Pediatric brain tumors such as medulloblastoma are a leading cause of child death. Medulloblastoma can spread to the thin layer of tissues and fluids that line the brain and spinal cord (called leptomeninges), causing severe symptoms and requiring irradiation of the brain and spine. Even when cured, survivors can suffer permanent treatment toxicities such as growth stunting and cognitive impairment, and these side effects are worse for younger patients. This is because the radiation required cannot be limited just to the tumors, but also reaches deep into healthy brain.
Our institution developed a radiopharmaceutical, NM600, which is entering clinical trials this year for other cancers. NM600 delivers molecular-targeting of radiation directly to tumor cells and spares normal brain tissues. To deliver the radiation even more precisely to the leptomeninges, our proposal will test NM600 injected intrathecally (i.e. “spinal tap” directly into the fluids in the spine).
In preclinical medulloblastoma models, intrathecal NM600 significantly extended survival with no measurable memory or motor skill losses unlike standard brain and spine irradiation, which is delivered from an external X-ray beam and which results in significant brain and cognitive toxicities.
To further augment efficacy, our proposal will combine NM600 with immune cells engineered to target medulloblastoma, termed CAR T cells. Radiation can enhance CAR T cell activation against medulloblastoma, which typically resists CAR T cells.
For this work, the Pediatric Cancer Research Foundation has funded Dr. Zachary Morris via the Will Irwin Research Grant.
Altogether, we aim to achieve curative treatments for medulloblastoma and its spread to the leptomeninges by combining a radiopharmaceutical therapy and CAR T cells delivered intrathecally, while also reducing toxicity compared to current treatments.
Because intrathecal injection is a routine procedure and NM600 and CAR T cells are already entering clinical trials for other cancers, we expect that positive results from this proposal will lead to rapid transition into clinical trials for pediatric medulloblastoma.
