 / 免疫チェックポイント阻害剤 / 肺がん / T細胞 / dysbiosis / 免疫療法 / 肺癌 / 腸内細菌 / がん免疫 / 腫瘍免疫微小環境 / がん免疫療法 / PDー1 / 腫瘍抗原 / COVID-19 / SARS-CoV-2 / PD-1 / PD-L1 / 末梢血単核球細胞(PBMC) / T 細胞
Outline of Final Research Achievements

The effectiveness of immune checkpoint inhibitors (ICIs) is limited, and the development of new therapeutic strategies is an urgent issue. In this study, we conducted research with the aim of developing a new cancer immunotherapy that combines ICI (tumor immune suppression release) and active immune promotion. We discovered that T cells expressing Drebrin, which is important for the formation of immune synapses between T cells and antigen-presenting cells, are exhausted T cells, and patients with an increased Drebrin-positive T cells infiltrated into tumor cell nests have a high risk of recurrence, suggesting a potential new predictive factor for cancer treatment efficacy. We also conducted research focusing on the possibility that intestinal bacteria promote active immunity, and found that when CBM588 was administered as an intestinal regulation agent, the dysbiosis of intestinal flora was improved and the response to ICI and survival in patients with lung cancer were improved.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、T細胞におけるdrebrin発現が新たな疲弊T細胞マーカーであることを見出したことにより腫瘍免疫学の発展に貢献する。また、肺がんの術後再発予測に貢献すると同時に周術期に用いられるようになった免疫チェックポイント阻害剤(ICI)の新たな効果予測因子同定の一助となりうる成果である。また、腸内細菌叢を標的とした治療により能動免疫を活性化する戦略とICIを組み合わせることにより、新たたな併用療法の可能性を示した。本研究成果は、腸内細菌叢を標的とし進行肺がん治療の開発への論理的根拠を築き、ICI単独では恩恵が得られない患者やICIに薬剤耐性を示す患者への新たな治療法の開発に貢献する。

Report

(7 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • 2020 Research-status Report
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (15 results)

All 2024 2023 2022 2021 2020 2019 2018

All Journal Article (12 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 12 results,  Open Access: 6 results) Presentation (2 results) (of which Invited: 1 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Association of Clostridium butyricum Therapy Using the Live Bacterial Product CBM588 with the Survival of Patients with Lung Cancer Receiving Chemoimmunotherapy Combinations2023

    • Author(s)
      Tomiya Y, Sakata S, Imamura K, Iyama S, Jodai T, et al.
    • Journal Title

      Cancers

      Volume: 16 Issue: 1 Pages: 47-47

    • DOI

      10.3390/cancers16010047

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinical Implications and Molecular Characterization of Drebrin-Positive, Tumor-Infiltrating Exhausted T Cells in Lung Cancer2022

    • Author(s)
      Imamura Kosuke、Tomita Yusuke、Sato Ryo、Ikeda Tokunori、Iyama Shinji、Jodai Takayuki、Takahashi Misako、Takaki Akira、Akaike Kimitaka、Hamada Shohei、Sakata Shinya、Saruwatari Koichi、Saeki Sho、Ikeda Koei、Suzuki Makoto、Sakagami Takuro
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 23 Issue: 22 Pages: 13723-13723

    • DOI

      10.3390/ijms232213723

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Clostridium butyricum therapy restores the decreased efficacy of immune checkpoint blockade in lung cancer patients receiving proton pump inhibitors2022

    • Author(s)
      Tomita Yusuke、Goto Yoshihiko、Sakata Shinya、Imamura Kosuke、Minemura Ayaka、Oka Kentaro、Hayashi Atsushi、Jodai Takayuki、Akaike Kimitaka、Anai Moriyasu、Hamada Shohei、Iyama Shinji、Saruwatari Koichi、Saeki Sho、Takahashi Motomichi、Ikeda Tokunori、Sakagami Takuro
    • Journal Title

      OncoImmunology

      Volume: 11 Issue: 1 Pages: 2081010-2081010

    • DOI

      10.1080/2162402x.2022.2081010

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] In small cell lung cancer patients treated with RRx-001, a downregulator of CD47, decreased expression of PD-L1 on circulating tumor cells significantly correlates with clinical benefit2021

    • Author(s)
      Tomita Yusuke、Oronsky Bryan、Abrouk Nacer、Cabrales Pedro、Reid Tony R.、Lee Min-Jung、Yuno Akira、Baker Jonathan、Lee Sunmin、Trepel Jane B.
    • Journal Title

      Translational Lung Cancer Research

      Volume: 10 Issue: 1 Pages: 274-278

    • DOI

      10.21037/tlcr-20-359

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Association between HLA gene polymorphisms and mortality of COVID‐19: An in silico analysis2020

    • Author(s)
      Tomita Yusuke、Ikeda Tokunori、Sato Ryo、Sakagami Takuro
    • Journal Title

      Immunity, Inflammation and Disease

      Volume: 8 Issue: 4 Pages: 684-694

    • DOI

      10.1002/iid3.358

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] BCG vaccine may generate cross-reactive T cells against SARS-CoV-2: In silico analyses and a hypothesis2020

    • Author(s)
      Tomita Yusuke、Sato Ryo、Ikeda Tokunori、Sakagami Takuro
    • Journal Title

      Vaccine

      Volume: 38 Issue: 41 Pages: 6352-6356

    • DOI

      10.1016/j.vaccine.2020.08.045

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Association of Probiotic Clostridium butyricum Therapy with Survival and Response to Immune Checkpoint Blockade in Patients with Lung Cancer2020

    • Author(s)
      Tomita Yusuke、Ikeda Tokunori、Sakata Shinya、Saruwatari Koichi、Sato Ryo、Iyama Shinji、Jodai Takayuki、Akaike Kimitaka、Ishizuka Shiho、Saeki Sho、Sakagami Takuro
    • Journal Title

      Cancer Immunology Research

      Volume: 8 Issue: 10 Pages: 1236-1242

    • DOI

      10.1158/2326-6066.cir-20-0051

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Heterogeneous Tumor-Immune Microenvironments between Primary and Metastatic Tumors in a Patient with ALK Rearrangement-Positive Large Cell Neuroendocrine Carcinoma2020

    • Author(s)
      Tashiro Takahiro、Imamura Kosuke、Tomita Yusuke、Tamanoi Daisuke、Takaki Akira、Sugahara Kazuaki、Sato Ryo、Saruwatari Koichi、Sakata Shinya、Inaba Megumi、Ushijima Sunao、Hirata Naomi、Sakagami Takuro
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 21 Issue: 24 Pages: 9705-9705

    • DOI

      10.3390/ijms21249705

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Heterogeneous tumor‐immune microenvironments between primary and metastatic carcinoid tumors differentially respond to anti‐PD‐L1 antibody therapy2020

    • Author(s)
      Sakata Shinya、Imamura Kosuke、Tajima Yuka、Masuda Yuiko、Sato Ryo、Yoshida Chieko、Okamoto Shinichiro、Saeki Sho、Tomita Yusuke、Sakagami Takuro
    • Journal Title

      Thoracic Cancer

      Volume: 12 Issue: 3 Pages: 397-401

    • DOI

      10.1111/1759-7714.13772

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The Risks and Benefits of Immune Checkpoint Blockade in Anti-AChR Antibody-Seropositive Non-Small Cell Lung Cancer Patients2019

    • Author(s)
      Saruwatari Koichi、Sato Ryo、Nakane Shunya、Sakata Shinya、Takamatsu Koutaro、Jodai Takayuki、Mito Remi、Horio Yuko、Saeki Sho、Tomita Yusuke、Sakagami Takuro
    • Journal Title

      Cancers

      Volume: 11 Issue: 2 Pages: 140-140

    • DOI

      10.3390/cancers11020140

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Disorder of Coagulation-Fibrinolysis System: An Emerging Toxicity of Anti-PD-1/PD-L1 Monoclonal Antibodies2019

    • Author(s)
      Sato Ryo、Imamura Kosuke、Sakata Shinya、Ikeda Tokunori、Horio Yuko、Iyama Shinji、Akaike Kimitaka、Hamada Shohei、Jodai Takayuki、Nakashima Kei、Ishizuka Shiho、Sato Nahoko、Saruwatari Koichi、Saeki Sho、Tomita Yusuke、Sakagami Takuro
    • Journal Title

      Journal of Clinical Medicine

      Volume: 8 Issue: 6 Pages: 762-762

    • DOI

      10.3390/jcm8060762

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Trousseau's syndrome triggered by an immune checkpoint blockade in a non-small cell lung cancer patient.2018

    • Author(s)
      Yuko Horio Koutaro Takamatsu Daisuke Tamanoi Ryo Sato Koichi Saruwatari Tokunori Ikeda Shunya Nakane Makoto Nakajima Sho Saeki Hidenori Ichiyasu Kazuhiko Fujii Yusuke Tomita
    • Journal Title

      European Journal of Immunology

      Volume: 48 Issue: 10 Pages: 1764-1767

    • DOI

      10.1002/eji.201847645

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Presentation] がん免疫療法における腸内細菌の重要性2023

    • Author(s)
      冨田 雄介
    • Organizer
      第82回九州山口薬学大会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 腸内細菌叢を考慮した進行肺癌の治療2023

    • Author(s)
      冨田 雄介
    • Organizer
      第 91 回日本呼吸器学会・日本結核 非結核性抗酸菌症学会・ 日本サルコイドーシス 肉芽腫性疾患学会 九州支部秋季学術講演会
    • Related Report
      2023 Annual Research Report
  • [Patent(Industrial Property Rights)] CD4-CD8-T細胞を増殖および/または活性化させるための組成物2024

    • Inventor(s)
      冨田雄介 本園千尋 坂上拓郎 高橋志達 岡健太郎 林篤史
    • Industrial Property Rights Holder
      冨田雄介 本園千尋 坂上拓郎 高橋志達 岡健太郎 林篤史
    • Industrial Property Rights Type
      特許
    • Filing Date
      2024
    • Related Report
      2023 Annual Research Report

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Published: 2018-04-23   Modified: 2025-01-30  

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