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

H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the disialoganglioside GD2 (ref. <sup>1</sup>). Chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) eradicated DMGs in preclinical models<sup>1</sup>. Arm A of Phase I trial no. NCT04196413 (ref. <sup>2</sup>) 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 × 10<sup>6</sup> kg<sup>-</sup><sup>1</sup>; DL2, 3 × 10<sup>6</sup> kg<sup>-1</sup>) following lymphodepleting chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) intracranial infusions (10-30 × 10<sup>6</sup> 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.

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Publication Details

Journal
Nature
Published
2024-11-13
DOI
https://doi.org/10.1038/s41586-024-08171-9
Citations
139
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
39.27
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article

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

Paul G. Fisher, Xiaobu Ye, Annie Kathleen Brown, Kara L. Davis et al.
139 citations
Nature
CAR-T cell therapy research
39.27
article

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

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

Abstract

H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the disialoganglioside GD2 (ref. <sup>1</sup>). Chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) eradicated DMGs in preclinical models<sup>1</sup>. Arm A of Phase I trial no. NCT04196413 (ref. <sup>2</sup>) 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 × 10<sup>6</sup> kg<sup>-</sup><sup>1</sup>; DL2, 3 × 10<sup>6</sup> kg<sup>-1</sup>) following lymphodepleting chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) intracranial infusions (10-30 × 10<sup>6</sup> 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.

NatureVol. 637(8046)
Howard Hughes Medical Institute (US), Johns Hopkins University (US), Johns Hopkins Medicine (US), Stanford Health Care (US), Parker Institute for Cancer Immunotherapy (US), Stanford Medicine (US), Stanford University (US)
Zero hunger
Openalex Percentile: Top 0%
CAR-T cell therapy research
39.27
DOIOpen Access PDFOpenAlex
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