Diffuse midline gliomas (DMGs) are some of the most aggressive and deadly childhood brain tumors. These cancers, which mainly affect children and young adults, are nearly always fatal and the median survival rate is just around one year. Surgery is not viable because these tumors infiltrate the brainstem, and traditional chemotherapy has been largely ineffective.

For decades, the standard of care has been palliative radiotherapy, which temporarily slows tumor growth but does not offer a cure. Now, this may soon change thanks to a groundbreaking form of immunotherapy. This approach, based on CAR T cells not only slowed down tumor growth but, in some instances, even eliminated the cancer.

CAR T-cell therapy

CAR T-cell therapy is an innovative type of immunotherapy that uses a patient’s own immune system to fight cancer.

Oftentimes, the problem is that our immune system isn’t capable of recognizing cancer cells. CAR T-cell therapy is essentially a process of teaching the immune system how to recognize and attack tumors.

The process begins by extracting T cells — white blood cells that play a key role in immune defense — from a patient’s blood. These cells are then genetically modified in a laboratory to express a special receptor called a chimeric antigen receptor (CAR), which is designed to recognize and attack a specific protein found in cancer cells. Once engineered, the CAR T cells are reproduced in large numbers and reinfused into the patient’s body, where they seek out and destroy tumor cells.

This customized approach enables the immune system to target cancer precisely, offering a potent and long-lasting treatment. The CAR T approach is particularly useful for blood cancers and, as this study suggests, for brain cancer.

A treatment for a horrendous tumor

The study, led by researchers at Stanford University and published in Nature, engineered (CAR) T cells to recognize GD2, a molecule found in abundance on the surface of DMG cells. GD2 is already a known target in neuroblastoma, another childhood cancer, but this study represents one of the first times it has been tested in brain tumors.

In this first-in-humans trial, 11 children and young adults received GD2-CAR T cells after undergoing chemotherapy to weaken their existing immune system. The therapy was delivered intravenously at one of two dose levels. Nine of these patients, who showed initial responses in symptoms or tumor shrinkage, then received additional infusions directly into the brain through an intracranial method.

There were substantial benefits.

“Four people showed major imaging responses (52–100% reductions in tumour volumes), and three exhibited smaller imaging responses. The tumour of one individual became undetectable, and this complete response is ongoing at the time of writing — now more than 40 months since trial enrolment,” the researchers write.

Beyond imaging results, the therapy led to significant improvements in quality of life. Several participants regained the ability to walk, eat, and hear better after treatment. This suggests that the therapy is not only shrinking tumors but also improving neurological function, an unprecedented outcome for DMG patients.

This is just a Phase I trial

CAR T-cell therapy is not without risks. Three patients who received the higher dose experienced high-grade cytokine release syndrome (CRS), a dangerous immune overreaction that can cause fever, inflammation, and organ damage. Fortunately, no life-threatening toxicity was observed at the lower dose, which researchers have now identified as the maximum tolerable level for intravenous delivery.

“Further work is needed to determine the optimal dose, route, and schedule of treatment for achieving maximal and durable benefit while reducing toxicity,” the researchers write in the study. The next step is to conduct larger, multi-center trials to confirm these findings and better understand how to maximize benefits while reducing risks.

Ultimately, though, the success of this therapy, even in a small cohort, suggests that immunotherapy could finally be a game-changer for childhood brain tumors. The approach had been useful for blood cancers, but this study demonstrates that, with careful engineering and delivery methods, CAR T cells can cross the blood-brain barrier and successfully attack brain tumors.

For families battling diffuse midline gliomas, this trial represents a rare glimmer of hope. The thought that a child’s tumor could disappear — and stay gone — is almost unimaginable in the context of a disease with such a grim prognosis. While it is too early to declare GD2-CAR T-cell therapy a cure, the results provide strong evidence that it can extend survival and improve quality of life in ways never seen before.

However, scaling is also a challenge. CAR T-cell therapies are complex and expensive to manufacture. They require specialized equipment and bespoke expertise. Scaling up this therapy and making it widely available won’t be easy.

Still, despite these challenges, the takeaway message is encouraging: Immunotherapy is beginning to change the landscape of pediatric oncology. For children diagnosed with diffuse midline gliomas, this could be the first step toward turning a terminal disease into a treatable one.

The study has been published in Nature Clinical Briefings.