Disrupting the Blood-Brain Barrier via Sonication to Improve Glioblastoma Treatment

Originally appeared on NYP Advances

Glioblastoma multiforme is a notoriously challenging brain tumor to treat. The blood-brain barrier (BBB) poses a formidable roadblock to the entry of anticancer agents into brain tumor tissue. And even if a tumor initially shrinks after treatment with chemotherapy drugs, such as temozolomide or lomustine, the cancer usually develops resistance to them and approximately 90% of patients experience tumor recurrence.

Neurosurgeons at NewYork-Presbyterian, Columbia, and Weill Cornell Medicine are participating in an international, randomized, open-label, multicenter study evaluating an innovative ultrasound technology designed to disrupt the BBB and enhance the penetration of therapeutic agents into glioblastoma tissue. The SONOBIRD phase 3 study is comparing sonication therapy administered using a surgically implanted SonoCloud-9 device versus standard treatment in adult patients planning to have a resection for glioblastoma at first recurrence.

Below, neurosurgeon Brian Gill, M.D., who is the site investigator at NewYork-Presbyterian and Columbia for the SONOBIRD trial, describes the clinical challenges posed by glioblastoma and the encouraging technology behind this potential new treatment approach.

Obstacles to Treating Glioblastoma Successfully

One of the biggest problems we have treating these patients is getting the chemotherapy drugs directly to the site in the brain where they need to go. The BBB is a hindrance because most drugs we use to treat cancer cannot cross the BBB. In patients with glioblastoma who do respond initially to standard treatment, the cancer almost always recurs. As a result, the average length of survival for patients with glioblastoma is just about eight months, and only about 7% of them live to five years.

Permeating the Blood-Brain Barrier With Focused Ultrasound

Focused ultrasound is a technique that uses sound waves to precisely target specific tissue in the body without harming surrounding tissue and structures. There are a lot of applications for this tool, such as using it in essential tremor and Parkinson’s disease to target parts of the brain, like the ventralis intermedius nucleus of the thalamus, to reduce tremors and improve quality of life. Focused ultrasound is an incredibly versatile tool that offers a minimally invasive and well-tolerated option to help improve patients’ quality of life.

With sonication, we are using focused ultrasound to break through the BBB to increase drug delivery to the area of the brain where the glioblastoma is located. It involves a surgically implanted low-intensity pulsed ultrasound device combined with an intravenous infusion of microbubbles into the region where the ultrasound is implanted. The ultrasound breaks down the microbubbles and that physical action results in a temporary opening of the BBB during which you can deliver chemotherapy directly to the brain.

SONOBIRD Trial Objectives

Through the SONOBIRD trial, we are seeking to show that the use of an existing chemotherapy agent – carboplatin – in conjunction with the implantable SonoCloud-9 ultrasound device will improve treatment efficacy and prolong life in patients with recurrent glioblastoma. The trial is assessing both the safety and effectiveness of this combination of sonication and chemotherapy in comparison to treatment with lomustine or temozolomide, the current standard of care treatment.

Patient Eligibility and Study Design

We are recruiting adult patients who are planning to have surgery for their first recurrence of glioblastoma. Additional eligibility criteria include that the tumor is not larger than 5 centimeters in diameter and that participants be fully recovered from the side effects of their prior cancer treatment. The participants are randomized into two groups — an experimental and a control group.

Those randomized into the experimental group will have the sonication device implanted at the end of their tumor resection. A window of skull is removed over the area where a tumor resides during the surgery and the surgeon replaces that portion of skull with the device and then closes the wound. The sonication device only acts on that one area of the brain.

After the implant is surgically placed, participants recover for a few days before beginning chemotherapy. They receive a 30-minute infusion of carboplatin and at the end of the infusion, the sonication implant is connected to a generator using a transdermal needle inserted through the scalp and into the implant, enabling the device to emit ultrasound.

At the same time that the device is activated, we give a short intravenous infusion of microbubbles. The physical action of the ultrasound on the microbubbles opens up the blood-brain barrier. The carboplatin that is already circulating in the patient’s body can now enter the brain and accumulate in the area where the tumor is. The participants will receive this treatment every three weeks for up to seven cycles.

Participants in the control group will undergo surgery without implantation of the sonication device. They will then receive either lomustine or temozolomide orally. Both groups will be monitored during the course of their treatment for up to seven months and may be followed for up to four years.

Optimism for the Future

Results from the phase 1 and phase 2 trials showed that the sonication device was safe and effective for disrupting the BBB. Additionally, progression-free survival and overall survival were longer in patients with clear BBB disruption compared to those with little or no disruption.

If we are successful in crossing the BBB, this will open the doors to reevaluating a litany of drugs that have failed in prior clinical trials because they couldn’t permeate the BBB. We really can't say that a treatment has failed if it never had the opportunity to succeed in the first place.

We have already begun recruiting patients for the trial at NewYork-Presbyterian, Columbia, and Weill Cornell Medicine as well as at other sites around the world. Because most glioblastoma recur or progress within a centimeter or less of where the original tumor occurred, by using sonication to target this specific area, we hope to reduce the risk of local progression as well as improve overall survival.