Combined therapy with natural killer cell and anti PD-1 antibody for glioblastoma

• Project/Area Number: 16K10768
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Nara Medical University
• Principal Investigator: Ryosuke Matsuda 奈良県立医科大学, 医学部, 学内講師 (60453164)
• Co-Investigator(Kenkyū-buntansha): 中村 光利 奈良県立医科大学, 医学部附属病院, 研究員 (00305715) ; 中澤 務 奈良県立医科大学, 医学部, 研究員 (00772500)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: glioblastoma / Natural killer cell / anti PD-1 antibody / immunotherapy / 膠芽腫 / γδT細胞 / NK細胞 / 抗PD-1抗体 / チェックポイント阻害剤 / 化学療法 / NOGマウス / PD-1 / 脳神経疾患 / 脳腫瘍 / 免疫チェックポインント阻害剤

Outline of Final Research Achievements

We established an effective method for the expansion of highly purified natural killer(NK) cells derived from human PBMCs. In this study, we examined the combined therapy with NK cells and anti PD-1 antibody for NOG mouse with subcutaneous injection of U87MG cells.The retro-orbital administration of NK cells and IL-2 prolonged the survival of NOG mice bearing U87MG-derived tumors. The administration of anti-PD-1 antibodies with NK cells and IL-2 did not show any additive effect on survival.

Academic Significance and Societal Importance of the Research Achievements

膠芽腫は現在の標準治療である手術、放射線療法、化学療法をもってしても予後不良の腫瘍である。我々はこれまで免疫治療の1つであるNK細胞について研究を行ってきた。がん細胞ががんに対する免疫監視機構から逃避すると、その効果は減弱されうる。脳腫瘍における抗PD-1抗体の治療効果についての報告は少ない。抗PD-1抗体とNK細胞を併用することにより、膠芽腫モデルに対して両者の相乗効果について検討した。結果、NK細胞においては、PD-1の発現自体が低く、今回のin vitro実験、in vivo実験ともに、抗PD-1抗体によるNK細胞との相乗効果は得られなかった。

Research Products

• [Journal Article] Ex vivo-expanded highly purified natural killer cells in combination with temozolomide induce antitumor effects in human glioblastoma cells in vitro (2019)
  • Author(s): Tanaka Y, Nakazawa T, Nakamura M, Nishimura F, Matsuda R, Omoto K, Shida Y, Murakami T, Nakagawa I, Motoyama Y, Morita H, Tsujimura T, Nakase H
  • Journal Title: PLoS One Volume: 6 Pages: 1-14
  • Peer Reviewed / Open Access
• [Journal Article] Novel Human NK Cell Line Carrying CAR Targeting EGFRvIII Induces Antitumor Effects in Glioblastoma Cells. (2018)
  • Author(s): Murakami T, Nakazawa T(equally contribution), Natsume A, Nishimura F, Nakamura M, Matsuda R, Omoto K, Tanaka Y, Shida Y, Park YS, Motoyama Y, Nakagawa I, Yamada S, Tamura K, Takeshima Y, Takamura Y,
  • Journal Title: Anticancer Res Volume: 38 Issue: 9 Pages: 5049-5056
  • DOI: 10.21873/anticanres.12824
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tumor-Inhibition Effect of Levetiracetam in Combination with Temozolomide in Glioblastoma Cells (2016)
  • Author(s): Marutani A., Nakamura M., Nishimura F., Nakazawa T., Matsuda R., Hironaka Y., Nakagawa I., Tamura K., Takeshima Y., Motoyama Y., Park Y-S, Ouji Y., Yoshikawa M., Nakase H.
  • Journal Title: Neurochemical Journal Volume: Volume10, No4 Issue: 1 Pages: 333-339
  • DOI: 10.1134/s1819712416040073
  • Peer Reviewed / Open Access
• [Journal Article] Antitumor effects of minodronate, a third-generation nitrogen-containing bisphosphonate, in synergy with γδT cells in human glioblastoma in vitro and in vivo. (2016)
  • Author(s): Nakazawa T, Nakamura M, Matsuda R, Nishimura F, Park YS, Motoyama Y, Hironaka Y, Nakagawa I, Yokota H, Yamada S, Tamura K, Takeshima Y, Omoto K, Tanaka Y, Ouji Y, Yoshikawa M, Tsujimura T, Nakase H.
  • Journal Title: J Neurooncol Volume: 129 Issue: 2 Pages: 231-241
  • DOI: 10.1007/s11060-016-2186-x
  • Peer Reviewed / Open Access
• [Presentation] Establishment of an efficient ex-vivo expansion method for highly purified human natural killer cells and evaluation of their antitumor activity on glioblastoma (2019)
  • Author(s): Tsutomu Nakazawa, Yoshitaka Tanaka, Yoichi Shida ,Mitsutoshi Nakamura, Fumihiko Nishimura, Ryosuke Matsuda, Toshiharu Murakami, Ichiro Nakagawa, Yasushi Motoyama, Takahiro Tsujimura, Hiroyuki Nakase
  • Organizer: Keystone symposia Innate and Non-Classical Immune Cell in Cancer Immunotherapy
  • Int'l Joint Research
• [Presentation] Capability of dendritic cells loaded with inducedpluripotent stem cells to induce cancer-responsive T cells from a donor with HLA class I-A33 in vitro (2019)
  • Author(s): Tsutomu Nakazawa, Fumihiko Nishimura, Ryosuke Matsuda, Mitsutoshi Nakamura, Yaeko Yamashita, Ichiro Nakagawa, Yasushi Motoyama, Takahiro Tsujimura, Hiroyuki Nakase
  • Organizer: European Association for Cancer Research: Defence is the Best Attack: Immuno-Oncology Breakthroughs
  • Int'l Joint Research
• [Presentation] Novel Human NK Cell Line Carrying CAR Targeting EGFRvIII Induces Antitumor Effects in Glioblastoma Cells (2019)
  • Author(s): Murakami T, Nakazawa T, Nishimura F, Natsume A, Wakabayashi T, Nakase H
  • Organizer: European Association for Cancer Research: Defence is the Best Attack: Immuno-Oncology Breakthroughs
  • Int'l Joint Research
• [Presentation] Novel human NK cell line carrying CAR targeting EGFRvIII induces antitumor effects in glioblastoma cells in vitro (2018)
  • Author(s): 村上敏春、中澤 務 、夏目敦至 、西村文彦 、中村光利 、松田良介 、至田洋一 、 朴 永銖 、本山 靖 、中川一郎 、山田修一 、田村健太郎 、竹島靖浩 、高村慶旭 、 若林俊彦 、中瀬裕之
  • Organizer: 第19回日本分子脳神経外科学会
• [Presentation] Anti-tumor effect of minodronate, a third-generation nitrogen-containing bisphosphonate, in synergy with γδT cells, in human glioblastoma invitro and in vivo (2018)
  • Author(s): Nakazawa T, Nakamura M, Matsuda R, Nishimura F, Park YS, Motoyama Y, Nakagawa I, Yokota H, Yamada S, Tamura K, Takeshima Y, Omoto K, Tanaka Y, Shida Y, Murakami T Takanabe R, Tsujimura T, Nakase H
  • Organizer: The AACR Special Conference on Immunobiology of Primary and Metastatic CNS Cancer
• [Presentation] 高純度NK細胞を用いた膠芽腫細胞に対する抗腫瘍効果とTMZを用いた併用効果の基礎的検討 (2017)
  • Author(s): 田中祥貴族、中澤務、中村光利、辻村貴弘、竹島靖浩、松田良介、田村健太郎、山田修一、中川一郎、西村文彦、横田浩、本山靖、朴永銖、中瀬裕之
  • Organizer: 第14回日本免疫治療学研究会学術集会
  • Place of Presentation: 東京大学伊藤国際学術研究センター
  • Year and Date: 2017-02-11