Intravenous and intracranial GD2-CAR T cells for H3K27Mdiffuse midline gliomas.

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

TLDR

  • Chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) showed promising results in patients with H3K27M-mutant diffuse midline gliomas (DMGs), with tumor regressions and neurological improvements observed.

Abstract

H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the disialoganglioside GD2 (ref.). Chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) eradicated DMGs in preclinical models. Arm A of Phase I trial no. NCT04196413 (ref.) 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 × 10kg; DL2, 3 × 10kg) following lymphodepleting chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) intracranial infusions (10-30 × 10GD2-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.

Overview

  • The study aimed to investigate the feasibility, tolerability, and efficacy of chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) in patients with H3K27M-mutant diffuse midline gliomas (DMGs).
  • The study enrolled 13 patients, with 11 receiving intravenous (IV) GD2-CART and 9 receiving subsequent intracranial infusions.
  • The primary objective was to identify the maximally tolerated IV dose, while secondary objectives included assessing the efficacy and tolerability of the treatment.

Comparative Analysis & Findings

  • The study found that the maximally tolerated IV dose was 1 × 10^6 GD2-CART/kg, with no dose-limiting toxicities occurring at this dose level.
  • Nine patients received ICV infusions, with no dose-limiting toxicities, and all patients exhibited tumour inflammation-associated neurotoxicity, which was managed safely.
  • Four patients demonstrated major volumetric tumour reductions, ranging from 52% to 100%, with a further three patients exhibiting smaller reductions, and one patient showed a complete response ongoing for over 30 months.

Implications and Future Directions

  • The study suggests that GD2-CART may be a promising therapy for patients with H3K27M-mutant DMGs, with potential for tumor regressions and neurological improvements.
  • Future studies should aim to further explore the optimal dose and schedule of GD2-CART, as well as its combination with other therapies.
  • Additionally, the study highlights the importance of close monitoring and care for patients receiving GD2-CART, particularly in terms of managing neurotoxicity.
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