Development of CAR-T cell therapy for pediatric solid malignancy using advantages of induced pluripotent stem cells
| Project/Area Number |
20K16869
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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 52050:Embryonic medicine and pediatrics-related
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| Research Institution | Tokyo Medical University |
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Principal Investigator |
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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 |
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2020: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
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| Keywords | CD99 / CAR / iPS細胞 / T細胞分化 / 小児悪性固形腫瘍 / T細胞 / 分化誘導効率 / CD99ノックダウンiPS細胞 / CAR立体構造 / CAR-T療法 / ヒトiPS細胞 / 抗CD99CAR / 小児腫瘍 / リンパ球分化 |
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| Outline of Research at the Start |
キメラ抗原受容体(Chimeric Antigen Receptor：CAR)-T療法は、腫瘍を認識する人工的受容体をT細胞に発現させ腫瘍を攻撃させるがん免疫療法である。造血器腫瘍では、難治性患者に完全寛解を来しうる画期的療法として開発が進む一方で、固形腫瘍に対するCAR-T療法は、世界的に未だ研究段階である。
本研究では、小児悪性固形腫瘍の約3割に発現するCD99を標的としたCAR-T療法の開発を行う。T細胞だけでなくヒトiPS細胞にCARを導入する。iPS細胞は、無限に近い増殖能を有し遺伝子操作性に優れることから、予め抗CD99CARを導入し、その後、T細胞へ分化誘導し抗腫瘍能を解析する。
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| Outline of Final Research Achievements |
The purpose of this study was to create a research system for a novel CAR-T therapy targeting CD99, which is frequently expressed in pediatric malignant solid tumors, using human iPS cells as a platform with excellent genetic manipulation properties. Anti-CD99 CARs were introduced into human iPS cells established from donor blood T cells, after that, induced into T cells. However, as strong expression of CD99 was observed in induced T cells, differentiation was performed after knockdown of CD99, but the differentiation efficiency decreased and CD99, which was supposed to be suppressed, was gradually expressed. Furthermore, during the research process, the affinity of the anti-CD99 CAR to CD99 could not be confirmed, and it was found that there was a problem with the three-dimensional structure of anti-CD99 scFv. We attempted to improve the structure, but were unable to make improvements.
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| Academic Significance and Societal Importance of the Research Achievements |
昨今のがん免疫療法の隆盛は、免疫チェックポイント阻害薬ならびにCAR-T療法の成功に拠るところが大きい。本研究は、CD99を標的とする今までにないCAR-T療法の開発を最終目標として、そのための実験システムを構築することを目的とした。CD99は小児の悪性固形腫瘍の3割程度に発現がみられる膜糖蛋白であり、標的分子として相応しいものと考えたが、当研究室で作製した抗CD99CARは、立体構造の問題点を克服することが出来ず、目的とした実験システムの構築に至ることは出来なかった。
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Report
(4 results)
Research Products
(8 results)
