| Project/Area Number |
17H04230
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Kyoto Prefectural University of Medicine |
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Principal Investigator |
Hosoi Hajime 京都府立医科大学, 医学(系)研究科(研究院), 教授 (20238744)
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| Co-Investigator(Kenkyū-buntansha) |
柳生 茂希 京都府立医科大学, 医学(系)研究科(研究院), 助教 (10572547)
家原 知子 京都府立医科大学, 医学(系)研究科(研究院), 准教授 (20285266)
菊地 顕 京都府立医科大学, 医学(系)研究科(研究院), 特任助教 (40453104)
宮地 充 京都府立医科大学, 医学(系)研究科(研究院), 助教 (40584983)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥14,950,000 (Direct Cost: ¥11,500,000、Indirect Cost: ¥3,450,000)
Fiscal Year 2019: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2017: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
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| Keywords | CAR-T細胞 / 横紋筋肉腫 / 免疫疲弊 / ヒギーバックトランスポゾン / 融合遺伝子 / エクソソーム / siRNA / 間葉系幹細胞 / ドラッグデリバリー / 遺伝子改変T細胞 |
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| Outline of Final Research Achievements |
We have developed mesenchymal stromal cells which were genetically engineered to express shRNA that could reduce the expression of PAX3-FOXO1 fusion gene(shPF-MSC). We infused the shPF-MSC into rhabdomyosarcoma (RMS) bearing immunodeficient mice via tail vain, and confirmed antitumor efficacy of these cells. We also developed chimeric antigen receptor T cells that redirected to EPHB4 molecules in RMS. The CAR-T cells exhibited a dominant stem cell memory fraction and low PD-1 expression after the 14 days expansion. The CAR-T cells presented strong and sustained inhibitory activity against the RMS cells even in multiple tumor challenges. Furthermore, in the in vivo experiment, The CAR-T cells also suppressed tumor growth in RMS xenograft-bearing mice. A nonclinical safety study on PB-EPHB4 CAR-T cell therapy targeting the EPHB4 positive tumors is underway, aiming future clinical trials in Japan.
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| Academic Significance and Societal Importance of the Research Achievements |
小児悪性軟部腫瘍に対する複合的な遺伝子細胞治療の開発が急務である。我々は、PAX3-FOXO1融合遺伝子を発現する予後不良な胞巣型横紋筋肉腫に対して、PAX3FOXO1遺伝子発現調整が可能なエクソソームを分泌する間葉系幹細胞、さらには、横紋筋肉腫細胞に高発現するEPHB4受容体を標的とするCAR-T細胞を開発した。将来的には本研究成果を臨床応用するために、非臨床試験を実施していく予定である。
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