针对胶质母细胞瘤中表达的抗原的过继性 T 细胞疗法已成为一种潜在的治疗策略，可预防或延迟这种侵袭性疾病的复发并延长总体生存期。肝配蛋白受体 A3 (EphA3)，在胶质母细胞瘤中高表达；尤其是针对肿瘤血管系统和脑癌干细胞，是基于免疫疗法的理想靶标。我们利用新型单克隆抗体的单链可变片段设计了一种靶向 EphA3 的嵌合抗原受体 (CAR)，并评估了其对免疫缺陷小鼠中表达 EphA3 的患者来源的胶质母细胞瘤神经球、类器官和异种移植胶质母细胞瘤肿瘤的治疗潜力。来自健康个体的体外扩增的 EphA3 CAR T 细胞在体外有效识别并杀死 EphA3 阳性胶质母细胞瘤细胞。此外，这些效应细胞在胶质母细胞瘤原位异种移植模型中表现出疗效。 EphA3 CAR T 细胞在靶向患者来源的神经球以及在胶质母细胞瘤来源的类器官中浸润、分解和诱导细胞凋亡方面同样有效。这项研究提供了令人信服的证据，支持 EphA3 CAR T 细胞疗法通过靶向与胶质母细胞瘤相关的 EphA3 来治疗胶质母细胞瘤。脑癌干细胞和肿瘤脉管系统。针对患者来源的胶质母细胞瘤的能力强调了这种 EphA3 CAR T 细胞疗法在追求有效和有针对性的胶质母细胞瘤治疗策略中的转化意义。© 作者（或其雇主）2024。允许重复使用根据 CC BY-NC。禁止商业再利用。请参阅权利和权限。英国医学杂志出版。

Adoptive T-cell therapy targeting antigens expressed in glioblastoma has emerged as a potential therapeutic strategy to prevent or delay recurrence and prolong overall survival in this aggressive disease setting. Ephrin receptor A3 (EphA3), which is highly expressed in glioblastoma; in particular, on the tumor vasculature and brain cancer stem cells, is an ideal target for immune-based therapies.We have designed an EphA3-targeted chimeric antigen receptor (CAR) using the single chain variable fragment of a novel monoclonal antibody, and assessed its therapeutic potential against EphA3-expressing patient-derived glioblastoma neurospheres, organoids and xenografted glioblastoma tumors in immunodeficient mice.In vitro expanded EphA3 CAR T cells from healthy individuals efficiently recognize and kill EphA3-positive glioblastoma cells in vitro. Furthermore, these effector cells demonstrated curative efficacy in an orthotopic xenograft model of glioblastoma. EphA3 CAR T cells were equally effective in targeting patient-derived neurospheres and infiltrate, disaggregate, and induce apoptosis in glioblastoma-derived organoids.This study provides compelling evidence supporting the therapeutic potential of EphA3 CAR T-cell therapy against glioblastoma by targeting EphA3 associated with brain cancer stem cells and the tumor vasculature. The ability to target patient-derived glioblastoma underscores the translational significance of this EphA3 CAR T-cell therapy in the pursuit of effective and targeted glioblastoma treatment strategies.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.