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

• 成果类型: Article
• 署名作者: 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
• 署名单位: Stanford University; Stanford University; Stanford University; Stanford Cancer Institute; Stanford University; Stanford University; Stanford University; Howard Hughes Medical Institute; Stanford University; Stanford University; Stanford Medicine; Stanford University; Johns Hopkins University; Johns Hopkins Medicine; Stanford University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1207
• DOI: 10.1038/s41586-024-08171-9
• 发表日期: 2025-01-16
• 关键词: intrinsic pontine glioma; central-nervous-system; high-grade; CHILDREN

摘要

H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the disialoganglioside GD2 (ref. 1). Chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) eradicated DMGs in preclinical models2. Arm A of Phase I 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 x 106 kg-1; DL2, 3 x 106 kg-1) following lymphodepleting chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) intracranial infusions (10-30 x 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. We evaluated the use of chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) for H3K27M+ diffuse midline glioma (DMG), finding that intravenous administration of GD2-CART, followed by intracranial infusions, induced tumour regressions and neurological improvements in patients with H3K27M-mutant pontine or spinal DMG.