A Phase I clinical trial has revealed promising outcomes for children and young adults battling diffuse midline gliomas, an otherwise incurable cancer affecting the central nervous system. The study, focusing on GD2-CAR T cells, engineered to target the GD2 molecule, demonstrated significant improvements in several participants, including one child whose tumor has remained undetectable for over three years.
Targeting GD2 in Diffuse Midline Gliomas
Diffuse midline gliomas, particularly those with the H3K27M mutation, represent a formidable challenge in pediatric oncology. This mutation is present in approximately 80% of younger patients. These tumors are difficult to remove surgically due to their location in critical brain areas. Traditional treatments like chemotherapy and radiation offer only temporary relief. Recognizing the urgent need for innovative therapies, researchers at Stanford University developed a CAR T-cell therapy targeting GD2, a molecule highly expressed in H3K27M-mutant diffuse midline gliomas.
Crystal L. Mackall, M.D., of Stanford Medicine, emphasized the significance of the findings, stating, "This study breaks new ground. It demonstrates that CAR T cells can have real, meaningful benefit for solid cancers, something that many people have not believed [was possible]."
Clinical Trial Results
The clinical trial involved 11 children and young adults with DIPG or spinal diffuse midline glioma. Participants received intravenous infusions of GD2 CAR T cells at varying doses. The study found that a lower dose of GD2 CAR T cells caused less inflammation. Nine of the eleven patients experienced neurological improvements, with seven showing tumor shrinkage. Symptomatic improvements included regained physical functions like hearing, walking, and taste sensation.
The median survival post-treatment was nearly two years, with two patients surviving beyond the 2.5-year follow-up. One patient achieved complete remission, remaining cancer-free four years post-diagnosis. The treatment involved initial intravenous infusions followed by direct administration into the brain via catheter every 1 to 3 months, contingent on disease stability. This approach was chosen based on preclinical data in mice, which suggested that direct brain delivery reduces inflammation and enhances cancer cell killing.
Impact and Future Directions
Rosandra N. Kaplan, M.D., of NCI’s Center for Cancer Research, noted, "It’s really remarkable. This is a tumor for which nothing has ever worked. I think this is the start of a revolution in understanding how to treat these patients."
While the results are promising, researchers are focused on understanding the variability in patient responses. Future research will investigate the tumor microenvironment's role in treatment efficacy and strategies to enhance the immune response. The Stanford team plans to launch a larger Phase 2 trial, expanding enrollment beyond their center. Other trials are underway, evaluating GD2 CAR T-cell therapy in neuroblastoma and osteosarcoma, and exploring other targets like B7-H3 in diffuse midline gliomas and glioblastoma.
Side effects observed in the trial included neurological issues such as headaches, fever, and fluid buildup in the brain, which were managed with standard treatments. These findings offer a beacon of hope for patients with diffuse midline gliomas, a disease with historically poor prognosis, and highlight the potential of CAR T-cell therapy in solid tumors.
