Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
J Immunother Cancer. 2024 Aug 7;12(8):e009486. doi: 10.1136/jitc-2024-009486.
High-grade gliomas including glioblastoma (GBM) and diffuse midline gliomas (DMG) represent the most lethal and aggressive brain cancers where current treatment modalities offer limited efficacy. Chimeric antigen receptor (CAR) T cell therapies have emerged as a promising strategy, boasting tumor-specific targeting and the unique ability to penetrate the blood-brain barrier. However, the effective clinical application hinges on the optimal choice of antigen, with a limited number, currently under investigation.
We employed cell surface proteomic analysis of primary human high-grade glioma samples from both adult and pediatric patients. This led to the identification of Ephrin type-A receptor 3 (EphA3) as a prevalently expressed target. We engineered a second-generation EphA3-targeted CAR T cell and assessed function using in vitro and in vivo models of GBM and DMG.
EphA3-targeted CAR T cells demonstrated robust antigen-specific killing of human GBM and DMG cell lines in vitro. In an orthotopic xenograft NSG mouse model, EphA3-targeted CAR T cells not only effectively eradicated tumors but also established a functional T cell population protective on rechallenge. Remarkably, mice rechallenged with a second contralateral orthotopic tumor implantation achieved complete tumor clearance and maintained a sustained complete response 6 months following initial treatment.
Building on the proven safety profile of EphA3 antibodies in clinical settings, our study provides compelling preclinical evidence supporting the efficacy of EphA3-targeted CAR T cells against high-grade gliomas. These findings underscore the potential for transitioning this innovative therapy into clinical trials, aiming to revolutionize the treatment landscape for patients afflicted with these formidable brain cancers.
高级别神经胶质瘤，包括胶质母细胞瘤（GBM）和弥漫性中线神经胶质瘤（DMG），是最致命和侵袭性的脑癌，目前的治疗方法疗效有限。嵌合抗原受体（CAR）T 细胞疗法已成为一种很有前途的策略，具有肿瘤特异性靶向和穿透血脑屏障的独特能力。然而，有效的临床应用取决于抗原的最佳选择，目前只有有限数量的抗原正在研究中。
我们对来自成人和儿科患者的原发性人高级别神经胶质瘤样本进行了细胞表面蛋白质组学分析。这导致鉴定出 Ephrin 型-A 受体 3（EphA3）为普遍表达的靶标。我们设计了第二代 EphA3 靶向 CAR T 细胞，并使用 GBM 和 DMG 的体外和体内模型评估了其功能。
EphA3 靶向 CAR T 细胞在体外对人 GBM 和 DMG 细胞系表现出强大的抗原特异性杀伤作用。在原位异种移植 NSG 小鼠模型中，EphA3 靶向 CAR T 细胞不仅有效地消除了肿瘤，而且建立了一个功能性 T 细胞群体，在再次挑战时具有保护作用。值得注意的是，用第二个对侧原位移植的肿瘤再次挑战的小鼠实现了完全肿瘤清除，并在初始治疗后 6 个月保持持续完全缓解。
在 EphA3 抗体在临床环境中已被证实的安全性基础上，我们的研究提供了令人信服的临床前证据，支持 EphA3 靶向 CAR T 细胞对高级别神经胶质瘤的疗效。这些发现强调了将这种创新疗法转化为临床试验的潜力，旨在为患有这些强大脑癌的患者带来治疗的变革。
