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GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas
Robbie G Majzner1,2,3, Sneha Ramakrishna1,2, Kristen W Yeom4
1Stanford Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
Nature
|February 7, 2022
Summary
Chimeric antigen receptor (CAR) T cell therapy targeting GD2 shows promise for lethal paediatric H3K27M-mutated diffuse midline gliomas. Early results indicate clinical and radiographic improvement in three of four patients with manageable toxicity.
Area of Science:
- Neuro-oncology
- Immunotherapy
- Paediatric oncology
Background:
- Diffuse intrinsic pontine glioma (DIPG) and diffuse midline gliomas (DMGs) with H3K27M mutations are aggressive paediatric brain tumors with poor prognosis.
- Disialoganglioside GD2 is a promising target due to its high expression on these tumor cells.
Purpose of the Study:
- To evaluate the safety and efficacy of GD2-directed chimeric antigen receptor (CAR) T cells in a first-in-human phase I clinical trial for H3K27M-mutated DIPG/DMG.
- To assess clinical outcomes, toxicity, and immune responses following CAR T cell administration.
Main Methods:
- A phase I clinical trial involving four patients with H3K27M-mutated DIPG or spinal cord DMG treated with GD2-CAR T cells at dose level 1.
- Intravenous administration of GD2-CAR T cells, with subsequent intracerebroventricular infusions for patients showing clinical benefit.
- Monitoring for toxicity, clinical and radiographic responses, and analysis of cytokine levels and single-cell transcriptomics.
Main Results:
- Three of four patients demonstrated clinical and radiographic improvement.
- Toxicity was primarily related to tumor location and was reversible with supportive care; no on-target, off-tumor toxicity was observed.
- Elevated pro-inflammatory cytokine levels were detected in plasma and cerebrospinal fluid, with heterogeneity in CAR T cell responses observed.
Conclusions:
- GD2-CAR T cell therapy represents a promising therapeutic strategy for H3K27M-mutated DIPG and spinal cord DMG.
- The study highlights the potential of this approach, with manageable toxicity and encouraging clinical responses in a challenging paediatric cancer population.
