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NK細胞様の特性をT細胞に付与するNKp44を用いたキメラ抗原受容体の開発と評価
http://hdl.handle.net/10191/0002000291
http://hdl.handle.net/10191/00020002913b1bf8a5-afb7-4691-ac52-95b92d6b9c20
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本文 (4.69MB)
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要旨 (546KB)
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| Item type | 学位論文 / Thesis or Dissertation(1) | |||||||||
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| 公開日 | 2022-04-04 | |||||||||
| タイトル | ||||||||||
| タイトル | Development and characterisation of NKp44-based chimeric antigen receptors that confer T cells with NK cell-like specificity | |||||||||
| 言語 | en | |||||||||
| タイトル | ||||||||||
| タイトル | NK細胞様の特性をT細胞に付与するNKp44を用いたキメラ抗原受容体の開発と評価 | |||||||||
| 言語 | ja | |||||||||
| 言語 | ||||||||||
| 言語 | eng | |||||||||
| キーワード | ||||||||||
| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| 主題 | acute myeloid leukaemia | |||||||||
| キーワード | ||||||||||
| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| 主題 | chimeric antigen receptor | |||||||||
| キーワード | ||||||||||
| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| 主題 | natural killer cell | |||||||||
| キーワード | ||||||||||
| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| 主題 | NKp44 | |||||||||
| キーワード | ||||||||||
| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| 主題 | paediatric solid tumors | |||||||||
| キーワード | ||||||||||
| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| 主題 | T-cell acute lymphoblastic leukaemia | |||||||||
| 資源タイプ | ||||||||||
| 資源 | http://purl.org/coar/resource_type/c_db06 | |||||||||
| タイプ | doctoral thesis | |||||||||
| アクセス権 | ||||||||||
| アクセス権 | open access | |||||||||
| アクセス権URI | http://purl.org/coar/access_right/c_abf2 | |||||||||
| 著者 |
笠原, 靖史
× 笠原, 靖史
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| 抄録 | ||||||||||
| 内容記述タイプ | Abstract | |||||||||
| 内容記述 | Objectives. One of the reasons as to why chimeric antigen receptors (CAR)-T cell therapy for malignancies other than CD19- or BCMA-positive tumors has yet to produce remarkable progress is the paucity of targetable antigens. NKp44 is only expressed by activated natural killer cells and detects a variety of transformed cells, while it reportedly does not react with normal tissues. The aim of this study is to develop CAR-T cell that can target multiple types of tumor cells. Methods. We created a series of novel CAR constructs in first-generation (1G) and second-generation (2G) CAR format with the extracellular immunoglobulin-like domain of NKp44 (NKp44-CAR). Results. Transduction of the best 1G construct into human primary T cells led to specific cytotoxic effects and cytokine secretion upon encountering multiple types of neoplastic cells including AML, T-ALL and childhood solid tumors. Replacement of the extracellular hinge domain of NKp44 with that of CD8α resulted in diminished CAR function. The 1G NKp44-CAR-T cells exhibited significantly better tumor control in long-term co-culture assays compared with activated NK cells, as well as with NK cells transduced with identical NKp44-CAR. T cells transduced with the best 2G-CAR construct with 4-1BB costimulatory domain proliferated at significantly higher levels upon single antigen exposure and showed significantly better tumor control compared with the 1G-CAR and 2G-CAR with CD28 costimulatory domain. Conclusions. NKp44-based CAR endows T cells with NK cell-like anti-tumor specificity. The CAR gene created in this study will be useful for the development of novel gene-modified T-cell immunotherapy. | |||||||||
| 言語 | en | |||||||||
| 内容記述 | ||||||||||
| 内容記述タイプ | Other | |||||||||
| 内容記述 | Clinical & Translational Immunology. 2020, 9(7), e1147 | |||||||||
| 言語 | en | |||||||||
| DOI | ||||||||||
| 識別子タイプ | DOI | |||||||||
| 関連識別子 | https://doi.org/10.1002/cti2.1147 | |||||||||
| 権利 | ||||||||||
| 言語 | en | |||||||||
| 権利情報 | 【○!C】 2020 The Authors. | |||||||||
| 権利 | ||||||||||
| 言語 | en | |||||||||
| 権利情報Resource | https://creativecommons.org/licenses/by-nc-nd/4.0/ | |||||||||
| 権利情報 | Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International | |||||||||
| 学位名 | ||||||||||
| 言語 | ja | |||||||||
| 学位名 | 博士（医学） | |||||||||
| 学位授与機関 | ||||||||||
| 学位授与機関識別子Scheme | kakenhi | |||||||||
| 学位授与機関識別子 | 13101 | |||||||||
| 言語 | ja | |||||||||
| 学位授与機関名 | 新潟大学 | |||||||||
| 言語 | en | |||||||||
| 学位授与機関名 | Niigata University | |||||||||
| 学位授与年月日 | ||||||||||
| 学位授与年月日 | 2021-03-23 | |||||||||
| 学位授与番号 | ||||||||||
| 学位授与番号 | 甲第4832号 | |||||||||
| 学位記番号 | ||||||||||
| 内容記述タイプ | Other | |||||||||
| 内容記述 | 新大院博(医)第986号 | |||||||||
| 言語 | ja | |||||||||
