Key Points
- For the first time in pediatric patients, focused ultrasound was found to safely and repeatedly open the blood–brain barrier without sedation.
- The clinical trial showed strong feasibility and tolerability, and clinical improvement was observed in two of three participants.
The research team led by Stergios Zacharoulis, MD, and Elisa Konofagou, PhD, at Columbia University, and Cheng Chia Wu, MD, PhD, previously at Columbia and currently at Virginia Tech and Children’s National Hospital, recently published results from a first-in-pediatrics clinical trial (NCT04804709) demonstrating the safety and feasibility of using focused ultrasound for blood–brain barrier (BBB) opening and drug delivery without the need for sedation.
Their work, published in Science Translational Medicine, describes the treatment of three pediatric patients with diffuse midline glioma (DMG) – previously classified as diffuse intrinsic pontine glioma (DIPG) – a class of tumors that arise in the midline structures of the brain. The disease has a poor prognosis, with a median overall survival of one year. Because these tumors are located in eloquent regions of the brain – such as the part that controls breathing – surgical resection is limited, making alternative treatment options greatly needed.
Dr. Konofagou and her team designed the portable Delsona focused ultrasound system, which is a 250-kHz single-element transducer with real-time imaging and cavitation mapping guidance. The system includes a focused ultrasound transducer tracker, position sensor, and passive cavitation mapping system, and it uses neuronavigation guidance, among other features. Delsona is currently being used in clinical trials for patients with Parkinson’s disease, Alzheimer’s disease, DMG, and peripheral neuropathy.
The article summarizes the results from the first three participants in the DMG clinical trial, which sought to perform BBB opening with focused ultrasound and Definity® microbubbles immediately before administration of the chemotherapy drug panobinostat, a histone deacetylase inhibitor (often abbreviated as HDAC inhibitors) that exhibited a survival benefit in preclinical DMG models when administered after focused ultrasound–induced BBB opening. These three participants were enrolled before panobinostat was removed from the US market. Before that removal, focused ultrasound was delivered in an outpatient setting as frequently as every two days, and it demonstrated good feasibility and tolerability.
The team successfully opened the BBB in all three patients, and in two of them, opened the BBB in two separate tumor sites. In one patient, it took one week to confirm BBB closure because the contrast enhancement was unclear.
Two participants showed clinical improvement, though some panobinostat-related toxicity was observed. Sadly, one participant unexpectedly passed away during the trial period, though the death was unrelated to the study protocol.
Overall, the study demonstrated that BBB opening using neuronavigation-guided focused ultrasound was feasible, repeatable, and safe in children with DMG, supporting ongoing and future trials.
After the study was terminated early, the team at Columbia opened a similar clinical trial using the chemotherapy etoposide. The replacement study (NCT05762419) is actively enrolling patients with DMG.
The panobinistat study was funded by the Focused Ultrasound Foundation, the National Institutes of Health, Gary Yael Fegel Foundation, St. Baldrick’s Foundation, Hannah’s Heroes, Sebastian Strong Foundation, Swim Across America, Matheson Foundation, Pediatric Cancer Foundation, Hope and Heroes, Team Jack Foundation, Hyundai Hope on Wheels Hope Scholar Award, Rally Foundation, Stache Strong Foundation, Musella Foundation, VP&S Interdisciplinary Research Initiative Seed Grant, Red Gate Foundation, and the Alzheimer’s Disease Research Center Research Education Program.
See Science Translational Medicine
Read Columbia University’s Coverage
For Patients
Learn More About the Etoposide Clinical Trial
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