The development of immunotherapy in malignant brain tumor to overcome cancer immunosuppression and immune evasion

• Project/Area Number: 25861270
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurosurgery
• Research Institution: National Hospital Organization Nagoya Medical Center
• Principal Investigator: Ohno Masasuke 独立行政法人国立病院機構(名古屋医療センター臨床研究センター), その他部局等, その他 (40402606)
• Co-Investigator(Renkei-kenkyūsha): NATSUME Atsushi 名古屋大学, 医学系研究科, 准教授 (30362255)
• Research Collaborator: OKADA Hideho ピッツバーグ大学, 脳神経外科, 教授 ; KURAMITSU Shunichiro 名古屋大学, 医学系研究科 ; SHIINA Satoshi 名古屋大学, 医学系研究科
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2014: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: cancer immunotherapy / CAR / glioblastoma / immunomodulatory drug / gene therapy / micro RNA / CAR T-Cell Therapy / immune modulator drugs / podplanin / immunotherapy / 免疫療法 / 遺伝子治療 / microRNA / 国際発表 アメリカ合衆国 / 細胞療法 / 養子免疫療法 / 免疫抑制 / 遺伝子療法

Outline of Final Research Achievements

Glioblastoma (GBM) is the most lethal malignant brain tumor in adults despite the improvement on outcomes with this combined chemoradiotherapy approach after maximal surgical resection. In recent years, immunotherapy has emerged as a promising strategy for the treatment of GBM, especially CAR T-cell therapy is considered to be the most promising method to cure cancer. Chimeric antigen receptor (CAR)-transduced T cells can recognize pre-defined tumor surface antigens independent of MHC restriction, which is often downregulated in GBM. We constructed several CARs that recognize antigens expressing on the surface of GBM cells. We also developed new combination therapies to overcome cancer immunosuppression and immune evasion. Additional gene therapy or immunomodulatory drug therapy showed marked improvements in the survival time of the mice models of GBM.

Research Products

• [Journal Article] CAR T Cells Targeting Podoplanin Reduce Orthotopic Glioblastomas in Mouse Brains (2016)
  • Author(s): Shiina S, Ohno M, Ohka F, Kuramitsu S, Yamamichi A, Kato A, Motomura K, Tanahashi K, Yamamoto T, Watanabe R, Ito I, Senga T, Hamaguchi M, Wakabayashi T, Kaneko MK, Kato Y, Chandramohan V, Bigner DD, Natsume A
  • Journal Title: Cancer immunology research Volume: 4 Issue: 3 Pages: 259-268
  • DOI: 10.1158/2326-6066.cir-15-0060
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Lenalidomide enhances the function of chimeric antigen receptor T cells against the epidermal growth factor receptor variant III by enhancing immune synapses (2015)
  • Author(s): Kuramitsu S, Ohno M, Ohka F, Shiina S, Yamamichi A, Kato A, Tanahashi K, Motomura K, Kondo G, Kurimoto M, Senga T, Wakabayashi T, Natsume A
  • Journal Title: Cancer Gene Therpy Volume: 22 Issue: 10 Pages: 487-495
  • DOI: 10.1038/cgt.2015.47
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Expression of miR-17-92 enhances anti-tumor activity of T-cells transduced with the anti-EGFRvIII chimeric antigen receptor in mice bearing human GBM xenografts (2013)
  • Author(s): Masasuke Ohno, Takayuki Ohkuri, Akemi Kosaka, Kuniaki Tanahashi, Carl H June, Atsushi Natsume, Hideho Okada
  • Journal Title: Journal for ImmunoTherapy of Cancer Volume: 1 Issue: 1 Pages: 112-112
  • DOI: 10.1186/2051-1426-1-21
  • Peer Reviewed
• [Presentation] Podoplanin 特異的キメラ抗原受容体を発現する T 細胞の GBM に対する抗腫瘍効果の検討 (2014)
  • Author(s): 椎名 諭、夏目 敦至、大野 真佐輔、倉光 俊一郎、加藤 幸成、Darell D. Bigner、若林 俊彦
  • Organizer: 第32回日本脳腫瘍学会学術集会
  • Place of Presentation: 千葉県浦安市舞浜
  • Year and Date: 2014-11-30 – 2014-12-02
• [Presentation] 免役シナプスを強化する lenalidomide と EGFRvIII キメラ抗原受容体発現 T 細胞の併用効果 (2014)
  • Author(s): 倉光 俊一郎 、夏目 敦至、大野 真佐輔、椎名 諭、若林 俊彦
  • Organizer: 第32回日本脳腫瘍学会学術集会
  • Place of Presentation: 千葉県浦安市舞浜
  • Year and Date: 2014-11-30 – 2014-12-02
• [Presentation] GBMに対するPodoplanin特異的キメラ抗原受容体を発現するT細胞の抗腫瘍効果の検討 (2014)
  • Author(s): 椎名 諭、夏目 敦至、大野 真佐輔、倉光 俊一郎、加藤 幸成、Darell D. Bigner、若林 俊彦
  • Organizer: 日本脳神経外科学会第73回学術総会
  • Place of Presentation: 東京都港区高輪
  • Year and Date: 2014-10-09 – 2014-10-11
• [Presentation] Expression of miR-17-92 enhances anti-tumor activity of T-cells transduced with the anti-EGFRvIII chimeric antigen receptor in mice bearing human GBM xenografts (2014)
  • Author(s): Masasuke Ohno, Takayuki Ohkuri, Akemi Kosaka, Carl H. June, Atsushi Natusme, Hideho Okada
  • Organizer: American Association for Cancer Research（AACR）, Annual Meeting 2014
  • Place of Presentation: San Diego, CA, U.S.A
  • Year and Date: 2014-04-05 – 2014-04-09
• [Presentation] EGFRｖIII特異的キメラ抗原レセプターを発現するT細胞へのmiR-17-92遺伝子導入はマウスGBMモデルにおいて抗腫瘍活性を増強させる (2013)
  • Author(s): 大野真佐輔 大栗敬幸 小坂朱 棚橋邦明 若林俊彦 夏目敦至 岡田秀穂
  • Organizer: 第72回日本脳神経外科学会
  • Place of Presentation: パシフィコ横浜
• [Presentation] GBMに対する化学療法による低免疫環境に耐性を持つ遺伝子改変T細胞療法の開発 (2013)
  • Author(s): 大野真佐輔 大栗敬幸 小坂朱 棚橋邦明 若林俊彦 夏目敦至 岡田秀穂
  • Organizer: 第31回日本脳腫瘍学会学術集会
  • Place of Presentation: 宮崎県宮崎市山崎町浜山 フェニックス・シーガイア・リゾート