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

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

doi:10.1038/s41586-024-08171-9

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

Nature. 2025 Jan;637(8046):708-715. doi: 10.1038/s41586-024-08171-9. Epub 2024 Nov 13.

Authors

Michelle Monje^{1

2

3

4

5

6}, Jasia Mahdi^{7

8}, Robbie Majzner^{9

8}, Kristen W Yeom^{7

10

11}, Liora M Schultz^{9

8}, Rebecca M Richards^{9

8}, Valentin Barsan^{9

8}, Kun-Wei Song^{7

8}, Jen Kamens^{9

8}, Christina Baggott⁸, Michael Kunicki⁸, Skyler P Rietberg⁸, Alexandria Sung Lim⁸, Agnes Reschke^{9

8}, Sharon Mavroukakis⁸, Emily Egeler⁸, Jennifer Moon⁸, Shabnum Patel⁸, Harshini Chinnasamy⁸, Courtney Erickson⁸, Ashley Jacobs⁸, Allison K Duh¹⁰, Ramya Tunuguntla⁸, Dorota Danuta Klysz⁸, Carley Fowler⁸, Sean Green⁹, Barbara Beebe⁸, Casey Carr⁸, Michelle Fujimoto⁸, Annie Kathleen Brown⁸, Ann-Louise G Petersen⁸, Catherine McIntyre¹², Aman Siddiqui¹², Nadia Lepori-Bui¹², Katlin Villar¹², Kymhuynh Pham¹², Rachel Bove¹², Eric Musa¹², Warren D Reynolds⁸, Adam Kuo⁸, Snehit Prabhu⁸, Lindsey Rasmussen¹³, Timothy T Cornell¹³, Sonia Partap⁷, Paul G Fisher⁷, Cynthia J Campen⁷, Gerald Grant¹⁰, Laura Prolo¹⁰, Xiaobu Ye¹⁴, Bita Sahaf⁸, Kara L Davis^{9

8}, Steven A Feldman⁸, Sneha Ramakrishna^{15

16}, Crystal Mackall^{17

18

19

20}

Affiliations

¹ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA. mmonje@stanford.edu.
² Division of Pediatric Hematology/Oncology/Stem Cell Transplant and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, CA, USA. mmonje@stanford.edu.
³ Stanford Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA, USA. mmonje@stanford.edu.
⁴ Department of Neurosurgery, Stanford University, Stanford, CA, USA. mmonje@stanford.edu.
⁵ Department of Pathology, Stanford University, Stanford, CA, USA. mmonje@stanford.edu.
⁶ Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA. mmonje@stanford.edu.
⁷ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
⁸ Stanford Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
⁹ Division of Pediatric Hematology/Oncology/Stem Cell Transplant and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, CA, USA.
¹⁰ Department of Neurosurgery, Stanford University, Stanford, CA, USA.
¹¹ Division of Neuroradiology, Department of Radiology, Stanford University, Stanford, CA, USA.
¹² Cellular Therapy Facility, Stanford Health Care, Palo Alto, CA, USA.
¹³ Department of Pediatrics, Division of Pediatric Critical Care Medicine, Stanford University, Stanford, CA, US.
¹⁴ Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD, USA.
¹⁵ Division of Pediatric Hematology/Oncology/Stem Cell Transplant and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, CA, USA. ramakrs@stanford.edu.
¹⁶ Stanford Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA, USA. ramakrs@stanford.edu.
¹⁷ Division of Pediatric Hematology/Oncology/Stem Cell Transplant and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, CA, USA. cmackall@stanford.edu.
¹⁸ Stanford Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA, USA. cmackall@stanford.edu.
¹⁹ Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. cmackall@stanford.edu.
²⁰ Division of Stem Cell Transplantation and Cell Therapy, Department of Medicine, Stanford University, Stanford, CA, USA. cmackall@stanford.edu.

Abstract

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 models¹. Arm A of Phase I trial no. NCT04196413 (ref. ²) 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.

Publication types

Clinical Trial, Phase I

MeSH terms

Administration, Intravenous
Adolescent
Adult
Brain Neoplasms / drug therapy
Brain Neoplasms / immunology
Brain Neoplasms / pathology
Brain Neoplasms / therapy
Brain Stem Neoplasms / genetics
Brain Stem Neoplasms / immunology
Brain Stem Neoplasms / pathology
Brain Stem Neoplasms / therapy
Child
Female
Gangliosides* / immunology
Gangliosides* / metabolism
Glioma* / drug therapy
Glioma* / immunology
Glioma* / pathology
Glioma* / therapy
Histones / metabolism
Humans
Immunotherapy, Adoptive / adverse effects
Infusions, Intraventricular
Male
Middle Aged
Receptors, Chimeric Antigen* / immunology
T-Lymphocytes / immunology
T-Lymphocytes / metabolism
T-Lymphocytes / transplantation
Young Adult

Substances

Gangliosides
ganglioside, GD2
Receptors, Chimeric Antigen
Histones

Abstract

Publication types

MeSH terms

Substances

Grants and funding