• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

GPC1 特异性 CAR-T 细胞可消除已建立的实体肿瘤而无不良反应，并与抗 PD-1 Ab 协同作用。

GPC1 specific CAR-T cells eradicate established solid tumor without adverse effects and synergize with anti-PD-1 Ab.

机构信息

Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.

Laboratory of Veterinary Surgery, Graduate school of agricultural and life sciences, The University of Tokyo, Tokyo, Japan.

出版信息

Elife. 2020 Mar 31;9:e49392. doi: 10.7554/eLife.49392.

DOI:10.7554/eLife.49392
PMID:32228854
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7108862/
Abstract

Current xenogeneic mouse models cannot evaluate on-target off-tumor adverse effect, hindering the development of chimeric antigen receptor (CAR) T cell therapies for solid tumors, due to limited human/mouse cross-reactivity of antibodies used in CAR and sever graft-versus-host disease induced by administered human T cells. We have evaluated safety and antitumor efficacy of CAR-T cells targeting glypican-1 (GPC1) overexpressed in various solid tumors. GPC1-specific human and murine CAR-T cells generated from our original anti-human/mouse GPC1 antibody showed strong antitumor effects in xenogeneic and syngeneic mouse models, respectively. Importantly, the murine CAR-T cells enhanced endogenous T cell responses against a non-GPC1 tumor antigen through the mechanism of antigen-spreading and showed synergistic antitumor effects with anti-PD-1 antibody without any adverse effects in syngeneic models. Our study shows the potential of GPC1 as a CAR-T cell target for solid tumors and the importance of syngeneic and xenogeneic models for evaluating their safety and efficacy.

摘要

目前的异种小鼠模型无法评估针对目标的肿瘤外不良效应，阻碍了嵌合抗原受体 (CAR) T 细胞疗法在实体瘤中的发展，这是由于 CAR 中使用的抗体与人类/小鼠的交叉反应有限，以及给予的人类 T 细胞引起的严重移植物抗宿主病。我们已经评估了针对在各种实体瘤中过表达的聚糖蛋白 1 (GPC1) 的 CAR-T 细胞的安全性和抗肿瘤疗效。我们从原始抗人/鼠 GPC1 抗体中生成的 GPC1 特异性人源和鼠源 CAR-T 细胞分别在异种和同基因小鼠模型中显示出强烈的抗肿瘤作用。重要的是，鼠源 CAR-T 细胞通过抗原扩展机制增强了针对非 GPC1 肿瘤抗原的内源性 T 细胞反应，并与抗 PD-1 抗体表现出协同抗肿瘤作用，而在同基因模型中没有任何不良反应。我们的研究表明 GPC1 作为 CAR-T 细胞治疗实体瘤的靶标具有潜力，并且同基因和异种模型对于评估其安全性和疗效非常重要。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55f2/7108862/ba987b1e93ec/elife-49392-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55f2/7108862/666449cb8be0/elife-49392-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55f2/7108862/b127170175d7/elife-49392-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55f2/7108862/3d4fe476bf25/elife-49392-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55f2/7108862/99871d22a68e/elife-49392-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55f2/7108862/ac65fd2fd666/elife-49392-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55f2/7108862/2f5d14efc128/elife-49392-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55f2/7108862/4231794a670f/elife-49392-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55f2/7108862/6efa26d133d4/elife-49392-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55f2/7108862/8af39be90361/elife-49392-fig5-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55f2/7108862/ba987b1e93ec/elife-49392-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55f2/7108862/666449cb8be0/elife-49392-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55f2/7108862/b127170175d7/elife-49392-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55f2/7108862/3d4fe476bf25/elife-49392-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55f2/7108862/99871d22a68e/elife-49392-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55f2/7108862/ac65fd2fd666/elife-49392-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55f2/7108862/2f5d14efc128/elife-49392-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55f2/7108862/4231794a670f/elife-49392-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55f2/7108862/6efa26d133d4/elife-49392-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55f2/7108862/8af39be90361/elife-49392-fig5-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55f2/7108862/ba987b1e93ec/elife-49392-fig6.jpg

相似文献

1
GPC1 specific CAR-T cells eradicate established solid tumor without adverse effects and synergize with anti-PD-1 Ab.GPC1 特异性 CAR-T 细胞可消除已建立的实体肿瘤而无不良反应，并与抗 PD-1 Ab 协同作用。
Elife. 2020 Mar 31;9:e49392. doi: 10.7554/eLife.49392.
2
Off-the-shelf Vδ1 gamma delta T cells engineered with glypican-3 (GPC-3)-specific chimeric antigen receptor (CAR) and soluble IL-15 display robust antitumor efficacy against hepatocellular carcinoma.现货即用型 Vδ1 γδ T 细胞经 GPC-3 特异性嵌合抗原受体（CAR）和可溶性 IL-15 修饰后，显示出针对肝细胞癌的强大抗肿瘤疗效。
J Immunother Cancer. 2021 Dec;9(12). doi: 10.1136/jitc-2021-003441.
3
CAR T cells targeting tumor-associated exons of glypican 2 regress neuroblastoma in mice.嵌合抗原受体 T 细胞靶向神经母细胞瘤糖蛋白 2 的肿瘤相关外显子可使其在小鼠中消退。
Cell Rep Med. 2021 Jun 1;2(6):100297. doi: 10.1016/j.xcrm.2021.100297. eCollection 2021 Jun 15.
4
Improved survival of chimeric antigen receptor-engineered T (CAR-T) and tumor-specific T cells caused by anti-programmed cell death protein 1 single-chain variable fragment-producing CAR-T cells.嵌合抗原受体工程 T（CAR-T）细胞和肿瘤特异性 T 细胞的生存时间延长是由抗程序性细胞死亡蛋白 1 单链可变片段产生的 CAR-T 细胞引起的。
Cancer Sci. 2019 Oct;110(10):3079-3088. doi: 10.1111/cas.14169. Epub 2019 Sep 17.
5
Combined antitumor effects of anti-EGFR variant III CAR-T cell therapy and PD-1 checkpoint blockade on glioblastoma in mouse model.抗 EGFR 变异 III 嵌合抗原受体 T 细胞治疗联合 PD-1 检查点阻断对小鼠模型胶质母细胞瘤的抗肿瘤作用。
Cell Immunol. 2020 Jun;352:104112. doi: 10.1016/j.cellimm.2020.104112. Epub 2020 Apr 9.
6
Increased antitumor activities of glypican-3-specific chimeric antigen receptor-modified T cells by coexpression of a soluble PD1-CH3 fusion protein.通过共表达可溶性 PD1-CH3 融合蛋白，提高了糖蛋白聚糖-3 特异性嵌合抗原受体修饰 T 细胞的抗肿瘤活性。
Cancer Immunol Immunother. 2018 Oct;67(10):1621-1634. doi: 10.1007/s00262-018-2221-1. Epub 2018 Aug 4.
7
Enhanced Cancer Immunotherapy by Chimeric Antigen Receptor-Modified T Cells Engineered to Secrete Checkpoint Inhibitors.嵌合抗原受体修饰的 T 细胞分泌检查点抑制剂增强癌症免疫治疗。
Clin Cancer Res. 2017 Nov 15;23(22):6982-6992. doi: 10.1158/1078-0432.CCR-17-0867. Epub 2017 Sep 14.
8
Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo.CAR-T 细胞靶向递送 PD-1 阻断 scFv 增强体内抗肿瘤疗效。
Nat Biotechnol. 2018 Oct;36(9):847-856. doi: 10.1038/nbt.4195. Epub 2018 Aug 13.
9
Adenovirus-mediated specific tumor tagging facilitates CAR-T therapy against antigen-mismatched solid tumors.腺病毒介导的特异性肿瘤标记有助于嵌合抗原受体 T 细胞疗法治疗抗原错配的实体瘤。
Cancer Lett. 2020 Sep 1;487:1-9. doi: 10.1016/j.canlet.2020.05.013. Epub 2020 May 23.
10
B7-H3 specific T cells with chimeric antigen receptor and decoy PD-1 receptors eradicate established solid human tumors in mouse models.具有嵌合抗原受体和诱饵性PD-1受体的B7-H3特异性T细胞可根除小鼠模型中已形成的人实体瘤。
Oncoimmunology. 2019 Nov 4;9(1):1684127. doi: 10.1080/2162402X.2019.1684127. eCollection 2020.

引用本文的文献

1
Structural Features of Glypicans and their Impact on Wnt Signaling in Cancer.磷脂酰肌醇蛋白聚糖的结构特征及其对癌症中Wnt信号传导的影响。
Proteoglycan Res. 2025 Apr;3(2). doi: 10.1002/pgr2.70029. Epub 2025 May 13.
2
CAR-T Therapy Beyond B-Cell Hematological Malignancies.CAR-T疗法在B细胞血液系统恶性肿瘤之外的应用
Cells. 2025 Jan 3;14(1):41. doi: 10.3390/cells14010041.
3
Development of CAR-T Therapies and Personalized Vaccines for the Treatment of Cholangiocarcinoma: Current Progress, Mechanisms of Action, and Challenges.用于治疗胆管癌的嵌合抗原受体T细胞疗法和个性化疫苗的发展：当前进展、作用机制及挑战

本文引用的文献

1
Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR.低亲和力 CD19 CAR 治疗儿童 ALL 患者可增强 CAR T 细胞扩增和延长持久性。
Nat Med. 2019 Sep;25(9):1408-1414. doi: 10.1038/s41591-019-0549-5. Epub 2019 Sep 2.
2
Approaches to treat immune hot, altered and cold tumours with combination immunotherapies.采用联合免疫疗法治疗免疫热、改变和冷肿瘤的方法。
Nat Rev Drug Discov. 2019 Mar;18(3):197-218. doi: 10.1038/s41573-018-0007-y.
3
Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia.
Am J Pathol. 2025 Mar;195(3):453-469. doi: 10.1016/j.ajpath.2024.10.021. Epub 2024 Dec 14.
4
CAR-T cell therapy: Advances in digestive system malignant tumors.嵌合抗原受体T细胞疗法：消化系统恶性肿瘤的研究进展
Mol Ther Oncol. 2024 Sep 10;32(4):200872. doi: 10.1016/j.omton.2024.200872. eCollection 2024 Dec 19.
5
Syngeneic Mouse Models for Pre-Clinical Evaluation of CAR T Cells.用于CAR T细胞临床前评估的同基因小鼠模型
Cancers (Basel). 2024 Sep 18;16(18):3186. doi: 10.3390/cancers16183186.
6
Empowering brain tumor management: chimeric antigen receptor macrophage therapy.赋能脑肿瘤管理：嵌合抗原受体巨噬细胞疗法。
Theranostics. 2024 Sep 3;14(14):5725-5742. doi: 10.7150/thno.98290. eCollection 2024.
7
Cancer therapy with antibodies.抗体癌症疗法。
Nat Rev Cancer. 2024 Jun;24(6):399-426. doi: 10.1038/s41568-024-00690-x. Epub 2024 May 13.
8
State of the Art in CAR-T Cell Therapy for Solid Tumors: Is There a Sweeter Future?嵌合抗原受体 T 细胞疗法治疗实体瘤的最新进展：未来是否更加美好？
Cells. 2024 Apr 23;13(9):725. doi: 10.3390/cells13090725.
9
CAR-NK cells in combination therapy against cancer: A potential paradigm.嵌合抗原受体自然杀伤细胞在癌症联合治疗中的应用：一种潜在模式。
Heliyon. 2024 Feb 29;10(5):e27196. doi: 10.1016/j.heliyon.2024.e27196. eCollection 2024 Mar 15.
10
Mucin-1-Targeted Chimeric Antigen Receptor T Cells Are Effective and Safe in Controlling Solid Tumors in Immunocompetent Host.嵌合抗原受体 T 细胞靶向黏蛋白-1 对免疫功能正常的宿主实体瘤具有疗效和安全性。
J Immunother. 2024 Apr 1;47(3):77-88. doi: 10.1097/CJI.0000000000000505. Epub 2024 Jan 25.
慢性淋巴细胞白血病中 CD19 嵌合抗原受体 (CAR) T 细胞治疗应答和耐药的决定因素。
Nat Med. 2018 May;24(5):563-571. doi: 10.1038/s41591-018-0010-1. Epub 2018 Apr 30.
4
CAR T cell immunotherapy for human cancer.嵌合抗原受体 T 细胞免疫疗法治疗人类癌症。
Science. 2018 Mar 23;359(6382):1361-1365. doi: 10.1126/science.aar6711.
5
Preclinical Models in Chimeric Antigen Receptor-Engineered T-Cell Therapy.嵌合抗原受体修饰 T 细胞疗法的临床前模型。
Hum Gene Ther. 2018 May;29(5):534-546. doi: 10.1089/hum.2017.243. Epub 2018 Mar 14.
6
Glypican-1 immunohistochemistry is a novel marker to differentiate epithelioid mesothelioma from lung adenocarcinoma.Glypican-1 免疫组化是一种鉴别上皮型间皮瘤和肺腺癌的新型标志物。
Mod Pathol. 2018 May;31(5):809-815. doi: 10.1038/modpathol.2017.190. Epub 2018 Jan 12.
7
Human PBMC-transferred murine MHC class I/II-deficient NOG mice enable long-term evaluation of human immune responses.人外周血单核细胞转输的 MHC Ⅰ/Ⅱ缺陷型 NOG 小鼠可实现对人类免疫应答的长期评估。
Cell Mol Immunol. 2018 Nov;15(11):953-962. doi: 10.1038/cmi.2017.106. Epub 2017 Nov 20.
8
Anti-glypican-1 antibody-drug conjugate exhibits potent preclinical antitumor activity against glypican-1 positive uterine cervical cancer.抗磷脂酰聚糖-1 抗体药物偶联物对磷脂酰聚糖-1 阳性宫颈癌具有强大的临床前抗肿瘤活性。
Int J Cancer. 2018 Mar 1;142(5):1056-1066. doi: 10.1002/ijc.31124. Epub 2017 Oct 31.
9
Involvement of local renin-angiotensin system in immunosuppression of tumor microenvironment.局部肾素-血管紧张素系统参与肿瘤微环境的免疫抑制作用。
Cancer Sci. 2018 Jan;109(1):54-64. doi: 10.1111/cas.13423. Epub 2017 Nov 9.
10
Therapeutically targeting glypican-2 via single-domain antibody-based chimeric antigen receptors and immunotoxins in neuroblastoma.通过基于单域抗体的嵌合抗原受体和免疫毒素靶向治疗神经母细胞瘤中的聚糖蛋白-2。
Proc Natl Acad Sci U S A. 2017 Aug 8;114(32):E6623-E6631. doi: 10.1073/pnas.1706055114. Epub 2017 Jul 24.