State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, P.R. China.
Sci Transl Med. 2020 Nov 25;12(571). doi: 10.1126/scitranslmed.aaz6667.
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.
用 T 细胞疗法治疗实体瘤迄今只取得了有限的治疗效果。虽然 T 细胞疗法与促炎细胞因子或免疫检查点抑制剂联合应用在一部分实体瘤中取得了临床前和临床的成功，但不理想的结果和严重的毒性使得需要开发有效的和安全的联合策略。在这里，脂质体阿伐他汀（一种代谢调节药物）通过脂质插入而不是干扰 T 细胞的生理功能被点击到 T 细胞表面。阿伐他汀可以在循环和渗出过程中被限制在 T 细胞表面，并局部释放，以增加 T 细胞膜中的胆固醇浓度，从而诱导 TCR 快速聚集和持续的 T 细胞激活。用表面锚定工程 T 细胞（包括小鼠 T 细胞受体转基因 CD8 T 细胞或人嵌合抗原受体 T 细胞）治疗，在黑色素瘤和神经胶质瘤的小鼠模型中产生了优异的抗肿瘤疗效。接受表面锚定工程嵌合抗原受体 T 细胞治疗的五只小鼠中有三只完全消除了神经胶质瘤，而其他治疗组的小鼠存活时间不超过 64 天。此外，工程 T 细胞的给药没有明显的全身副作用。由于这些细胞表面锚定工程 T 细胞具有简单的生成和安全的特点，因此具有转化潜力。
