GD2-CAR T Induces Tumor Regression in H3K27M-Mutant Diffuse Midline Gliomas

Microscopic photorealistic image of CAR T cells - Generated with Google Gemini AI

A phase 1 clinical trial (NCT05316155) investigating the use of GD2-targeted chimeric antigen receptor (CAR) T cells for the treatment of H3K27M-mutant diffuse midline gliomas (DMGs) yielded promising results, demonstrating the feasibility, safety, and early efficacy of this approach.¹

The trial enrolled 13 patients, with 11 receiving GD2-CAR T-cell therapy. Here, GD2-CAR T-cell therapy led to substantial tumor regressions in several patients, with 4 patients experiencing major reductions in tumor volume (52%-100%). One patient had a complete response that was sustained for over 30 months. An additional 9 patients showed neurological improvement.

In the study, GD2-CAR T cells were successfully manufactured from patient-derived immune cells in all enrolled subjects. For safety, no dose-limiting toxicities (DLTs) were observed in the lower dose cohort of 1×10⁶ cells/kg, but 3 patients in the higher dose cohort of 3×10⁶ cells/kg experienced dose-limiting cytokine release syndrome, establishing the lower dose as the maximally tolerated intravenous (IV) dose.

Following the IV infusion, 9 patients were further treated with intracerebroventricular infusions of GD2-CAR T, which led to no additional DLTs. However, tumor inflammation-associated neurotoxicity was seen among all patients, which was managed with intensive monitoring.

“The present study establishes GD2-CAR T-cell therapy as a promising modality for a historically lethal [central nervous system] cancer. The rate of clinical improvements and tumor regressions on MRI imaging, including a complete response by RANO 2.0 criteria sustained for over 30 months and throughout the duration of this report, is reason for cautious optimism…for CAR T-cell therapy of solid tumors,” wrote study authors in findings published in Nature.

About the Phase 1 Trial of GD2-CAR T-Cell Therapy

The phase 1 study sought to test whether GD2-CAR T cells could be successfully generated from immune cells collected from pediatric and young adult patients with H3K27M-mutant diffuse intrinsic pontine glioma (DIPG) and spinal DMG.² Patients were required to undergo lymphodepleting chemotherapy prior to receiving a single IV dose of autologous GD2-CAR T cells at 2 dose levels.

Enrollment was open to patients aged 2 to 50 years with H3K27M-mutant DIPG or spinal DMG who had completed prior standard radiation therapy and chemotherapy. Patients were required to have normal organ and marrow function and a Karnofsky performance score ≥60% or an ECOG performance status of 0 or 1. Additionally, patients with controlled systemic disease were eligible to participate.

A total of 13 patients were enrolled, with 11 receiving treatment, including 3 patients in the DL1 cohort (all with DIPG) and 8 patients in the DL2 cohort (6 with DIPG and 2 with spinal DMG).

The primary end points of the study were manufacturing feasibility, safety, and identification of the maximally tolerated dose. Secondary end points included preliminary efficacy, with a focus on tumor response and neurological benefit.

Clinical trials with larger patient cohorts are needed to confirm the results of this phase 1 study.

“Ongoing and future work will define the optimal route of administration, the role of lymphodepleting chemotherapy and potential combination strategies for optimization of this promising therapy to achieve more complete and durable responses for children and adults with H3K27M-mutated diffuse midline gliomas,” added study authors.

REFERENCES:

1. Monje M, Mahdi J, Majzner R, et al. Intravenous and intracranial GD2-CAR T cells for H3K27M+ diffuse midline gliomas. Nature. Published online November 13, 2024. doi:10.1038/s41586-024-08171-9

2. GD2 CAR T cells in diffuse intrinsic pontine gliomas(DIPG) & spinal diffuse midline glioma(DMG). ClinicalTrials.gov. October 17, 2024. Accessed November 19, 2024. https://clinicaltrials.gov/study/NCT04196413