GD2-directed CAR T cell therapy for H3K27M+ spinal cord diffuse midline glioma
Diffuse midline gliomas (DMGs) are inoperable, lethal, high-grade central nervous system cancers primarily affecting children and young adults. We discovered that DMGs, which are characterized by the presence of a specific mutation called H3K27M+, exhibit high levels of a signal called GD2 and that immune cells engineered to recognize this signal called chimeric antigen receptor T cells (GD2-CAR T cells) mediate impressive antitumor effects in numerous patient-derived mouse models of DMG, including spinal cord DMG. Based on these compelling laboratory findings, this proposal delivers bench-to-bedside translation of GD2-CART therapy for children and young adults with H3K27M+ DMGs through conduct of a Phase I clinical trial and in parallel, undertakes bedside-to-bench translation focused on learning as much as possible from the clinical course and outcomes of patients enrolled on this Phase I trial in order to optimize this promising immunotherapeutic approach. The Phase I trial includes 4 arms for individuals with pontine and spinal cord DMGs, and for CAR T cell administration intravenously (IV) or directly into the central nervous system (intracerebroventricularly, ICV). This grant proposal focuses on the spinal cord DMG arms of the clinical trial and on optimizing immunotherapy for spinal cord tumors in general, as our early results suggest important differences in the tumor response to CART cell therapy in brain and in spinal cord.
Project Update 2024:
We are testing GD2-CAR T cell immunotherapy for gliomas of the brainstem and spinal cord, and are working to determine the safest and most effective dose, route of administration and preconditioning regimen. By studying how the child’s immune system responds to this immunotherapy approach, we are identifying several factors that correlate with better or worse response to the therapy, which gives us new insights about how we might optimize this promising approach in the future.
