Diffuse intrinsic pontine glioma (DIPG) is an aggressive and fatal pediatric brain tumor – fewer than 10% of children survive two years after diagnosis. DIPG tumors are not contained in a single mass but diffuse through and infiltrate surrounding healthy brain tissue, making targeted treatment difficult. However, results from a recent phase 1 clinical trial led by physicians and researchers from NewYork-Presbyterian, Weill Cornell Medicine, and Memorial Sloan Kettering Cancer Center showed the safety of a new radioimmunotherapy (coupling of radiation and immunotherapy) direct drug delivery approach to treat and image DIPG.
Results from the study, which were published in Neuro-Oncology, established that infusing 124I-omburtamab directly into the brainstem is a safe way to permeate the blood-brain barrier to maximize delivery of the drug right where DIPG tumors develop without impacting the rest of the body.
“We’ve shown we can deliver the drug in meaningful concentrations, and we can do it safely,” says study lead Mark Souweidane, M.D., FACS, FAAP, pediatric neurosurgeon at NewYork-Presbyterian and Weill Cornell Medicine and vice chairman of the Department of Neurological Surgery at Weill Cornell Medicine. “Now we can start laying the groundwork for modification, tailoring, redosing, and scheduling.”
Direct Delivery to the Brainstem
In the trial, Dr. Souweidane and his team used convection-enhanced delivery (CED) to inject 124I-omburtamab, a radio-labeled monoclonal antibody, directly into the brainstem. CED is a recently approved drug delivery technique that uses a pressure gradient and infusion catheter to bypass the blood-brain barrier and deliver medication to specific areas of the brain while minimizing systemic side effects.
Preclinical models showed that the brainstem could be targeted accurately using CED, and that the fluid volume injected into the brain could be tolerated by the patient without injury. “That opened up an amazing opportunity and hope that we could do this,” he says.
After testing many classes of therapeutic agents, Dr. Souweidane and the research team chose 124I-omburtamab because it finds the tumor cells and delivers a dose of radiation that kills them. At the same time, the drug can be visualized in positron emission tomography (PET) scan images, helping clinicians see how much drug is being delivered to the brain, how quickly it gets there, and its precise location. The body clears the radiation within a few weeks.
Building Off Past Success
In 2018, Dr. Souweidane published the results from an initial study in The Lancet Oncology with 28 children receiving CED treatment for DIPG who previously received external beam radiation therapy (EBRT). In that study, the research team used 124I-8H9 (a radioimmunotherapy agent targeting the glioma-associated B7-H3 antigen) and delivered it to the brainstem using CED. The findings showed that CED was a safe therapeutic strategy.
Their new study builds off the success of that initial trial. In the current study, Dr. Souweidane and his colleagues enrolled 50 patients in the phase 1 protocol to assess safety and determine the best dosages of 124I-omburtamab to treat DIPG. They used CED to slowly infuse the antibody over 12 hours into the brains of patients and conducted PET scans before and after infusions to monitor drug kinetics and dosimetry.
“We showed reproducibly that our approach increased the therapeutic concentration at the tumor site nearly 1,000-fold greater than throughout the body,” says Dr. Souweidane. “We’re essentially eliminating any concern about systemic toxicity, which usually limits the dose we can administer.”
Forty patients completed a single CED infusion, five patients completed two serial infusions, and one patient underwent three serial infusions. The team determined that the maximum tolerated activity of the drug was 6 millicuries, which is similar to the exposure of a standard thyroid scan using radioactive iodine. They also found that patients could tolerate up to 8 milliliters, a little over a teaspoon, of the drug safely. The mean lesion-to-whole-body absorbed dose ratio was 1,285. The concentration of activity occurred in the tumor with minimal whole-body exposure. There were no clinically significant, procedure-related complications or deaths.
Looking Toward the Future
“For someone like me who’s been in this field for about 40 years, ‘survival’ is not a word we use with DIPG — these findings offer a glimmer of hope where there was none,” Dr. Souweidane says. “There are three long-term survivors. One is approaching four years, one is about seven years, and another one is almost 11 years from their diagnoses.”
This study further supports the procedural safety of CED infusions into the brainstem and their continued exploration in future clinical trials in children with DIPG. The next step is a phase I/II clinical trial to test a new form of the drug and to methodically evaluate how effective this treatment is for a larger group of DIPG patients. Says Dr. Souweidane, “I’m enthusiastic, and we’re jumping in headfirst.”
A version of this article originally appeared in Weill Cornell Medicine’s newsroom.
Many NewYork-Presbyterian physicians at Weill Cornell Medicine maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, please see the profile for Dr. Mark Souweidane.
This work was supported in part through the National Institutes of Health/National Cancer Institute Support Grant P30 CA 008748 and Y-mAbs.
