嵌合抗原受体
T细胞
免疫疗法
CD8型
癌症研究
细胞
医学
免疫系统
细胞疗法
细胞毒性T细胞
药理学
免疫学
化学
生物化学
体外
作者
Meixi Hao,Siyuan Hou,Weishuo Li,Kaiming Li,Lingjing Xue,Qifan Hu,Lin Zhu,Yue Chen,Hongbin Sun,Caoyun Ju,Can Zhang
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2020-11-25
卷期号:12 (571)
被引量:86
标识
DOI:10.1126/scitranslmed.aaz6667
摘要
Treatment of solid tumors with T cell therapy has yielded limited therapeutic benefits to date. Although T cell therapy in combination with proinflammatory cytokines or immune checkpoints inhibitors has demonstrated preclinical and clinical successes in a subset of solid tumors, unsatisfactory results and severe toxicities necessitate the development of effective and safe combinatorial strategies. Here, the liposomal avasimibe (a metabolism-modulating drug) was clicked onto the T cell surface by lipid insertion without disturbing the physiological functions of the T cell. Avasimibe could be restrained on the T cell surface during circulation and extravasation and locally released to increase the concentration of cholesterol in the T cell membrane, which induced rapid T cell receptor clustering and sustained T cell activation. Treatment with surface anchor-engineered T cells, including mouse T cell receptor transgenic CD8+ T cells or human chimeric antigen receptor T cells, resulted in superior antitumor efficacy in mouse models of melanoma and glioblastoma. Glioblastoma was completely eradicated in three of the five mice receiving surface anchor-engineered chimeric antigen receptor T cells, whereas mice in other treatment groups survived no more than 64 days. Moreover, the administration of engineered T cells showed no obvious systemic side effects. These cell-surface anchor-engineered T cells hold translational potential because of their simple generation and their safety profile.
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