Development of cancer immunotherapy using T cells regenerated from iPS cells and genetically engineered monkeys
Project/Area Number |
18K07171
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 49070:Immunology-related
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Research Institution | Shiga University of Medical Science |
Principal Investigator |
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Project Period (FY) |
2018-04-01 – 2022-03-31
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Project Status |
Completed (Fiscal Year 2021)
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Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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Keywords | ゲノム編集 / CRISPR/Cas9 / カセット交換法(RMCE) / がん抗原 / T細胞受容体(TCR) / iPS細胞 / カニクイザル / 腫瘍浸潤リンパ球(TIL) / カセット交換法 RMCE / カセット交換法 / RMCE / カセット交換法 RMCE / がんモデル動物 / キラーT細胞 / T細胞受容体 |
Outline of Final Research Achievements |
We knocked-in tumor antigen-specific T cell receptor (TCR) genes into the endogenous TCR locus of human iPS cells using genome editing and cassette exchange methods and induced differentiation into T cells, which exhibited high cytotoxic activity in a tumor antigen-specific manner. Furthermore, in order to create a non-human primate cancer model that can be extrapolated to humans, we generated cynomolgus macaques that express four cancer-related genes in a drug-inducible manner and obtained transgenic offspring. In parallel, we transplanted monkey tumor cells and isolated TCR genes from T cells which infiltrated into the formed tumors. We then introduced the TCR genes into T cells regenerated from iPS cells and found that the frequently appearing TCRs could kill tumor cells.
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Academic Significance and Societal Importance of the Research Achievements |
本研究で開発した方法により、ランダムな遺伝子挿入によるがん化のない、安全で細胞傷害活性の高いT細胞を効率よく作製することが可能となった。また腫瘍に浸潤するT細胞から出現頻度の高いTCR遺伝子を単離し、カセット交換法によりiPS細胞で次々に遺伝子交換することが可能となり、細胞製剤として早期の治療応用も期待できる。 一方、がん免疫療法の前臨床試験において、マウスで得られた知見がヒトに外挿できない例が知られている。そのためヒトへの外挿性が高い霊長類を用いたがん研究の推進が必要不可欠であり、本研究で作製された遺伝子導入サルで薬剤誘導性に腫瘍が形成されれば、世界初の非ヒト霊長類のがんモデルとなる。
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Report
(5 results)
Research Products
(29 results)
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[Journal Article] Cytotoxic T lymphocytes regenerated from iPS cells have therapeutic efficacy in a patient-derived xenograft solid tumor model.2020
Author(s)
Kashima S, Maeda T, Masuda K, Nagano S, Inoue T, Takeda M, Kono Y, Kobayashi T, Saito S, Higuchi T, Ichise H, Kobayashi Y, Iwaisako K, Terada K, Agata Y, Nakamura K, Saito M, Narita S, Ogawa O, Habuchi T, Kawamoto H.
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Journal Title
iScience
Volume: 23
Issue: 4
Pages: 100998-100998
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Long non-coding RNA MANCR is a target of BET bromodomain protein BRD4 and plays a critical role in cellular migration and invasion abilities of prostate cancer.2020
Author(s)
Nagasawa M, Tomimatsu K, Terada K, Kondo K, Miyazaki K, Miyazaki M, Motooka D, Okuzaki D, Yoshida T, Kageyama S, Kawamoto H, Kawauchi A, Agata Y.
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Journal Title
Biochem Biophys Res Commun.
Volume: 526
Issue: 1
Pages: 128-134
DOI
NAID
Related Report
Peer Reviewed
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[Presentation] Isolation of TCR genes with tumor-killing activity from tumor-infiltrating lymphocytes in a tumor rejection cynomolgus macaque model2021
Author(s)
Koji Terada, Kenta Kondo, Hirohito Ishigaki, Ayaka Nagashima, Hiroki Satooka, Seiji Nagano, Kyoko Masuda, Teruhisa Kawamura, Takako Hirata, Kazumasa Ogasawara, Yasushi Itoh, Hiroshi Kawamoto, Yasutoshi Agata
Organizer
第50回 日本免疫学会学術集会、奈良、2021年12月8-10日
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[Book] 標準免疫学 第4版2021
Author(s)
宮坂 昌之(執筆分担者 縣 保年)
Total Pages
434
Publisher
医学書院
ISBN
9784260042383
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