An early-phase clinical trial at Stanford Medicine has demonstrated promising results using CAR-T cell therapy to combat diffuse midline gliomas, including diffuse intrinsic pontine glioma (DIPG), a devastating brain cancer in children. The trial, published in Nature, showed tumor regression and improved neurological function in the majority of participants, offering hope for a disease with historically poor outcomes. One patient experienced a complete response, with no detectable tumor after treatment.
Targeting GD2 with CAR-T Cells
The study utilized CAR-T cells engineered to target GD2, a surface marker found on diffuse midline glioma cells. Researchers, led by Michelle Monje, MD, PhD, and Crystal Mackall, MD, developed the GD2-targeting CAR-T cell therapy at Stanford Medicine. The approach involves extracting a patient's T cells and modifying them to express a receptor that binds to GD2. These modified cells are then infused back into the patient to trigger an immune response against the tumor cells.
Clinical Trial Results
The clinical trial enrolled 13 patients with DIPG or spinal cord diffuse midline glioma. The median age of participants was 15 years, and tumors were diagnosed a median of five months prior to enrollment. Eleven patients received CAR-T cell infusions. The primary goals of the trial were to assess the feasibility of manufacturing CAR-T cells for each patient, determine a safe dose, and monitor side effects. Secondary aims included evaluating clinical benefits.
Nine of the eleven participants who received CAR-T cells experienced benefits, including tumor volume reduction, improved neurological function, or both. Four patients experienced tumor volume reductions of over 50%, with one patient achieving a complete response. Notably, many participants experienced improvements in neurological symptoms, such as walking, continence, and pain, as their tumors shrank. The median survival after diagnosis for study participants was 20.6 months, with some patients living significantly longer.
Administration and Side Effects
Participants received an initial intravenous dose of CAR-T cells, followed by monitoring for immune and neurological side effects. All participants experienced some degree of cytokine release syndrome (CRS), characterized by fever, low blood pressure, and temporary neurological side effects. A lower dose of CAR-T cells was found to be safer, resulting in less severe CRS. Subsequent doses of CAR-T cells were administered directly into the cerebrospinal fluid, which reduced side effects.
Future Directions
The research team is analyzing biological samples collected during the trial to identify factors associated with the best responses. They are also exploring ways to improve the therapy, such as suppressing immune responses that may favor tumor growth and targeting tumor-specific biological characteristics. The FDA has granted the therapy a regenerative medicine advanced therapy designation, which will expedite the approval process.
"While this trial represents progress, we still have work to do to diminish the toxicity of treatment and enhance benefit for patients," said Mackall. "But now we have a path forward."
