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.
CAR-T（CAR-T）细胞在血液系统恶性肿瘤中的应用推动了这种免疫治疗形式的显著进展。
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
针对低抗原密度调校的 GPC2-CAR-T 细胞介导对神经母细胞瘤的强效活性且无毒性
英文原题：GPC2-CAR T cells tuned for low antigen density mediate potent activity against neuroblastoma without toxicity.
查看英文原题
GPC2-CAR T cells tuned for low antigen density mediate potent activity against neuroblastoma without toxicity.
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中文摘要
儿童癌症常模拟胎儿组织，并表达在出生后通常被沉默的蛋白质，这些蛋白质可作为免疫靶点。我们开发了表达靶向 glypican-2 (GPC2) 的嵌合抗原受体 (CAR) 的 T 细胞，GPC2 是一种在神经母细胞瘤 (NB) 和其他几种实体瘤上表达的胎儿抗原。使用标准设计工程化的 CAR 能控制具有转基因 GPC2 过表达的 NB，但不能控制表达临床相关 GPC2 位点密度（5,000 分子/细胞，范围 1-6 10 3）的 NB。对跨膜 (TM) 和共刺激结构域的迭代工程化以及 c-Jun 的过表达降低了 GPC2-CAR 抗原密度阈值，使得能够有效且持久地清除表达临床相关 GPC2 抗原密度的 NB，且无毒性。这些研究突出了 CAR 设计与抗原密度阈值之间的关键相互作用，证明了适合临床测试的先导 GPC2-CAR 候选物的有效性和安全性，并证实癌胚抗原作为 CAR-T 细胞治疗实体瘤的一类有前景的靶点。
展开英文摘要原文
Pediatric cancers often mimic fetal tissues and express proteins normally silenced postnatally that could serve as immune targets.
We developed T cells expressing chimeric antigen receptors (CARs) targeting glypican-2 (GPC2), a fetal antigen expressed on neuroblastoma (NB) and several other solid tumors. CARs engineered using standard designs control NBs with transgenic GPC2 overexpression, but not those expressing clinically relevant GPC2 site density ( 5,000 molecules/cell, range 1-6 10 3 ).
Iterative engineering of transmembrane (TM) and co-stimulatory domains plus overexpression of c-Jun lowered the GPC2-CAR antigen density threshold, enabling potent and durable eradication of NBs expressing clinically relevant GPC2 antigen density, without toxicity.
These studies highlight the critical interplay between CAR design and antigen density threshold, demonstrate potent efficacy and safety of a lead GPC2-CAR candidate suitable for clinical testing, and credential oncofetal antigens as a promising class of targets for CAR T cell therapy of solid tumors.
论文信息
- 作者
- Heitzeneder S、Bosse KR、Zhu Z、Zhelev D、Majzner RG、Radosevich MT、Dhingra S、Sotillo E
- 第一作者单位
- Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Lorry Lokey Building, Suite G3141, MC: 5456, 265 Campus Drive, Stanford, CA 94305, USA.United States
- 通讯作者单位
- Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Lorry Lokey Building, Suite G3141, MC: 5456, 265 Campus Drive, Stanford, CA 94305, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 941209, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: cmackall@stanford.edu.United States
- 文献类型
- 美国 NIH 资助研究 · 非美国政府资助研究
- 期刊
- Cancer cell2022 Jan 10
- 原文标识
- PubMed 34971569 · DOI 10.1016/j.ccell.2021.12.005
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