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Basic study of CAR-NK cell therapy derived from iPS cells.

Research Project

Project/Area Number 18H02915
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 56010:Neurosurgery-related
Research InstitutionNara Medical University

Principal Investigator

Nakase Hiroyuki  奈良県立医科大学, 医学部, 教授 (10217739)

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)
松田 良介  奈良県立医科大学, 医学部, 学内講師 (60453164)
西村 文彦  奈良県立医科大学, 医学部, 講師 (70433331)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥13,260,000 (Direct Cost: ¥10,200,000、Indirect Cost: ¥3,060,000)
Fiscal Year 2020: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Fiscal Year 2018: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000)
Keywords膠芽腫 / iPS / CAR 遺伝子 / Natural killer cell / glioblastoma / EGFRvIII / natural killer 細胞 / natural killer cell / EGFRvIII-CAR / iPS cell / EGFRvIII特異的CAR / iPS由来NK細胞 / 細胞免疫療法
Outline of Final Research Achievements

We established human iPSC derived from human peripheral blood T cells by episomal vector mixture expressing six genes (OCT3/4, KLF4, SOX2, L-MYC, LIN28, and dominant negative mouse p53), and transduced the EvCAR gene by lentivirus vector. The EvCAR-iPSC expressed EvCAR and stem cell markers (NANOG, OCT3/4, SSEA4, TRA-1-60). Matrigel-suspended EvCAR-iPSC formed teratoma in NOG mice subcutaneously. Whole-genome analysis revealed that the EvCAR-iPSC harbored T cell receptor recombination and seven non-synonymous heterozygous mutations. The EvCAR transgenes were inserted into the introns of the CLBP, TMEM132D, and PSMF1 genes. Next, we induced EvCAR-NKC via spin embryoid body (EB) culture. The established EvCAR-iPSC were cultured in APEL 2 medium containing SCF, VEGF, BMP4, and Y-27632 in 96-well round-bottom plates for 10 days to form EB. The EBs included 37.5% CD34/CD43-positive hematopoietic stem/progenitor cells.

Academic Significance and Societal Importance of the Research Achievements

研究の成果は、iPSC から EGFRvIII 特異的 CAR 発現 NK を大量に準備することが可能で、off-the-shelf の NK 細胞免疫療法の開発として、難治性悪性腫瘍である膠芽腫に対する有力な新規併用療法の1つとなる可能性があり、創造性に富んだ研究であると考える。CAR 発現 NK (CAR-NK) は CAR-T より安全性が高い可能性がある。不均一で多様性の強い細胞集団である膠芽腫に対して、安全で高い治療効果を期待できる CAR-NK はより有用な抗がん免疫細胞であると考えられる。本研究の成果は、予後不良の膠芽腫に対する新規併用療法になると期待される。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report

Research Products

(17 results)

All 2021 2020 2019 2018

All Journal Article (8 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 8 results,  Open Access: 8 results) Presentation (9 results) (of which Int'l Joint Research: 7 results,  Invited: 6 results)

  • [Journal Article] CRISPR-Cas9?Mediated TIM3 Knockout in Human Natural Killer Cells Enhances Growth Inhibitory Effects on Human Glioma Cells2021

    • Author(s)
      Morimoto Takayuki、Nakazawa Tsutomu、Matsuda Ryosuke、Nishimura Fumihiko、Nakamura Mitsutoshi、Yamada Shuichi、Nakagawa Ichiro、Park Young-Soo、Tsujimura Takahiro、Nakase Hiroyuki
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Pages: 3489-3489

    • DOI

      10.3390/ijms22073489

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] KHYG-1 Cells With EGFRvIII-specific CAR Induced a Pseudoprogression-like Feature in Subcutaneous Tumours Derived from Glioblastoma-like Cells2020

    • Author(s)
      NAKAZAWA TSUTOMU、MURAKAMI TOSHIHARU、NATSUME ATSUSHI、NISHIMURA FUMIHIKO、MORIMOTO TAKAYUKI、MATSUDA RYOSUKE、NAKAMURA MITSUTOSHI、YAMADA SHUICHI、NAKAGAWA ICHIRO、PARK YOUNG-SOO、MOTOYAMA YASUSHI、TSUJIMURA TAKAHIRO、WAKABAYASHI TOSHIHIKO、NAKASE HIROYUKI
    • Journal Title

      Anticancer Research

      Volume: 40 Pages: 3231-3237

    • DOI

      10.21873/anticanres.14304

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effect of CRISPR/Cas9-Mediated PD-1-Disrupted Primary Human Third-Generation CAR-T Cells Targeting EGFRvIII on in vitro Human Glioblastoma Cell Growth2020

    • Author(s)
      Nakazawa T, Nishimura F, Matsuda R, Nakamura M, Nakase H et al.
    • Journal Title

      Cells

      Volume: 9 Pages: 998-1017

    • DOI

      10.3390/cells9040998

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Linac-based fractionated stereotactic radiotherapy with a micro-multileaf collimator for large brain metastasis unsuitable for surgical resection2020

    • Author(s)
      Matsuda Ryosuke、Tamamoto Tetsuro、Sugimoto Tadashi、Hontsu Shigeto、Yamaki Kaori、Miura Sachiko、Takeshima Yasuhiro、Tamura Kentaro、Yamada Shuichi、Nishimura Fumihiko、Nakagawa Ichiro、Motoyama Yasushi、Park Young-Su、Nakase Hiroyuki、Hasegawa Masatoshi
    • Journal Title

      Journal of Radiation Research

      Volume: 61 Pages: 546-553

    • DOI

      10.1093/jrr/rraa038

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Linac-Based Fractionated Stereotactic Radiotherapy With a Micro-Multileaf Collimator for Brainstem Metastasis2019

    • Author(s)
      T Sugimoto , R Matsuda , T Tamamoto , S Hontsu , K Yamaki , S Miura , Y-S Park , H Nakase , M Hasegawa
    • Journal Title

      World Neurosurg

      Volume: 132 Pages: 680-686

    • DOI

      10.1016/j.wneu.2019.08.049

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [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(corresponding author), 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: 14

    • DOI

      10.1371/journal.pone.0212455

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Expression of peptide transporter 1 has a positive correlation in protoporphyrin IX accumulation induced by 5-aminolevulinic acid with photodynamic detection of non-small cell lung cancer and metastatic brain tumor specimens originating from non-small cell lung cancer.2019

    • Author(s)
      Omoto K, Matsuda R, Nakai Y, Tatsumi Y, Nakazawa T, Tanaka Y, Shida Y, Murakami T, Nishimura F, Nakagawa I, Motoyama Y, Nakamura M, Fujimoto K, Hiroyuki N.
    • Journal Title

      Photodiagnosis Photodyn Ther

      Volume: 25 Pages: 309-316

    • DOI

      10.1016/j.pdpdt.2019.01.009

    • Related Report
      2018 Annual Research Report
    • 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 RESEARCH

      Volume: 38 Pages: 5049-5056

    • DOI

      10.21873/anticanres.12824

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Complecations avoidance in dumbbell lumbar spine neurinoma2021

    • Author(s)
      Nakase H.
    • Organizer
      3rd International Conference on Complications in Neurosurgery
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 脳卒中治療の現状と展望:脳卒中・循環器病対策基本法と抗血栓療法を含めて2021

    • Author(s)
      中瀬 裕之
    • Organizer
      秋田県の脳卒中連携を考える会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] シミュレーションとモニタリングの手術への貢献2020

    • Author(s)
      中瀬 裕之
    • Organizer
      第43回日本脳神経CI学会総会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Strategic planning using virtual reality simulation in neurosurgical operations2019

    • Author(s)
      Nakase H, Nishimura F et al
    • Organizer
      Second International and Seventh Annual Conference of Nepalese Society of Neurosurgeons In collaboration with World Federation of Neurosurgical Societies
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Comprehensive neurosurgical management for Deep-seated brain AVMs2019

    • Author(s)
      Nakase H, Nishimura F et al
    • Organizer
      The 14th Korea-Japan Joint Conference on Surgery for Cerebral Stroke
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] The strategic planning using virtual reality simulation in spine surgery2019

    • Author(s)
      Nakase H
    • Organizer
      4th International Society of Minimally Invasive Neurosurgery(ISMINS)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Establishment of an efficient ex-vivo expansion method for highly purified human natural killer cells and evaluation of their antitumor activity on glioblastoma2019

    • Author(s)
      Nakazawa T, Nakamura M, Nishimura F, Matsuda R, Nakase H et al.
    • Organizer
      Keystone Symposia
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Capability of dendritic cells loaded with induced-pluripotent stem cells to induce cancer-responsive T cells from a donor with HLA class I-A33 alleles in vitro2019

    • Author(s)
      Nakazawa T, Nishimura F, Matsuda R, Nakamura M, Nakase H et al.
    • Organizer
      European Association for Cancer Research
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Antitumor effects of minodronate, a third-generation nitrogen-containing bisphosphonate, in synergy with γδT cells in human glioblastoma in vitro and in vivo.2018

    • Author(s)
      Nakazawa T, Nakamura M, Matsuda R, Nishimura F, Nakase H et al.
    • Organizer
      American Association for Cancer Research
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research

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Published: 2018-04-23   Modified: 2022-01-27  

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