美国斯坦福大学Crystal Mackall等研究人员合作发现，静脉注射和颅内注射GD2-CAR T细胞可用于治疗H3K27M⁺扩散性中线胶质瘤。2024年11月13日，《自然》杂志在线发表了这项成果。

研究人员表示，H3K27M突变的弥漫性中线胶质瘤（DMG）表达高水平的二神经酰基糖脂GD2。针对GD2的嵌合抗原受体（CAR）改造T细胞（GD2-CART）已在临床前模型中消除DMG。

NCT04196413号I期临床试验的A组对H3K27M突变的脑桥（DIPG）或脊柱DMG（sDMG）患者进行了一次静脉（IV）给药，使用自体GD2-CART，剂量分为两级（DL1, 1×10⁶/kg；DL2, 3×10⁶/kg），并在淋巴去除化疗后进行治疗。对于临床或影像学上有益的患者，符合条件接受后续的脑室内（ICV）脑内输注（10–30×10⁶ GD2-CART）。主要目标是评估制造可行性、耐受性和确定最大耐受IV剂量。次要目标包括初步的疗效评估。共招募13名患者，11名患者接受了IV GD2-CART治疗（n=3，DL1（3名DIPG患者）；n=8，DL2（6名DIPG患者，2名sDMG患者））。

所有患者的GD2-CART制造均成功。DL1组未出现剂量限制性毒性，但在DL2组有三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IV剂量。9名患者接受了ICV输注，未发生剂量限制性毒性。所有患者均表现出肿瘤炎症相关的神经毒性，经过密切监控和治疗得到了安全管理。四名患者出现了肿瘤体积显著减少（分别为52%，54%、91%和100%），另外三名患者则有较小的减少。一名患者在入组后超过30个月持续表现完全缓解。九名患者在按协议指导的临床改善评分中表现出神经学改善。IV给药后随即进行ICV GD2-CART治疗，在DIPG患者及sDMG患者中均诱导了肿瘤的退缩和神经学改善。

附：英文原文

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

Author: Monje, Michelle, Mahdi, Jasia, Majzner, Robbie, Yeom, Kristen W., Schultz, Liora M., Richards, Rebecca M., Barsan, Valentin, Song, Kun-Wei, Kamens, Jen, Baggott, Christina, Kunicki, Michael, Rietberg, Skyler P., Lim, Alexandria Sung, Reschke, Agnes, Mavroukakis, Sharon, Egeler, Emily, Moon, Jennifer, Patel, Shabnum, Chinnasamy, Harshini, Erickson, Courtney, Jacobs, Ashley, Duh, Allison K., Tunuguntla, Ramya, Klysz, Dorota Danuta, Fowler, Carley, Green, Sean, Beebe, Barbara, Carr, Casey, Fujimoto, Michelle, Brown, Annie Kathleen, Petersen, Ann-Louise G., McIntyre, Catherine, Siddiqui, Aman, Lepori-Bui, Nadia, Villar, Katlin, Pham, Kymhuynh, Bove, Rachel, Musa, Eric, Reynolds, Warren D., Kuo, Adam, Prabhu, Snehit, Rasmussen, Lindsey, Cornell, Timothy T., Partap, Sonia, Fisher, Paul G., Campen, Cynthia J., Grant, Gerald, Prolo, Laura, Ye, Xiaobu, Sahaf, Bita, Davis, Kara L., Feldman, Steven A., Ramakrishna, Sneha, Mackall, Crystal

Issue&Volume: 2024-11-13

Abstract: H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the disialoganglioside GD2 (ref. 1). Chimeric antigen receptor-modified Tcells targeting GD2 (GD2-CART) eradicated DMGs in preclinical models2. ArmA of PhaseI trial no. NCT04196413 (ref. 3) 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, 1×106kg1; DL2, 3×106kg1) 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 (3DIPG); n=8 DL2 (6DIPG, 2sDMG)). 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 forover30months 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.

DOI: 10.1038/s41586-024-08171-9

Source: https://www.nature.com/articles/s41586-024-08171-9