Development of combinatorial CAR-T cell therapy improving immunosupressive tumor microenvironment
| Project/Area Number |
20K07641
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 50020:Tumor diagnostics and therapeutics-related
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| Research Institution | Kyoto Prefectural University of Medicine |
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Principal Investigator |
Yagyu Shigeki 京都府立医科大学, 医学(系)研究科(研究院), 助教 (10572547)
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| Co-Investigator(Kenkyū-buntansha) |
吉田 秀樹 京都府立医科大学, 医学(系)研究科(研究院), 助教 (10643546)
菊地 顕 京都府立医科大学, 医学(系)研究科(研究院), 特任講師 (40453104)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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| Keywords | CAR-T細胞 / 固形腫瘍 / 免疫疲弊 / 神経芽腫 / 腫瘍微小環境 / 遺伝子改変T細胞 / オフターゲット |
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| Outline of Research at the Start |
本研究では以下の2点を明らかにし、固形腫瘍に対するCAR-T細胞療法の臨床応用への橋渡しを行う。
1 腫瘍微小環境による免疫逃避機構出現を回避させる事が可能な分子標的薬と、CAR-T細胞による複合的な遺伝子改変細胞療法の開発
2 Off target効果による予期せぬ有害事象出現時に、CAR-T細胞による細胞傷害を完全に停止させるためのセーフガードシステムの開発
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| Outline of Final Research Achievements |
To enhance the efficacy of CAR-T cell therapy for solid tumors, it is important to suppress immunosuppressive mechanisms by the tumor microenvironment. In this study, we investigated the potential of molecularly targeted drugs and combination therapies to prevent CAR-T cells from being exhausted by the immunosuppressive tumor microenvironment and to improve the efficacy of CAR-T cell therapy. A synergistic antitumor effect was observed in the trametinib plus GD2-CAR-T cell combination therapy group compared to the GD2-CAR-T cell monotherapy group in neuroblastoma-bearing murine xenograft model, regardless of the mutation status of Raf/MEK pathway. These results suggest that trametinib suppresses excessive activation and exhaustion of CAR-T cells and synergistically enhances antitumor effects of GD2-CAR-T cells. Based on these findings, the efficacy of alectinib, an ALK inhibitor, in combination with GD2-CAR-T cells in ALK-mutant neuroblastoma is also being investigated.
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| Academic Significance and Societal Importance of the Research Achievements |
固形腫瘍に対するCAR-T細胞療法の応用が期待されているが、CAR-T細胞療法の効果を向上させるためには、さらなる遺伝子改変や併用療法の開発が望まれている。本研究は、すでに他疾患で承認されているRaf/MEK阻害剤が、CAR-T細胞の過剰活性化と疲弊を抑制することで相乗的な効果を発揮することを明らかにした。今後、神経芽腫に対してGD2-CAR-T細胞療法が臨床応用されていく中で、分子標的薬との併用療法が有望であることが証明された点で学術的、社会的意義が高いと考えられる。
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Report
(4 results)
Research Products
(31 results)
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[Journal Article] Development of non-viral, ligand-dependent, EPHB4-specific chimeric antigen receptor T cells for treatment of rhabdomyosarcoma.2021
Author(s)
Kubo H, Yagyu S, Nakamura K, Yamashima K, Tomida A, Kikuchi K, Iehara T, Nakazawa Y, Hosoi H.
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Journal Title
Molecular Therapy - Oncolytics
Volume: 20
Pages: 646-658
DOI
Related Report
Peer Reviewed / Open Access
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