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Development of CAR function-tuning technology that contributes to the optimization of CAR-T cell therapy

Research Project

Project/Area Number 20K20462
Project/Area Number (Other) 19H05552 (2019)
Research Category

Grant-in-Aid for Challenging Research (Pioneering)

Allocation TypeMulti-year Fund (2020)
Single-year Grants (2019)
Review Section Medium-sized Section 47:Pharmaceutical sciences and related fields
Research InstitutionOsaka University

Principal Investigator

Okada Naoki  大阪大学, 大学院薬学研究科, 教授 (90312123)

Project Period (FY) 2019-06-28 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥26,000,000 (Direct Cost: ¥20,000,000、Indirect Cost: ¥6,000,000)
Fiscal Year 2021: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
Fiscal Year 2020: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000)
Fiscal Year 2019: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000)
Keywordsキメラ抗原受容体 / 構造活性相関 / 細胞療法 / 腫瘍免疫
Outline of Research at the Start

本研究が目指すCARの構造活性相関に関する体系的な基礎情報の集積によって、これまでは経験則に基づきつつも半ば闇雲に構築されてきたCARの設計思想に有効性増強や副作用低減のための構造情報を導入することが可能となる。本研究成果が個々の研究者が独自構造のCARを用いて進めている研究に活用されることで有効性の向上や副作用の低減に貢献し、さらにそれらの情報を統合することによって理論的・科学的根拠に基づいたCAR設計・創製技術の開発へとつながることが期待される。

Outline of Final Research Achievements

(1) Among CARs constructed using various scFv clones, there are structures that are expressed on the T cell membrane but have very poor antigen-binding affinity, or that aggregate in cytosol.
(2) The hinge domain (HD) defines the expression efficiency and signal input threshold of CAR by its structure (length and flexibility) or complex formation, and the transmembrane domain (TMD) defines CAR expression stability on the cell membrane or subcellular localization of CAR.
(3) When designing the intracellular signal transduction domain (STD) of the second-generation CAR, it is necessary to consider not only the signal characteristics of STDs, but also CAR intracellular structural changes.

Academic Significance and Societal Importance of the Research Achievements

がん免疫療法が標的とする抗原分子の多くは、量の多寡はあるもののがん細胞のみならず正常細胞にも発現している。抗体療法やワクチン療法といった患者体内の免疫細胞にがん細胞の排除を担わせる免疫療法においては、標的分子のがん細胞/正常細胞発現比の大きいことが主作用と副作用の分離に必須の条件とされてきた。一方、それ自身ががん細胞を傷害するCAR-T細胞医薬においては、CAR機能のチューニングを行うことによって標的分子密度をより厳密に見分けた作用発揮のON/OFFが実現できるかもしれない。本研究の成果たるCARの構造活性相関情報は、有効性増強や副作用低減のための構造情報を導入したCAR設計に貢献する。

Report

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

    (16 results)

All 2022 2021 2020 2019

All Journal Article (7 results) (of which Peer Reviewed: 7 results,  Open Access: 5 results) Presentation (9 results)

  • [Journal Article] Binding and Efficacy of Anti-Robo4 CAR-T Cells against Solid Tumors2022

    • Author(s)
      Hirobe Sachiko、Nagai Seina、Tachibana Masashi、Okada Naoki
    • Journal Title

      Biomedicines

      Volume: 10 Issue: 6 Pages: 1273-1273

    • DOI

      10.3390/biomedicines10061273

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The Effects of Chimeric Antigen Receptor (CAR) Hinge Domain Post-Translational Modifications on CAR-T Cell Activity2022

    • Author(s)
      Hirobe Sachiko、Imaeda Keisuke、Tachibana Masashi、Okada Naoki
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 23 Issue: 7 Pages: 4056-4056

    • DOI

      10.3390/ijms23074056

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Structure of the Signal Transduction Domain in Second-Generation CAR Regulates the Input Efficiency of CAR Signals2021

    • Author(s)
      Fujiwara Kento、Kitaura Masaki、Tsunei Ayaka、Kusabuka Hotaka、Ogaki Erika、Okada Naoki
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 5 Pages: 2476-2476

    • DOI

      10.3390/ijms22052476

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Predicting the Efficacy and Safety of TACTICs (Tumor Angiogenesis-Specific CAR-T Cells Impacting Cancers) Therapy for Soft Tissue Sarcoma Patients2020

    • Author(s)
      Fujiwara Kento、Sasawatari Shigemi、Nakai Sho、Imaeda Keisuke、Nagai Seina、Matsuno Yoshihiro、Hatanaka Kanako、Hatanaka Yutaka、Takenaka Satoshi、Okada Naoki
    • Journal Title

      Cancers

      Volume: 12 Issue: 10 Pages: 2735-2735

    • DOI

      10.3390/cancers12102735

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Development and functional analysis of an anticancer T‐cell medicine with immune checkpoint inhibitory ability2020

    • Author(s)
      Fujiwara Kento、Shigematsu Kazuki、Tachibana Masashi、Okada Naoki
    • Journal Title

      IUBMB Life

      Volume: 72 Issue: 8 Pages: 1649-1658

    • DOI

      10.1002/iub.2280

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Impact of scFv structure in chimeric antigen receptor on receptor expression efficiency and antigen recognition properties2020

    • Author(s)
      Fujiwara Kento、Masutani Mizuki、Tachibana Masashi、Okada Naoki
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 527 Issue: 2 Pages: 350-357

    • DOI

      10.1016/j.bbrc.2020.03.071

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Hinge and Transmembrane Domains of Chimeric Antigen Receptor Regulate Receptor Expression and Signaling Threshold2020

    • Author(s)
      Fujiwara Kento、Tsunei Ayaka、Kusabuka Hotaka、Ogaki Erika、Tachibana Masashi、Okada Naoki
    • Journal Title

      Cells

      Volume: 9 Issue: 5 Pages: 1182-1182

    • DOI

      10.3390/cells9051182

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 長井聖奈, 立花雅史, 岡田直貴2021

    • Author(s)
      抗原親和性の異なる抗Robo4 CAR-T細胞間での抗腫瘍効果の比較
    • Organizer
      日本薬学会第141年会
    • Related Report
      2020 Research-status Report
  • [Presentation] 軟部肉腫に対する腫瘍血管障害性CAR-T細胞療法の奏功予測研究2020

    • Author(s)
      第53回日本整形外科学会 骨・軟部腫瘍学術集会
    • Organizer
      中井 翔, 藤原健人, 今枝啓輔, 長井聖奈, 安田直弘, 前 裕和, 王谷英達, 濱田健一郎, 岡田直貴, 竹中 聡
    • Related Report
      2020 Research-status Report
  • [Presentation] 固形がんに対する抗Robo4 CAR-T細胞療法の開発に向けた基礎的検討2020

    • Author(s)
      長井聖奈, 藤原健人, 立花雅史, 岡田直貴
    • Organizer
      第36回日本DDS学会学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] キメラ抗原受容体 (CAR) が受ける翻訳後修飾のCAR-T細胞機能への影響2020

    • Author(s)
      今枝啓輔, 藤原健人, 立花雅史, 岡田直貴
    • Organizer
      日本薬学会第140年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 固形がんに対するCAR-T細胞療法におけるROBO4標的化の有用性評価とROBO4特異的CARの構築2020

    • Author(s)
      長井聖奈, 藤原健人, 福井麻琴, 立花雅史, 岡田直貴
    • Organizer
      日本薬学会第140年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 軟部肉腫に対する腫瘍血管傷害性CAR-T細胞療法の有効性・安全性予測に関する検討2020

    • Author(s)
      藤原健人, 中井 翔, 安田直弘, 王谷英達, 濱田健一郎, 竹中 聡, 立花雅史, 岡田直貴
    • Organizer
      日本薬学会第140年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Research to predict the effectiveness of tumor vessel-injuring CAR-T cell therapy for soft tissue sarcoma2019

    • Author(s)
      Kento Fujiwara, Sho Nakai, Naohiro Yasuda, Hidetatsu Otani, Kenichiro Hamada, Satoshi Takenaka, Masashi Tachibana, Naoki Okada
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] CARの細胞外領域に適したscFv構築法の確立に向けた基礎的検討2019

    • Author(s)
      藤原健人, 升谷美月, 立花雅史, 岡田直貴
    • Organizer
      第23回日本がん免疫学会総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] キメラ抗原受容体のscFv構造と膜発現強度との連関解析2019

    • Author(s)
      藤原健人, 升谷美月, 立花雅史, 岡田直貴
    • Organizer
      第19回日本蛋白質科学会年会/第71回日本細胞生物学会大会 合同年次大会
    • Related Report
      2019 Annual Research Report

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Published: 2019-07-04   Modified: 2024-03-26  

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