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MAGE-A4 pMHC-targeted CAR-T cells exploiting TCR machinery exhibit significantly improved in vivo function while retaining antigen specificity
http://hdl.handle.net/10076/0002001464
http://hdl.handle.net/10076/00020014648758741a-4e92-4e6a-98a7-16947e05e02c
| 名前 / ファイル | ライセンス | アクション |
|---|---|---|
2024DM0322.pdf (6.30 MB)
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| アイテムタイプ | 学位論文 / Thesis or Dissertation(1) | |||||||
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| 公開日 | 2025-05-19 | |||||||
| タイトル | ||||||||
| タイトル | MAGE-A4 pMHC-targeted CAR-T cells exploiting TCR machinery exhibit significantly improved in vivo function while retaining antigen specificity | |||||||
| 言語 | en | |||||||
| 言語 | ||||||||
| 言語 | eng | |||||||
| 資源タイプ | ||||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_db06 | |||||||
| 資源タイプ | 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 |
Liu, Meiou
× Liu, Meiou
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| 著者（ヨミ） | ||||||||
| 姓名 | リュウ, メイオウ | |||||||
| 言語 | ja | |||||||
| 抄録 | ||||||||
| 内容記述タイプ | Abstract | |||||||
| 内容記述 | Background: The development of chimeric antigen receptor (CAR)-T cell therapies for solid tumors has attracted considerable attention, yet their clinical efficacy remains limited. Therefore, various efforts have been made to improve the efficacy of CAR-T cell therapy. As one promising strategy, incorporating the T-cell receptor (TCR) machinery into CAR structures has been reported to improve the efficacy of CAR-T cells in studies using conventional CARs targeting such as EGFR. However, in the case of peptide/major histocompatibility complex (pMHC)-targeted CARs, the advantages of exploiting TCR machinery have not been fully elucidated. We recently developed MAGE-A4-derived pMHC (MAGE-A4 pMHC)-targeted CAR-T cells (MA-CAR-T cells) using a highly specific human scFv antibody against MAGE-A4p230-239/HLA-A*02:01. We aimed to determine whether MAGE-A4 pMHC-targeted CAR-T cells using the TCR machinery (Hybrid MA-TCR-T cells) exhibit superior functionality without compromising antigen specificity. Methods: We constructed a retroviral vector expressing Hybrid MA-TCR where MAGE-A4 pMHC-specific scFv are fused to human TCR constant chains. Results: Hybrid MA-TCR-T cells demonstrated superior in vitro functions compared with MA-CAR-T cells, while maintaining strict antigen specificity. In addition, functional superiority of Hybrid MA-TCR-T cells to MA-CAR-T cells became more pronounced on repetitive antigen stimulation. In particular, Hybrid MA-TCR-T cells significantly inhibited tumor growth in an immunodeficient mouse model more effectively than MA-CAR-T cells. Ex vivo analyses indicated that their enhanced therapeutic efficacy might result from higher infiltration of functionally active, less differentiated Hybrid MA-TCR-T cells in tumor tissues. Conclusions: These findings suggest that leveraging the TCR machinery is a promising strategy for enhancing pMHC-targeted CAR-T cell therapy for solid tumors, potentially leading to more effective treatments. |
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| 言語 | en | |||||||
| 内容記述 | ||||||||
| 内容記述タイプ | Other | |||||||
| 内容記述 | 本文 / Personalized Cancer Immunotherapy, Mie University Graduate School of Medicine, Tsu, Japan | |||||||
| 内容記述 | ||||||||
| 内容記述タイプ | Other | |||||||
| 内容記述 | 19p | |||||||
| 書誌情報 |
発行日 2025-03-25 |
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| DOI | ||||||||
| 識別子タイプ | DOI | |||||||
| 関連識別子 | 10.1136/jitc-2024-010248 | |||||||
| フォーマット | ||||||||
| 内容記述タイプ | Other | |||||||
| 内容記述 | application/pdf | |||||||
| 出版者 | ||||||||
| 出版者 | 三重大学 | |||||||
| 出版者（ヨミ） | ||||||||
| 値 | ミエダイガク | |||||||
| 学位名 | ||||||||
| 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 | 14101 | |||||||
| 学位授与機関名 | 三重大学 | |||||||
| 学位授与年月日 | ||||||||
| 学位授与年月日 | 2025-03-25 | |||||||
| 学位授与番号 | ||||||||
| 学位授与番号 | 甲医学第2306号 | |||||||
| 資源タイプ（三重大） | ||||||||
| 値 | Doctoral Dissertation / 博士論文 | |||||||
