嵌合抗原受体
T细胞
癌症研究
细胞疗法
肿瘤微环境
细胞因子
细胞
抗原
药物输送
体内
T细胞受体
药理学
化学
免疫学
医学
免疫系统
生物
生物化学
有机化学
生物技术
作者
Li Tang,Yiran Zheng,Mariane B. Melo,Llian Mabardi,Ana P. Castaño,Yuqing Xie,Na Li,Sagar B. Kudchodkar,Hing C. Wong,Emily K. Jeng,Marcela V. Maus,Darrell J. Irvine
摘要
Cytokines released after T cell activation improve the efficacy of T cell therapies in mice. Adoptive cell therapy (ACT) with antigen-specific T cells has shown remarkable clinical success; however, approaches to safely and effectively augment T cell function, especially in solid tumors, remain of great interest. Here we describe a strategy to 'backpack' large quantities of supporting protein drugs on T cells by using protein nanogels (NGs) that selectively release these cargos in response to T cell receptor activation. We designed cell surface–conjugated NGs that responded to an increase in T cell surface reduction potential after antigen recognition and limited drug release to sites of antigen encounter, such as the tumor microenvironment. By using NGs that carried an interleukin-15 super-agonist complex, we demonstrated that, relative to systemic administration of free cytokines, NG delivery selectively expanded T cells 16-fold in tumors and allowed at least eightfold higher doses of cytokine to be administered without toxicity. The improved therapeutic window enabled substantially increased tumor clearance by mouse T cell and human chimeric antigen receptor (CAR)-T cell therapy in vivo.
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