David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.
Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Nat Biotechnol. 2018 Sep;36(8):707-716. doi: 10.1038/nbt.4181. Epub 2018 Jul 9.
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.
过继细胞疗法（ACT）使用抗原特异性 T 细胞已显示出显著的临床成功；然而，安全有效地增强 T 细胞功能的方法，特别是在实体肿瘤中，仍然非常有意义。在这里，我们描述了一种通过使用蛋白纳米凝胶（NGs）将大量支持蛋白药物“背包”在 T 细胞上的策略，这些 NGs 可以选择性地响应 T 细胞受体激活来释放这些货物。我们设计了细胞表面偶联的 NGs，这些 NGs 在抗原识别后 T 细胞表面还原电势增加时做出响应，并将药物释放限制在抗原存在的部位，如肿瘤微环境。通过使用携带白细胞介素-15 超激动剂复合物的 NGs，我们证明与游离细胞因子的系统给药相比，NG 给药可使肿瘤中 T 细胞选择性扩增 16 倍，并可在无毒性的情况下给予至少 8 倍更高剂量的细胞因子。改善的治疗窗口使小鼠 T 细胞和人嵌合抗原受体（CAR）-T 细胞治疗在体内更有效地清除肿瘤。
