Intravenous and intracranial GD2-CAR T cells for H3K27M+ diffuse midline gliomas

Affiliations

• Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
• Division of Pediatric Hematology/Oncology/Stem Cell Transplant and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, CA, USA
• Stanford Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA, USA
• Department of Neurosurgery, Stanford University, Stanford, CA, USA
• Department of Pathology, Stanford University, Stanford, CA, USA
• Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA
• Division of Neuroradiology, Department of Radiology, Stanford University, Stanford, CA, USA
• Cellular Therapy Facility, Stanford Health Care, Palo Alto, CA, USA
• Department of Pediatrics, Division of Pediatric Critical Care Medicine, Stanford University, Stanford, CA, US
• Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD, USA
• Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA
• Division of Stem Cell Transplantation and Cell Therapy, Department of Medicine, Stanford University, Stanford, CA, USA

PMID:  #  DOI: 10.1038/s41586-024-08171-9

Abstract

H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the disialoganglioside GD2. Chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) eradicated DMGs in preclinical models. Arm A of Phase I trial no. NCT04196413 administered one intravenous (IV) dose of autologous GD2-CART to patients with H3K27M-mutant pontine (DIPG) or spinal DMG (sDMG) at two dose levels (DL1, 1 × 106 kg−1; DL2, 3 × 106 kg−1) following lymphodepleting chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) intracranial infusions (10–30 × 106 GD2-CART). Primary objectives were manufacturing feasibility, tolerability and the identification of maximally tolerated IV dose. Secondary objectives included preliminary assessments of benefit. Thirteen patients enroled, with 11 receiving IV GD2-CART on study (n = 3 DL1 (3 DIPG); n = 8 DL2 (6 DIPG, 2 sDMG)). GD2-CART manufacture was successful for all patients. No dose-limiting toxicities occurred on DL1, but three patients experienced dose-limiting cytokine release syndrome on DL2, establishing DL1 as the maximally tolerated IV dose. Nine patients received ICV infusions, with no dose-limiting toxicities. All patients exhibited tumour inflammation-associated neurotoxicity, safely managed with intensive monitoring and care. Four patients demonstrated major volumetric tumour reductions (52, 54, 91 and 100%), with a further three patients exhibiting smaller reductions. One patient exhibited a complete response ongoing for over 30 months since enrolment. Nine patients demonstrated neurological benefit, as measured by a protocol-directed clinical improvement score. Sequential IV, followed by ICV GD2-CART, induced tumour regressions and neurological improvements in patients with DIPG and those with sDMG.

H3K27M突变型弥漫性中线胶质瘤（DMGs）表达高水平的二唾液酸神经节苷脂GD2。经过嵌合抗原受体（CAR）修饰的T细胞靶向GD2（GD2-CART）在临床前模型中能够清除DMGs。I期临床试验（编号NCT04196413）A组将自体GD2-CART静脉注射（IV）给患有H3K27M突变型脑桥（DIPG）或脊髓DMG（sDMG）的患者，分为两个剂量水平（DL1，1×10^6 kg−1；DL2，3×10^6 kg−1），并进行淋巴消除化疗。对临床或影像学上有益的患者可进行后续脑室内（ICV）颅内输注（10–30×10^6 GD2-CART）。主要目标为制造可行性、耐受性以及最大耐受静脉剂量的确定。次要目标包括初步效益评估。共有13名患者入组，其中11名患者在研究中接受了静脉GD2-CART治疗（DL1组3例（均为DIPG），DL2组8例（6例DIPG，2例sDMG））。所有患者的GD2-CART制造均成功。DL1组未发生剂量限制性毒性，而DL2组有3名患者出现剂量限制性细胞因子释放综合症，确立DL1为最大耐受静脉剂量。9名患者接受了ICV输注，未出现剂量限制性毒性。所有患者均表现出与肿瘤炎症相关的神经毒性，但通过密切监测和护理得以安全管理。4名患者出现了显著的肿瘤体积减少（分别为52%、54%、91%和100%），另外3名患者则显示出较小的减少。一名患者在入组后超过30个月持续出现完全缓解。9名患者表现出神经功能改善，依据临床改进评分系统评估。静脉注射GD2-CART后，随之进行ICV输注，能够在患有DIPG和sDMG的患者中诱导肿瘤退缩和神经功能改善。

关键词：胶质瘤，CAR-T，细胞治疗，GD2，GD2-CAR T，抗体