肿瘤细胞治疗研究
英文原题：Targeting overexpressed antigens in glioblastoma via CAR T cells with computationally designed high-affinity protein binders.
靶向肿瘤细胞受体的嵌合抗原受体（CAR）T 细胞在胶质母细胞瘤患者中取得的成功有限。
靶向肿瘤细胞受体的嵌合抗原受体（CAR）T 细胞在胶质母细胞瘤患者中的疗效有限。本文报告 CAR 构建体的开发及治疗效果；这些构建体采用计算机从头设计的高亲和力蛋白结合分子，靶向胶质母细胞瘤中过表达的表皮生长因子受体（EGFR）或肿瘤相关抗原 CD276。与使用抗体来源单链可变片段作为抗原结合结构域的 CAR-T 细胞相比，采用设计型结合分子的 CAR-T 细胞增殖更多、分泌更多细胞毒性细胞因子、对细胞耗竭更具抵抗力，并在体外和体内显示更强抗肿瘤效能。此外，整体和单细胞转录分析显示，采用设计型结合分子的 CAR 表面表达更高、降解抵抗力更强。针对特异性肿瘤抗原从头设计结合结构域，有望增强 CAR-T 细胞治疗其他实体癌的抗肿瘤疗效。
Chimeric antigen receptor (CAR) T cells targeting receptors on tumour cells have had limited success in patients with glioblastoma. Here we report the development and therapeutic performance of CAR constructs leveraging protein binders computationally designed de novo to have high affinity for the epidermal growth factor receptor (EGFR) or the tumour-associated antigen CD276, which are overexpressed in glioblastoma. With respect to T cells with a CAR using an antibody-derived single-chain variable fragment as antigen-binding domain, the designed binders on CAR T cells promoted the proliferation of the cells, the secretion of cytotoxic cytokines and their resistance to cell exhaustion, and improved antitumour performance in vitro and in vivo. Moreover, CARs with the binders exhibited higher surface expression and greater resistance to degradation, as indicated by bulk and single-cell transcriptional profiling of the cells. The de novo design of binding domains for specific tumour antigens may potentiate the antitumour efficacy of CAR T cell therapies for other solid cancers.
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