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膠芽腫微小環境の理解に基づくNKT細胞標的治療の開発

Research Project

Project/Area Number 23K24441
Project/Area Number (Other) 22H03182 (2022-2023)
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeMulti-year Fund (2024)
Single-year Grants (2022-2023)
Section一般
Review Section Basic Section 56010:Neurosurgery-related
Research InstitutionChiba University

Principal Investigator

本橋 新一郎  千葉大学, 大学院医学研究院, 教授 (60345022)

Co-Investigator(Kenkyū-buntansha) 木村 元子  千葉大学, 大学院医学研究院, 教授 (00345018)
小林 正芳  千葉大学, 医学部附属病院, 助教 (10867857)
岩立 康男  千葉大学, 大学院医学研究院, 教授 (70272309)
Project Period (FY) 2022-04-01 – 2025-03-31
Project Status Granted (Fiscal Year 2024)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2024: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2023: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2022: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000)
Keywords免疫療法 / 膠芽腫 / NKT細胞 / iPS細胞
Outline of Research at the Start

悪性脳腫瘍である膠芽腫はあらゆるがんの中で最も予後不良であり、有効な治療法が求められている。近年、免疫療法が多くのがんで標準治療となったが、膠芽腫に対して有効性が確立したものはない。そこで本研究では膠芽腫の治療成績向上に向けて、膠芽腫に対するNKT細胞を用いたがん免疫療法の確立を目指し、NKT細胞による腫瘍認識機構や抗腫瘍効果発揮メカニズムを明らかとし、臨床研究実施に向けた基盤構築を行う。

Outline of Annual Research Achievements

膠芽腫はヒトの悪性腫瘍の中でも最も予後不良な疾患である。そこで膠芽腫に対する新たな治療法開発研究として、ヒト膠芽腫を移植したマウスモデルを用いて、NKT細胞の養子免疫療法に関する抗腫瘍効果の検討を行った。
ヒトIL-7/IL-15遺伝子を導入した重症免疫不全マウスであるIL7/15 KI-NSGマウスに膠芽腫細胞株を用いた樹立した同所性マウスモデルに対して、ヒト末梢血由来NKT細胞の腫瘍局所投与として髄腔内投与による養子免疫療法を行った。その結果、NKT細胞が他の免疫細胞へのアジュバント効果を発揮できる環境をマウス内に再構築した場合にのみ、末梢血由来NKT細胞の髄腔内投与による腫瘍増大抑制や全生存期間の延長といった抗腫瘍効果を認めた。NKT細胞投与後に脳組織を摘出し、腫瘍浸潤リンパ球(TIL)を抽出して単細胞RNA-sequence解析を実施し、NKT細胞の示すアジュバント効果発揮の機序解明を行っている。
さらに、iPS細胞由来NKT細胞(iPS-NKT細胞)を用いた養子免疫療法の有効性について、同じ膠芽腫細胞株による同所性モデルを用いて検討を行った。その結果、iPS-NKT細胞の腫瘍内投与によっても、腫瘍増大の抑制や全生存期間の延長といった明らかな抗腫瘍効果を認めることを確認した。さらにiPS-NKT細胞の投与自体の安全性を確認するために、神経系に対する影響についても確認を行った。末梢血由来NKT細胞とiPS-NKT細胞による抗腫瘍効果発揮メカニズムの差異について詳細な検討を行っている。

Current Status of Research Progress
Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

NKT細胞の投与方法について新たに髄腔内投与法を確立し、その抗腫瘍効果の作用機序について、腫瘍浸潤リンパ球を用いた単細胞RNA-sequence解析を行った。さらに膠芽腫に対するiPS-NKT細胞の抗腫瘍効果についても確認した。

Strategy for Future Research Activity

IL-7/IL-15 KI NSGマウスに樹立した膠芽腫細胞株を用いた同所性モデルを用いて、NKT細胞およびiPS-NKT細胞の局所投与の有効性の検討及び作用機序の解明を継続する。膠芽腫同所性モデルから採取したTILを用いて行った単細胞RNA-sequence解析の結果から、抗腫瘍効果を増強する分子を同定し、iPS細胞への遺伝子導入を行って抗腫瘍効果の増強効果を確認する。さらにNKT細胞を用いた養子免疫療法に併用する候補薬剤を同定し、NKT細胞を用いた新たな併用療法の有効性について検討する。

Report

(2 results)
  • 2023 Annual Research Report
  • 2022 Annual Research Report
  • Research Products

    (24 results)

All 2024 2023 2022

All Journal Article (8 results) (of which Peer Reviewed: 8 results,  Open Access: 7 results) Presentation (16 results) (of which Int'l Joint Research: 2 results,  Invited: 6 results)

  • [Journal Article] Progress in Natural Killer T Cell-Based Immunotherapy for Cancer: Use of Allogeneic and Gene-Edited Cells2024

    • Author(s)
      Aoki Takahiro、Motohashi Shinichiro
    • Journal Title

      Critical Reviews in Oncogenesis

      Volume: 29 Issue: 1 Pages: 1-9

    • DOI

      10.1615/critrevoncog.2023049526

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Anti-Vα24Jα18 TCR Antibody Tunes iNKT Cell Responses to Target and Kill CD1d-negative Tumors in an FcγRII (CD32)-dependent Manner2024

    • Author(s)
      Takami Mariko、Aoki Takahiro、Nishimura Katsuhiro、Tanaka Hidekazu、Onodera Atsushi、Motohashi Shinichiro
    • Journal Title

      Cancer Research Communications

      Volume: 4 Issue: 2 Pages: 446-459

    • DOI

      10.1158/2767-9764.crc-23-0203

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Regeneration of invariant natural killer T (iNKT) cells: application of iPSC technology for iNKT cell-targeted tumor immunotherapy2023

    • Author(s)
      Aoki Takahiro、Motohashi Shinichiro、Koseki Haruhiko
    • Journal Title

      Inflammation and Regeneration

      Volume: 43 Issue: 1 Pages: 27-27

    • DOI

      10.1186/s41232-023-00275-5

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] CD69 Imposes Tumor-Specific CD8+ T-cell Fate in Tumor-Draining Lymph Nodes2023

    • Author(s)
      Koyama-Nasu Ryo、Kimura Motoko Y.、Kiuchi Masahiro、Aoki Ami、Wang Yangsong、Mita Yukiyoshi、Hasegawa Ichita、Endo Yukihiro、Onodera Atsushi、Hirahara Kiyoshi、Motohashi Shinichiro、Nakayama Toshinori
    • Journal Title

      Cancer Immunology Research

      Volume: 11 Issue: 8 Pages: 1085-1099

    • DOI

      10.1158/2326-6066.cir-22-0406

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Anti-CD20 Antibody and Calcineurin Inhibitor Combination Therapy Effectively Suppresses Antibody-Mediated Rejection in Murine Orthotopic Lung Transplantation.2023

    • Author(s)
      Matsumoto H, Suzuki H, Yamanaka T, Kaiho T, Hata A, Inage T, Ito T, Kamata T, Tanaka K, Sakairi Y, Motohashi S, Yoshino I.
    • Journal Title

      Life (Basel)

      Volume: 13(10) Issue: 10 Pages: 2042-2042

    • DOI

      10.3390/life13102042

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Immunomodulatory Cell Therapy Using αGalCer-Pulsed Dendritic Cells Ameliorates Heart Failure in a Murine Dilated Cardiomyopathy Model.2022

    • Author(s)
      Ikeda M, Ide T, Matsushima S, Ikeda S, Okabe K, Ishikita A, Tadokoro T, Sada M, Abe K, Sato M, Hanada A, Arai S, Ohtani K, Nonami A, Mizuno S, Morimoto S, Motohashi S, Akashi K, Taniguchi M, Tsutsui H.
    • Journal Title

      Circ Heart Fail.

      Volume: 15 Issue: 12 Pages: 1125-1139

    • DOI

      10.1161/circheartfailure.122.009366

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Antibodies against complement component C5 prevent antibody-mediated rejection after lung transplantation in murine orthotopic models with skin-graft-induced pre-sensitization2022

    • Author(s)
      Shiina Yuki、Suzuki Hidemi、Hata Atsushi、Kaiho Taisuke、Matsumoto Hiroki、Toyoda Takahide、Sakairi Yuichi、Wada Hironobu、Motohashi Shinichiro、Yoshino Ichiro
    • Journal Title

      General Thoracic and Cardiovascular Surgery

      Volume: 70 Issue: 12 Pages: 1032-1041

    • DOI

      10.1007/s11748-022-01844-0

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effect of Atezolizumab plus Bevacizumab in Patients with Hepatocellular Carcinoma Harboring CTNNB1 Mutation in Early Clinical Experience.2022

    • Author(s)
      Ogawa K, Kanzaki H, Chiba T, Ao J, Qiang N, et al.
    • Journal Title

      J Cancer

      Volume: 13 Issue: 8 Pages: 2656-2661

    • DOI

      10.7150/jca.71494

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] iPS cell-derived NKT cells retain the adjuvant activity of inducing memory phenotype T cells2024

    • Author(s)
      Aoki, T., Motohashi, S., Koseki, H.
    • Organizer
      第52回日本免疫学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] CD69 regulates tumor-specific CD8 T cell differentiation in tumor-draining lymph nodes2024

    • Author(s)
      Nasu, R., Wang, Y., Endo, Y., Hasegawa, I., Mita, Y., Motohashi, S., Nakayama, T., Kimura, MY.
    • Organizer
      第52回日本免疫学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] HER2/CD3 bispecific antibody enhances antitumor immunity of NKT cells in lung cancer2024

    • Author(s)
      Takami, M., Motohashi, S.
    • Organizer
      第52回日本免疫学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Clinical application of iPS cell-derived NKT cells to cancer immunotherapy2024

    • Author(s)
      Motohashi, S. Aoki, T., Takami, M.
    • Organizer
      CD1-MR1 2024
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] HER2/CD3 bispecific antibody induces antitumor immunity of NKT cells in lung cancer2024

    • Author(s)
      Takami, M., Motohashi, S.
    • Organizer
      CD1-MR1 2024
    • Related Report
      2023 Annual Research Report
  • [Presentation] Current status and future perspective of cancer immunotherapy using allogeneic iPS cell-derived NKT cells2023

    • Author(s)
      本橋新一郎
    • Organizer
      第110回日本泌尿器科学会総会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] iPS cell-derived NKT cells show indirect anti-tumor effect with inducing tumor-reactive T cells with memory phenotype2023

    • Author(s)
      Aoki, T., Okoshi, M., Kobayashi, M., Yamaguchi, M., Okura, H., Yakushiji, N., Kawamura, M., Fujii, S., Motohashi, S., Koseki, H.
    • Organizer
      第27回日本がん免疫学会総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Anti-Va24Ja18 TCR antibody enhances NKT cell responses to target and kill CD1d (-) tumors in a CD32 dependent manner2023

    • Author(s)
      Takami, M., Motohashi, S.
    • Organizer
      第27回日本がん免疫学会総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 自然免疫系リンパ球を用いた遺伝子改変養子免疫療法の現状と課題2023

    • Author(s)
      本橋新一郎
    • Organizer
      第64回日本肺癌学会学術集会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 他家NKT細胞を用いたがん免疫療法へのアプローチ2023

    • Author(s)
      本橋新一郎
    • Organizer
      第36回日本バイオセラピィ学会学術集会総会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] iPS 細胞を用いたがん免疫細胞療法2022

    • Author(s)
      本橋新一郎, 飯沼智久, 青木孝浩
    • Organizer
      第11回JAPSAM PRP・幹細胞研究会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Alpha-galactosylceramide-loaded antigen-presenting cells induce direct cytotoxicity and adjuvant effects of induced pluripotent stem cell-derived natural killer T cells.2022

    • Author(s)
      Aoki, T., Kitahara, G., Okoshi, M., Kobayashi, M., Yamaguchi, M., Okura, H., Kawamura, M., Iyoda, T., Shimizu, K., Fujii, S., Motohashi, S., Koseki, H.
    • Organizer
      第51回日本免疫学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Anti-NKT cell antibody treatment enhances anti-tumor activity of NKT cells toward CD1d (-) tumors in a CD32 dependent manner.2022

    • Author(s)
      Takami, M., Motohashi, S.
    • Organizer
      第51回日本免疫学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Blockade of aryl hydrocarbon receptor (AhR) signaling enhances anti-tumor efficacy of iNKT cell-based immunotherapy.2022

    • Author(s)
      Ishii, A., Takami, M., Motohashi, S.
    • Organizer
      第51回日本免疫学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Clinical application of iPS cell-derived NKT cells to cancer immunotherapy.2022

    • Author(s)
      Motohashi, S.
    • Organizer
      EMBO workshop CD1/MR1-restricted T lymphocytes
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Anti-NKT cell antibody treatment enhances anti-tumor activity of NKT cells toward CD1d (-) tumors in a CD32 dependent manner.2022

    • Author(s)
      Takami, M., Motohashi, S.
    • Organizer
      EMBO workshop CD1/MR1-restricted T lymphocytes
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research

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Published: 2022-04-19   Modified: 2024-12-25  

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