美国西雅图大学Nicholas A. Vitanza等研究人员完成儿童和青年脑癌患者HER2特异性CAR T细胞治疗的期中分析。该项研究成果于2021年7月12日在线发表在《自然—医学》杂志上。

研究人员表示，嵌合抗原受体（CAR）T细胞的局部灌注能够在胶质母细胞瘤成年患者中产生客观反应，但是尚未评估这种方法的可行性和耐受性是否可用于儿童的中枢神经系统（CNS）肿瘤。

在原位异种移植物髓母细胞瘤模型中，研究人员发现，中等长度CAR间隔序列的工程化增强了人ERB-B2受体酪氨酸激酶2（HER2）特异性CAR T细胞的治疗效果。研究人员将这些发现转化为Brainchild-01（NCT03500991），这是在西雅图儿童研究所进行的一项临床研究，用于评估这些HER2特异性CAR T细胞在具有复发/难治性CNS肿瘤的儿童和青年（包括弥漫性中线神经胶质瘤）中的反复给药剂量。主要目标是评估可行性、安全性和耐受性；次要目的包括评估CAR T细胞分布和疾病反应。

在门诊环境中，患者通过CNS导管接受输注进入肿瘤腔或心室系统。最初的三名患者没有经过剂量限制毒性，并表现出局部CNS免疫激活的证据，包括脑脊髓液中的高浓度CXCL10和CCL2。该期中报告支持HER2特异性CAR T细胞疗法的可行性，并表明其反复的CNS递送可能具有良好的耐受性，并能激活儿童和青年患者的局部免疫应答。

附：英文原文

Title: Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: an interim analysis

Author: Nicholas A. Vitanza, Adam J. Johnson, Ashley L. Wilson, Christopher Brown, Jason K. Yokoyama, Annette Knkele, Cindy A. Chang, Stephanie Rawlings-Rhea, Wenjun Huang, Kristy Seidel, Catherine M. Albert, Navin Pinto, Juliane Gust, Laura S. Finn, Jeffrey G. Ojemann, Jason Wright, Rimas J. Orentas, Michael Baldwin, Rebecca A. Gardner, Michael C. Jensen, Julie R. Park

Issue&Volume: 2021-07-12

Abstract: Locoregional delivery of chimeric antigen receptor (CAR) T cells has resulted in objective responses in adults with glioblastoma, but the feasibility and tolerability of this approach is yet to be evaluated for pediatric central nervous system (CNS) tumors. Here we show that engineering of a medium-length CAR spacer enhances the therapeutic efficacy of human erb-b2 receptor tyrosine kinase 2 (HER2)-specific CAR T cells in an orthotopic xenograft medulloblastoma model. We translated these findings into BrainChild-01 (NCT03500991), an ongoing phase 1 clinical trial at Seattle Children’s evaluating repetitive locoregional dosing of these HER2-specific CAR T cells to children and young adults with recurrent/refractory CNS tumors, including diffuse midline glioma. Primary objectives are assessing feasibility, safety and tolerability; secondary objectives include assessing CAR T cell distribution and disease response. In the outpatient setting, patients receive infusions via CNS catheter into either the tumor cavity or the ventricular system. The initial three patients experienced no dose-limiting toxicity and exhibited clinical, as well as correlative laboratory, evidence of local CNS immune activation, including high concentrations of CXCL10 and CCL2 in the cerebrospinal fluid. This interim report supports the feasibility of generating HER2-specific CAR T cells for repeated dosing regimens and suggests that their repeated intra-CNS delivery might be well tolerated and activate a localized immune response in pediatric and young adult patients.

DOI: 10.1038/s41591-021-01404-8

Source: https://www.nature.com/articles/s41591-021-01404-8