Gust Juliane, Cole Bonnie L, Ronsley Rebecca, Wilson Ashley L, Seidel Kristy, Wendler Jason, Pattabhi Sowmya, Brown Christopher, Rawlings-Rhea Stephanie D, Shtanukhina Nadezhda, Browd Samuel R, Hauptman Jason S, Lee Amy, Ojemann Jeffrey G, Crotty Erin E, Leary Sarah E S, Perez Francisco A, Wright Jason N, Albert Catherine M, Pinto Navin, Gardner Rebecca A, Vitanza Nicholas A, Jensen Michael C, Park Julie R
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington.
Division of Pediatric Neurology, Department of Neurology, University of Washington, Seattle, Washington.
Neuro Oncol. 2025 Mar 12. doi: 10.1093/neuonc/noaf064.
Relapsed/refractory pediatric CNS tumors have a poor prognosis. EGFR is commonly overexpressed, but EGFRvIII mutations are uncommon. To target these tumors, we used chimeric antigen receptor (CAR) T cells with a binder based on mAb806 which recognizes ectopically expressed wild-type EGFR and EGFRvIII.
In this open-label phase 1 clinical trial, patients age 1-26 years with EGFR+ CNS tumors received weekly infusions of 1-2.5 x 107 CAR T cells into the tumor resection bed or the lateral ventricle via an implanted catheter. No lymphodepletion was used.
Eleven patients were enrolled. Four (3 with high-grade glioma, 1 with atypical teratoid-rhabdoid tumor) were treated and received 5-10 CAR T cell infusions without dose-limiting toxicities. The trial closed prior to reaching planned dose regimens. All treatment-related adverse events were no higher than CTCAE grade 2. The most common were headache and nausea. One patient had a grade 1 seizure, and three had new sensory changes, weakness and/or urinary changes (grade 1-2) that were possibly related to CAR T cell infusion. Three of the four treated patients had progressive disease. One patient with spinal cord diffuse midline glioma had progressive peritumoral edema that could not be conclusively attributed to either progression or pseudoprogression and was therefore defined as stable disease, followed by a complete response to subsequent chemotherapy.
Intracranially infused EGFR806-CAR T cells were tolerable at tested doses, with a best response of stable disease. EGFR is a potentially useful target for cellular therapy against pediatric brain tumors, particularly high-grade gliomas.
复发/难治性小儿中枢神经系统肿瘤预后较差。表皮生长因子受体（EGFR）通常过度表达，但EGFRvIII突变并不常见。为了靶向这些肿瘤，我们使用了嵌合抗原受体（CAR）T细胞，其结合物基于单克隆抗体806，该抗体可识别异位表达的野生型EGFR和EGFRvIII。
在这项开放标签的1期临床试验中，年龄在1 - 26岁、患有EGFR阳性中枢神经系统肿瘤的患者通过植入导管每周向肿瘤切除床或侧脑室输注1 - 2.5×10⁷个CAR T细胞。未使用淋巴细胞清除疗法。
招募了11名患者。4名患者（3名患有高级别胶质瘤，1名患有非典型畸胎样横纹肌样瘤）接受了治疗，并接受了5 - 10次CAR T细胞输注，未出现剂量限制性毒性。该试验在达到计划剂量方案之前结束。所有与治疗相关的不良事件均不高于美国国立癌症研究所常见不良反应事件评价标准（CTCAE）2级。最常见的是头痛和恶心。1名患者出现1级癫痫发作，3名患者出现可能与CAR T细胞输注有关的新的感觉改变、虚弱和/或泌尿改变（1 - 2级）。4名接受治疗的患者中有3名病情进展。1名患有脊髓弥漫性中线胶质瘤的患者出现肿瘤周围进行性水肿，无法明确归因于进展或假性进展，因此被定义为病情稳定，随后对后续化疗完全缓解。
在测试剂量下，颅内输注EGFR806 - CAR T细胞耐受性良好，最佳反应为病情稳定。EGFR是针对小儿脑肿瘤，特别是高级别胶质瘤进行细胞治疗的一个潜在有用靶点。
