| Project/Area Number |
18K15319
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 50020:Tumor diagnostics and therapeutics-related
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| Research Institution | Kobe University |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | がん免疫 / PDXモデル / 免疫ヒト化 / 免疫チェックポイント阻害薬 / マイクロサテライト不安定性 / PDXマウスモデル / 免疫ヒト化マウスモデル / 前臨床試験 / MSI-H大腸癌 / Lynch症候群 / メチレーション / MSI-H大腸がん / 免疫ヒト化PDXマウスモデル / トランスレーショナルリサーチ |
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| Outline of Final Research Achievements |
There has been an increasing demand for appropriate preclinical mice models for evaluating the efficacy of cancer immunotherapies. Because conventional mouse models have limitations in cancer immunity research, we newly established a humanized patient-derived xenograft (PDX) model using microsatellite instability-high (MSI-H) colorectal cancer (CRC) tissues and patient-derived PBMCs.
PDX models were established from three patients with MSI-H CRC. PDX tumors were compared to the original patient tumors in terms of histological and genetic characteristics. PDX with the germline mutation (PDX1) was histologically similar to the patient tumor, and retained the genetic characteristics, including MSI-H. When T cells from the same patient with MLH1 mutation were injected into the PDX1 through the tail vein, they were detected in the PDX tumor. Finally, we performed drug (anti PD-1 antibody) test by using humanized PDX1, and we found tendency for the increased number of infiltrating T cells.
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| Academic Significance and Societal Importance of the Research Achievements |
免疫チェックポイント阻害薬は、がん患者の生存期間の延長に寄与している。しかしながら、免疫チェックポイント阻害薬単剤の奏効割合は各がん種で概ね20%とその効果は限定的である。従って、更なるがん免疫および免疫療法の研究開発が必要であるが、現在の動物実験モデルではヒトがん免疫の再現が十分でないため、前臨床試験モデルを用いた免疫療法の薬効評価やバイオマーカーの探索を行うことが難しい。
今回の研究は、ヒトのがん免疫をマウス内に再現することを目指したものである。これによりがん免疫療法の薬効評価が進めば、がん免疫療法の奏効率の上昇に寄与する研究が加速するものと考える。
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