The experimental therapy shifted immune cells to shrink children’s brain tumors, restore neurologic function, and, in one case of a Stanford Medicine clinical trial participant with an incurable brain cancer, effectively eliminate detectable disease.
The trial is one of the few successes to date against solid tumors touted by engineered immune cells, called Chimeric antigen receptor T cells (CAR-T cells), for children with a group of fearsome brain and spinal cord tumors, including cancer known as diffuse intrinsic pontine glioma (DIPG). The findings were published online on November 13 in Nature.
9 of the 11 patients given CAR-T cells in the trial experienced benefits. Functional improvement in disabilities caused by their disease occurred in nine. Another 4 saw their tumor volume cut by more than half. Of those 4 participants, 1 had a complete response, meaning his tumor disappeared from brain scans. It’s too early to say if it has worked, but he has been healthy for four years since the diagnosis.
“It’s a universally lethal disease and we’ve found a therapy that can cause meaningful tumor regressions and clinical improvement,” said the trial’s lead author, Milan Gambhir Professor in Pediatric Neuro-Oncology and professor of neurology at Stanford Medicine, Michelle Monje, MD, Ph.D.
The only radiation therapy offers only temporary relief, and there are no effective chemotherapy drugs. All the tumors mix their malignant cells with healthy cells in important parts of the brain, so they cannot be surgically removed. The form that affects the brainstem (DIPG) has a five-year survival rate of less than 1%.
So far, preclinical studies in rodents have been promising, but against this bleak landscape, the research team wasn’t sure how much to expect from the CAR-T cells. Chimeric antigen receptor T cells, or CAR-T cells occur when some of a patient’s T cells are removed and modified to bind to a certain molecule.
They return the cells to the patient’s body, where they cause an immune response against cancer cells that have the molecular target. Since 2017, the Food and Drug Administration has approved CAR-T cells for struggling against blood cancers that have not yet proven effective against solid tumors.
As the tumors progress, they cause profound disabilities, often stripping patients of their ability to walk, smile, swallow, hear, and speak. According to them, they typically experience shooting or burning neuropathic pain, sometimes in a severe degree, a symptom of spinal cord damage, and paralysis, loss of sensation, and incontinence.
Monje said that we’ve already gleaned some hypotheses about how to improve outcomes, both for this therapy and more generally for immunotherapy for solid cancers in the central nervous system. This trial has many important lessons for advancing brain tumor immunotherapy.
The findings have also been used to refine protocols for the CAR-T cell clinical trial. The study continues to enroll participants. The FDA’s regenerative medicine advanced therapy designation, designed to light up approval of regenerative medicine therapies that promise to treat a life-threatening disease, will allow scientists to lean on regulatory experts to refine and perfect the research and potentially fast-track the cell therapy.
This trial is a step forward, but we have more work to do to reduce the toxicity of treatment and give more benefit to patients, Mackall responded. “But that becomes a path forward now.” Drew has a path forward, too. He’s planning to use his degree to do conservation, rewilding things like after logging, or other human use.
Reference: 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
