Research And Grants

Combining FLASH and immunotherapy to target medulloblastoma relapse

Medulloblastoma (MB) is the most common childhood malignant brain tumor. Despite aggressive treatments such as surgical resection, radiotherapy and chemotherapy, the prognosis for many MB patients is grim: almost half of the patients die following tumor relapse. Thus, there is an urgent need for improved treatment of MB recurrence, which has hardly improved at all for decades. This presents a challenge and unmet need for novel therapeutic modalities to improve patient survival while minimizing side effects. Proton therapy is one of the most precise and advanced forms of radiation therapy, employing pencil-beam scanning to target tumors specifically while sparing surrounding healthy tissues. Our preliminary study demonstrating the effectiveness of an innovative precision ultrahigh dose-rate proton radiation strategy known as FLASH in shrinking tumor growth indicates that FLASH could open a whole new landscape in MB therapy. FLASH exhibits remarkable tissue-sparing effects without compromising efficacy of tumor cure, and allows for higher safe doses of radiation and faster treatment. Unfortunately, the tumors eventually re-grow after FLASH treatment. Therefore, we hypothesize that combining proton radiotherapy with CAR-T cells and/or immune checkpoint inhibitors (ICIs) may represent a more effective cutting-edge treatment to prevent tumor relapse, which is often lethal. Combining FLASH radiation with other therapeutic modalities such as immunotherapy has the potential to revolutionize treatments to prevent tumor recurrence in this pediatric brain malignancy. Preclinical data have demonstrated impressive synergy between radiation and immune checkpoint blockade, even appearing to extend beyond the irradiated target. We anticipate that the combination of the precise FLASH therapy and immunotherapy will achieve a better outcome compared to single treatment modality alone. This study, if successful, could be a game changer for the treatment of aggressive medulloblastoma, while reducing treatment-related long-term side effects in pediatric patients.