Researchers from Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center have demonstrated that a targeted approach to treating diffuse intrinsic pontine glioma (DIPG), a deadly brain tumor in children, is safe. The Phase I clinical trial, published February 19 in Neuro-Oncology, represents the first larger-scale study using a radiation-based direct drug delivery approach to both treat and image DIPG.
DIPG is an aggressive cancer with a devastating prognosis—fewer than 10% of children survive two years after diagnosis. The tumor infiltrates the brainstem, which controls vital functions including breathing, heart rate, and muscle control, making it particularly challenging to treat. Traditional approaches like chemotherapy and surgery are ineffective due to the tumor's location at the base of the brain.
"We've shown we can deliver the drug, and we can do it safely," said study lead Dr. Mark Souweidane, professor of neurological surgery in pediatrics and a pediatric neurosurgeon at NewYork-Presbyterian/Weill Cornell Medical Center and Memorial Sloan Kettering Cancer Center. "Now we can start laying the groundwork for modification, tailoring, redosing and scheduling."
Innovative Drug Delivery Technique
The research team utilized convection enhanced delivery (CED), a recently approved technique that allows direct injection of medication into the tumor region. CED employs a syringe attached to a long, thin tube inserted into the patient's brain, with gentle pressure delivering medication through the tube to the targeted area.
After extensive testing of various therapeutic agents, the researchers selected 124I-Omburtamab, a radio-labeled monoclonal antibody that binds to proteins overexpressed on tumor cells. This antibody not only delivers targeted radiation to kill cancer cells but can also be visualized through Positron Emission Tomography (PET) scans, allowing researchers to track drug distribution, concentration, and location within the brain.
"That opened up an amazing opportunity and hope that we could do this," Dr. Souweidane explained, referring to preclinical models that demonstrated the brainstem could be accurately targeted and tolerate the fluid volume without injury.
Trial Design and Key Findings
The Phase I clinical trial enrolled 50 patients to assess safety and determine optimal drug dosages. Researchers used CED to slowly infuse 124I-Omburtamab over 12 hours into patients' brains, conducting PET scans before and after infusions to monitor drug distribution.
"We showed reproducibly that our approach increased the therapeutic concentration at the tumor site nearly 1,000-fold greater than throughout the body," said Dr. Souweidane, who also serves as director of pediatric neurological surgery. "We're essentially eliminating any concern about systemic toxicity, which usually limits the dose we can administer."
The team determined that the maximum tolerated activity of the drug was 6 millicuries—approximately equivalent to the radiation exposure from a standard thyroid scan using radioactive iodine. Patients could safely tolerate up to 8 milliliters (slightly more than a teaspoon) of the drug. Importantly, there were no clinically significant procedure-related complications or deaths, though researchers noted that infusion location and pre-operative symptoms likely influence drug tolerance.
Promising Survival Outcomes
While the trial was designed primarily to assess safety rather than efficacy, the researchers observed encouraging survival outcomes. Approximately 18% of patients lived for two years after diagnosis, significantly higher than typical survival rates for DIPG.
"For someone like me who's been in this field for about 40 years, 'survival' is not a word we use with this disease—these findings offer a glimmer of hope where there was none," Dr. Souweidane remarked. The trial identified three long-term survivors: one approaching four years, another at about seven years, and a third almost 11 years from diagnosis.
This trial builds upon Dr. Souweidane's 2018 study published in The Lancet Oncology, which initially evaluated CED treatment in 28 children with DIPG.
Future Directions
The research team is now preparing for a Phase I/II clinical trial to test a new formulation of the drug and systematically evaluate treatment efficacy in a larger cohort of DIPG patients.
"I'm enthusiastic, and we're jumping in headfirst," Dr. Souweidane said, reflecting the renewed optimism this approach has brought to a field long characterized by limited treatment options and poor outcomes.
The innovative approach of delivering targeted therapy directly to brain tumors could potentially transform treatment paradigms for DIPG and possibly other difficult-to-treat brain cancers, offering new hope to patients and families affected by these devastating diseases.
