CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
抗 CD19/CTLA-4 开关提高靶向 CD80/86 上调的弥漫大 B 细胞淋巴瘤的 CAR-T 细胞疗效与选择性
英文原题：An anti-CD19/CTLA-4 switch improves efficacy and selectivity of CAR T cells targeting CD80/86-upregulated DLBCL.
查看英文原题
An anti-CD19/CTLA-4 switch improves efficacy and selectivity of CAR T cells targeting CD80/86-upregulated DLBCL.
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中文摘要
CAR-T 细胞疗法是复发/难治性（r/r）B细胞淋巴瘤的一种强效治疗，但仅在40%的患者中带来持久缓解，并与严重不良事件相关。我们在接受tisagenlecleucel治疗的（r/r）弥漫性大B细胞淋巴瘤（DLBCL）患者的肿瘤组织中发现CD80和/或CD86上调。这一发现促成了CAR/CCR（嵌合检查点受体）设计的开发，该设计由CD19特异性第一代CAR与带有4-1BB共刺激结构域的重组CTLA-4连接受体共表达组成。与CAR-T 细胞相比，CAR/CCR T细胞在异种移植小鼠模型中显示出更优的疗效、更优的长期活性，并在与非恶性CD19 + 细胞的体外实验中显示出更优的选择性。此外，免疫健全小鼠在CAR/CCR T细胞治疗后显示出完整的CD80 - CD19 + B细胞群。这些结果揭示，CAR/CCR设计是进一步转化研究的一种有前景的策略。
展开英文摘要原文
Chimeric antigen receptor T cell (CAR T) therapy is a potent treatment for relapsed/refractory (r/r) B cell lymphomas but provides lasting remissions in only 40% of patients and is associated with serious adverse events.
We identify an upregulation of CD80 and/or CD86 in tumor tissue of (r/r) diffuse large B cell lymphoma (DLBCL) patients treated with tisagenlecleucel. This finding leads to the development of the CAR/CCR (chimeric checkpoint receptor) design, which consists of a CD19-specific first-generation CAR co-expressed with a recombinant CTLA-4-linked receptor with a 4-1BB co-stimulatory domain.
CAR/CCR T cells demonstrate superior efficacy in xenograft mouse models compared with CAR T cells, superior long-term activity, and superior selectivity in in vitro assays with non-malignant CD19 + cells.
In addition, immunocompetent mice show an intact CD80 - CD19 + B cell population after CAR/CCR T cell treatment. The results reveal the CAR/CCR design as a promising strategy for further translational study.
论文信息
- 作者
- Prinz LF、Riet T、Neureuther DF、Lennartz S、Chrobok D、Hübbe H、Uhl G、Riet N
- 第一作者单位
- Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany. Electronic address: lars.prinz1@uk-koeln.de.Germany
- 通讯作者单位
- Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany. Electronic address: markus.chmielewski@uk-koeln.de.Germany
- 文献类型
- 非美国政府资助研究
- 期刊
- Cell reports. Medicine2024 Feb 20
- 原文标识
- PubMed 38340727 · DOI 10.1016/j.xcrm.2024.101421
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