Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMGs) with mutated histone H3 K27M (H3-K27M)^1-5 are aggressive and universally fatal pediatric brain cancers ⁶ . Chimeric antigen receptor (CAR)-expressing T cells have mediated impressive clinical activity in B cell malignancies^7-10, and recent results suggest benefit in central nervous system malignancies^11-13. Here, we report that patient-derived H3-K27M-mutant glioma cell cultures exhibit uniform, high expression of the disialoganglioside GD2. Anti-GD2 CAR T cells incorporating a 4-1BBz costimulatory domain ¹⁴ demonstrated robust antigen-dependent cytokine generation and killing of DMG cells in vitro. In five independent patient-derived H3-K27M⁺ DMG orthotopic xenograft models, systemic administration of GD2-targeted CAR T cells cleared engrafted tumors except for a small number of residual GD2^lo glioma cells. To date, GD2-targeted CAR T cells have been well tolerated in clinical trials^15-17. Although GD2-targeted CAR T cell administration was tolerated in the majority of mice bearing orthotopic xenografts, peritumoral neuroinflammation during the acute phase of antitumor activity resulted in hydrocephalus that was lethal in a fraction of animals. Given the precarious neuroanatomical location of midline gliomas, careful monitoring and aggressive neurointensive care management will be required for human translation. With a cautious multidisciplinary clinical approach, GD2-targeted CAR T cell therapy for H3-K27M⁺ diffuse gliomas of pons, thalamus and spinal cord could prove transformative for these lethal childhood cancers.

中文翻译：

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抗 GD2 CAR T 细胞在 H3-K27M+ 弥漫性中线神经胶质瘤中具有有效的抗肿瘤功效。


具有突变组蛋白 H3 K27M (H3-K27M) ^1-5的弥漫性内质性脑桥胶质瘤 (DIPG) 和其他弥漫性中线胶质瘤 (DMG) 是侵袭性且普遍致命的儿童脑癌⁶ 。表达嵌合抗原受体 (CAR) 的 T 细胞在 B 细胞恶性肿瘤中发挥了令人印象深刻的临床活性^7-10 ，最近的结果表明对中枢神经系统恶性肿瘤有益^11-13 。在这里，我们报告患者来源的 H3-K27M 突变神经胶质瘤细胞培养物表现出均匀、高表达的二唾液酸神经节苷脂 GD2。整合了 4-1BBz 共刺激结构域¹⁴的抗 GD2 CAR T 细胞在体外表现出强大的抗原依赖性细胞因子生成和杀伤 DMG 细胞的能力。在五个独立的源自患者的 H3-K27M ⁺ DMG 原位异种移植模型中，全身施用 GD2 靶向 CAR T 细胞清除了移植的肿瘤，除了少量残留的 GD2lo^神经胶质瘤细胞。迄今为止，GD2 靶向 CAR T 细胞在临床试验中具有良好的耐受性^15-17 。尽管大多数携带原位异种移植物的小鼠可以耐受 GD2 靶向 CAR T 细胞给药，但抗肿瘤活性急性期的瘤周神经炎症会导致部分动物致命的脑积水。鉴于中线神经胶质瘤的神经解剖学位置不稳定，人工翻译需要仔细监测和积极的神经重症监护管理。通过谨慎的多学科临床方法，针对 H3-K27M ⁺脑桥、丘脑和脊髓的弥漫性神经胶质瘤的 GD2 靶向 CAR T 细胞疗法可能会为这些致命的儿童癌症带来变革。