An immune-cell therapy has shown promising results in shrinking brain tumors, restoring neurologic function, and even eradicating all detectable traces of a typically incurable brain cancer in children, according to a Stanford Medicine clinical trial. The study, published in Nature, marks one of the first successes against solid tumors using CAR-T cell therapy.
The trial focused on children with diffuse midline gliomas, including diffuse intrinsic pontine glioma (DIPG), a particularly deadly form of brain cancer. In October, the therapy received a regenerative medicine advanced therapy designation from the FDA, potentially accelerating its approval.
Clinical Outcomes
Of the 11 participants who received CAR-T cells, nine experienced benefits. These included functional improvement in disabilities caused by the disease and tumor volume reduction. Four participants saw their tumors shrink by more than half, and one achieved a complete response, with the tumor disappearing from brain scans. This patient remains healthy four years after diagnosis, though it is too soon to declare a cure.
"This is a universally lethal disease for which we’ve found a therapy that can cause meaningful tumor regressions and clinical improvements," said lead author Michelle Monje, MD, PhD, the Milan Gambhir Professor in Pediatric Neuro-Oncology and professor of neurology at Stanford Medicine. "While there is still a long way to go to figure out how to optimize this for every patient, it’s very exciting that one patient had a complete response. I’m hopeful he has been cured."
The Patient Experience
One notable patient, Drew, diagnosed with DIPG in 2020, experienced significant improvements. Before treatment, the tumor affected his hearing, balance, and gait, requiring him to use a wheelchair. Following CAR-T cell therapy, Drew regained the ability to walk and is now pursuing a college degree.
Understanding Diffuse Midline Gliomas
Diffuse midline gliomas affect a few hundred children and young adults in the United States each year. The median survival time is approximately one year. Traditional treatments like radiation therapy offer only temporary relief, and effective chemotherapy drugs are lacking. The tumors' intermingling with healthy brain cells prevents surgical removal. DIPG, a subtype occurring in the brainstem, has a five-year survival rate below 1%.
CAR-T Cell Therapy Details
CAR-T cells are created by extracting a patient’s T cells and modifying them to target a specific molecular marker on cancer cells. These modified cells are then reintroduced into the patient's body to trigger an immune response against the tumor. While CAR-T cell therapy has been successful in treating blood cancers, its application to solid tumors has been challenging.
In this study, the CAR-T cells targeted GD2, a surface marker found on DIPG and other diffuse midline glioma tumor cells. Previous research by Monje’s team had identified GD2 as a promising target, and Mackall’s team had engineered CAR-T cells to target it. Preclinical studies in animal models showed that GD2-targeting CAR-T cells could eradicate DIPG tumors.
Trial Protocol and Side Effects
The clinical trial (NCT04196413) enrolled patients with DIPG or spinal cord diffuse midline glioma. Participants underwent chemotherapy before receiving CAR-T cells to prevent immune rejection. The initial dose of CAR-T cells was administered intravenously, with monitoring for immune and neurological side effects.
All participants experienced some degree of cytokine release syndrome, including fever, low blood pressure, and temporary neurological side effects due to inflammation within the tumor. Researchers determined that a lower dose of CAR-T cells was safer due to reduced cytokine storm effects.
Nine participants who benefited from the initial intravenous dose received additional doses of CAR-T cells directly into the cerebrospinal fluid, which resulted in fewer side effects. These infusions were administered every one to three months as long as they provided benefit. Many participants experienced improvements in neurologic symptoms and tumor size reduction. Some regained lost abilities, such as walking, or experienced reversal of symptoms like incontinence, paralysis, or neuropathic pain.
In the four participants with the best responses, tumor volumes decreased by 52%, 54%, 91%, and 100%.
Future Directions
Researchers are now analyzing biological samples collected during the trial to identify factors that contributed to the best responses. They are also exploring ways to improve the therapy, such as suppressing aspects of the immune response that might favor tumor growth and targeting the tumors’ biological quirks with targeted therapies.
"Sometimes this tumor grows so fast that it feels like a race between the CAR-T cells fighting and the cancer cells replicating," Monje said. "A therapy that slows the growth of the tumor is going to help the CAR-T cells work better."
