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Development of Novel Vaccine Immunotherapy for Malignant Glioma

Research Project

Project/Area Number 17H04306
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurosurgery
Research InstitutionKeio University

Principal Investigator

Toda Masahiro  慶應義塾大学, 医学部(信濃町), 准教授 (20217508)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000)
Fiscal Year 2019: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2018: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2017: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Keywords悪性神経膠腫 / 免疫チェックポイント / PD-1 / VEGFR / ネオアンチゲン / 免疫療法 / 脳腫瘍学 / ワクチン / 腫瘍抗原 / 腫瘍免疫
Outline of Final Research Achievements

In the present study, we established a novel combinational immunotherapy using epitope peptide targeting glioma neoantigen and vascular endothelial growth factor receptor (VEGFR)1/2, and anti-programmed cell death (PD)-1. Induced cytotoxic T lymphocytes could kill not only tumor vessel cells but also tumor cells and immunosuppressive regulatory T cells (Tregs) expressing VEGFRs. Remarkable prolonged survival was achieved in the glioma mouse model. Furthermore, we revealed that VEGFR2 is highly expressed in the glioma stem cells (GSCs). This approach could inhibit the proliferation of GSCs in an orthotopic mouse model. The histopathological findings of pre- and post-VEGFRs vaccination glioblastoma specimens demonstrated that more apoptosis was detected in tumor cells, and the number of Foxp3-positive cells decreased after vaccination.
This novel immunotherapy targeting a large variety of cells has the possibility to show higher treatment efficacy for the patients with malignant glioma.

Academic Significance and Societal Importance of the Research Achievements

グリオーマ細胞におけるNeoantigenを標的とするエピトープペプチドと抗PD-1抗体を組み合わせた複合免疫療法に、さらにVEGFR1/VEGFR2を標的とするエピトープペプチドを上乗せすることで、腫瘍細胞のみならず、腫瘍血管内皮細胞や免疫抑制性の制御性T細胞といった腫瘍関連微小環境をも統合的に標的可能であった。さらにBTSCには特にVEGFR2が高発現するため、BTSCを標的とする治療にも応用可能であった。腫瘍の増大には、腫瘍細胞のみならず周囲微小環境が重要な役割を果たすため、本複合免疫療法は新たな治療戦略となり得る。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (27 results)

All 2020 2019 2018 2017

All Journal Article (12 results) (of which Peer Reviewed: 12 results,  Open Access: 9 results) Presentation (10 results) (of which Int'l Joint Research: 1 results,  Invited: 2 results) Book (1 results) Patent(Industrial Property Rights) (4 results)

  • [Journal Article] Clinical and histopathological analyses of VEGF receptors peptide vaccine in patients with primary glioblastoma - a case series.2020

    • Author(s)
      Tamura R, Morimoto Y, Kosugi K, Sato M, Oishi Y, Ueda R, Kikuchi R, Nagashima H, Noji S, Kawakami Y, Sasaki H, Yoshida K, Toda M.
    • Journal Title

      BMC Cancer.

      Volume: Apr 14;20(1) Issue: 1 Pages: 301-301

    • DOI

      10.1186/s12885-020-06783-8

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Quantitative assessment and clinical relevance of VEGFRs-positive tumor cells in refractory brain tumors2020

    • Author(s)
      Tamura Ryota、Sato Mizuto、Morimoto Yukina、Ohara Kentaro、Kosugi Kenzo、Oishi Yumiko、Kuranari Yuki、Murase Makoto、Yoshida Kazunari、Toda Masahiro
    • Journal Title

      Experimental and Molecular Pathology

      Volume: 114 Pages: 104408-104408

    • DOI

      10.1016/j.yexmp.2020.104408

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A VEGF receptor vaccine demonstrates preliminary efficacy in neurofibromatosis type 2.2019

    • Author(s)
      Tamura Ryota, Fujioka Masato, Morimoto Yukina, Ohara Kentaro, Kosugi Kenzo, Oishi Yumiko, Sato Mizuto, Ueda Ryo, Fujiwara Hirokazu, Noji Shinobu, Oishi Naoki, Ogawa Kaoru, Kawakami Yutaka, Ohira Takayuki, Yoshida Kazunari, Toda Masahiro.
    • Journal Title

      Nature Communications

      Volume: 10 Issue: 1 Pages: 5758-5768

    • DOI

      10.1038/s41467-019-13640-1

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A Pilot Study of Vaccine Therapy with Multiple Glioma Oncoantigen/Glioma Angiogenesis-Associated Antigen Peptides for Patients with Recurrent/Progressive High-Grade Glioma2019

    • Author(s)
      Kikuchi Ryogo、Ueda Ryo、Saito Katsuya、Shibao Shunsuke、Nagashima Hideaki、Tamura Ryota、Morimoto Yukina、Sasaki Hikaru、Noji Shinobu、Kawakami Yutaka、Yoshida Kazunari、Toda Masahiro
    • Journal Title

      Journal of Clinical Medicine

      Volume: 8 Issue: 2 Pages: 263-263

    • DOI

      10.3390/jcm8020263

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] An Analysis of Various Tracts of Mastoid Air Cells Related to Cerebrospinal Fluid Leak after the Anterior Transpetrosal Approach.2018

    • Author(s)
      Tamura R, Tomio R, Mohammad F, Toda M, Yoshida K.
    • Journal Title

      J Neurosurg.

      Volume: -

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Histopathological vascular investigation of the peritumoral brain zone of glioblastomas.2018

    • Author(s)
      Tamura R, Ohara K, Sasaki H, Morimoto Y, Yoshida K, Toda M.
    • Journal Title

      J Neurooncol.

      Volume: 136 Issue: 2 Pages: 233-241

    • DOI

      10.1007/s11060-017-2648-9

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The analysis of the cerebral venous blood volume in cavernous sinus using 320 row multi-detector CT.2018

    • Author(s)
      Mizutania K, Toda M, Yajima Y, Akiyama T, Fujiwara H, Yoshida K, Jinzaki M
    • Journal Title

      Clin Neurol Neurosurg

      Volume: 167 Pages: 11-16

    • DOI

      10.1016/j.clineuro.2018.02.007

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Intraosseous venous structures adjacent to the jugular tubercle associated with an anterior condylar dural arteriovenous fistula.2018

    • Author(s)
      Mizutani T, Akiyama T, Minami Y, Toda M, Fujiwara H, Jinzaki M, Yoshida K
    • Journal Title

      Neuroradiology

      Volume: 60 Issue: 5 Pages: 487-496

    • DOI

      10.1007/s00234-018-1990-8

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Stem cell-based therapies for neurological disorders2018

    • Author(s)
      Tamura R, Toda M
    • Journal Title

      AIMS Cell and Tissue Engineering

      Volume: 2 Pages: 24-47

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A pilot study of peptide vaccines for VEGF receptor 1 and 2 in patients with recurrent/progressive high grade glioma2018

    • Author(s)
      Shibao S, Ueda R, Saito K, Kikuchi R, Nagashima H, Kojima A, Kagami H, Sasaki H, Noji S, Kawakami Y, Yoshida K, Toda M
    • Journal Title

      Oncotarget

      Volume: -

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinical and molecular prognostic factors for long-term survival of the patients with glioblastomas in a single institutional consecutive cohort.2017

    • Author(s)
      Nakagawa Y, Sasaki H, Ohara K, Ezaki T, Toda M, Ohira T, Kawase T, Yoshida K.
    • Journal Title

      World Neurosurg.

      Volume: 106 Pages: 165-173

    • DOI

      10.1016/j.wneu.2017.06.126

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Surgical Outcome of Endoscopic Endonasal Surgery for Non-Functional Pituitary Adenoma by a Team of Neurosurgeons and Otolaryngologists Adenoma by a Team of Neurosurgeons and Otolaryngologists.2017

    • Author(s)
      Kikuchi R, Toda M, Tomita T, Ogawa K, Yoshida K.
    • Journal Title

      Turkish Neurosurg.

      Volume: 27 Pages: 1-7

    • DOI

      10.5137/1019-5149.jtn.14354-15.0

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 神経線維腫症2型に対するVEGFRワクチンの病理組織学的検討2019

    • Author(s)
      田村亮太、戸田正博、尾原健太郎、森本佑紀奈、藤岡正人、大石直樹、小川 郁、大平貴之、吉田一成
    • Organizer
      第28回日本聴神経腫瘍研究会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 神経線維腫症2型に対するVEGFRワクチンの臨床試験と今後の展望について2019

    • Author(s)
      戸田正博、田村亮太、森本佑紀奈、藤岡正人、大石直樹、小川 郁、大平貴之、吉田一成
    • Organizer
      第28回日本聴神経腫瘍研究会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 脊索腫におけるVEGF受容体発現解析とペプチドワクチンの臨床試験2019

    • Author(s)
      森本佑紀奈、戸田正博、田村亮太、尾原健太郎、大石裕美子、吉田一成
    • Organizer
      第31回日本頭蓋底外科学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] マウスグリオーマモデルを用いた腫瘍抗原/VEGF receptorワクチンと抗PD-1抗体併用療法の有効性の検討2018

    • Author(s)
      森本佑紀奈、戸田正博、田村亮太、谷口智憲、河上裕、吉田一成
    • Organizer
      第77回 日本脳神経外科学会総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 悪性神経膠腫に対するVEGFR2ワクチンと抗PD-1抗体併用療法の有効性の検討2018

    • Author(s)
      森本佑紀奈、戸田正博、田村亮太、谷口智憲、河上 裕、吉田一成
    • Organizer
      第36回 日本脳腫瘍学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Endoscopic endonasal approach for the treatment of parasellar lesions2017

    • Author(s)
      戸田正博
    • Organizer
      8th World Congress of Neuroendoscopy
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 神経線維腫症2型に対するVEGFR1/2ペプチドワクチンの臨床試験2017

    • Author(s)
      戸田正博、田村亮太、大平貴之、吉田一成
    • Organizer
      第26回日本聴神経腫瘍研究会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 下垂体-傍鞍部腫瘍2017

    • Author(s)
      戸田正博
    • Organizer
      第22回日本脳腫瘍の外科学会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 悪性神経膠腫に対するヒトiPS細胞を用いた自殺遺伝子細胞療法2017

    • Author(s)
      田村亮太、戸田正博、三好浩之、岩澤千鶴、峯 裕、森本佑紀奈、Sampetrean Oltea、佐谷秀行、岡野栄之、吉田一成
    • Organizer
      第35回日本脳腫瘍学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 神経線維腫症2型に対するVEGFRペプチドワクチンの臨床試験2017

    • Author(s)
      戸田正博、田村亮太、大平貴之、吉田一成
    • Organizer
      第35回日本脳腫瘍学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Book] Brain Tumor-Stem cell research for the treatment of malignant glioma.-2017

    • Author(s)
      Toda M, Tamura R
    • Total Pages
      10
    • Publisher
      InTech
    • Related Report
      2017 Annual Research Report
  • [Patent(Industrial Property Rights)] 癌治療用キット2020

    • Inventor(s)
      戸田正博、森本佑紀奈、田村亮太、河上裕、谷口智憲
    • Industrial Property Rights Holder
      戸田正博、森本佑紀奈、田村亮太、河上裕、谷口智憲
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2020-002439
    • Filing Date
      2020
    • Related Report
      2019 Annual Research Report
  • [Patent(Industrial Property Rights)] 神経線維腫症ⅠⅠ型患者に発生する腫瘍に対するペプチドワクチン及びペプチドワクチン組成物2017

    • Inventor(s)
      戸田正博、田村亮太
    • Industrial Property Rights Holder
      慶應義塾
    • Industrial Property Rights Type
      特許
    • Filing Date
      2017
    • Related Report
      2017 Annual Research Report
  • [Patent(Industrial Property Rights)] 脳腫瘍治療用細胞製剤2017

    • Inventor(s)
      戸田正博、岡野栄之、三好浩之、田村亮太
    • Industrial Property Rights Holder
      慶應義塾
    • Industrial Property Rights Type
      特許
    • Filing Date
      2017
    • Related Report
      2017 Annual Research Report
  • [Patent(Industrial Property Rights)] iPS細胞を用いた自殺遺伝子脳腫瘍治療薬2017

    • Inventor(s)
      戸田正博、岡野栄之、三好浩之、田村亮太
    • Industrial Property Rights Holder
      慶應義塾
    • Industrial Property Rights Type
      特許
    • Filing Date
      2017
    • Related Report
      2017 Annual Research Report

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Published: 2017-04-28   Modified: 2021-02-19  

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