The current chemotherapy drug used to treat the deadly brain cancer glioblastoma is weak—but it’s also the only one that has been successful in crossing the blood-brain barrier. For many doctors and patients, it’s a case of “better than nothing.”
Now, the positive results of an ongoing phase 2 clinical trial may change that. In a first, scientists at Northwestern Medicine successfully opened the blood-brain barrier to deliver chemotherapy to large, critical regions of the brain.
They team used a novel, skull-implantable ultrasound device to enable the four-minute treatment—which results show have been safe and well-tolerated, with some patients even getting up to six cycles of the treatment.
Ultrasound emitters
The skull-implantable grid comprising nine ultrasound emitters was designed by Carthera, a French biotechnology company. It is the second device designed for the project. The initial devise was a single-ultrasound emitter implant that worked, but was too small. The second device opens the blood-brain barrier in a volume of brain that is 9x larger than the initial device.
The researchers say this is critical as this approach requires coverage of a large region of the brain adjacent to the cavity that remains in the brain after removal of glioblastoma tumors.
The right timing
Previous human studies have shown that the blood-brain barrier is completely restored 24 hours after brain sonication. Those results, in combination with some animal studies, led to the prevailing assumption that the blood-brain barrier stays open for about 6 hours post-sonification. However, this study shows that window is drastically shorter.
According to the paper, published in The Lancet Oncology, most of the blood-brain barrier restoration happens in the first 30 to 60 minutes after sonication.
“There is a critical time window after sonification when the brain is permeable to drugs circulating in the bloodstream,” said lead investigator Adam Sonabend, an associate professor of neurological surgery at Northwestern University and a Northwestern Medicine neurosurgeon.
This knowledge will help scientists optimize the sequence of drug delivery and ultrasound activation to maximize drug penetration in the future.
6x increase
Seventeen patients with recurrent glioblastoma are enrolled in the ongoing phase 2 trial. In phase 1 of the trial, the patients underwent surgery for resection of their tumors and implantation of the ultrasound device. A few weeks later, they started treatment.
Scientists chose two different chemotherapy drugs for treatment—paclitaxel and carboplatin. In normal circumstances, neither of the drugs can cross the blood-brain barrier. But, as the trial results show thus far, both drugs have been able to repeatedly permeate large, critical regions of the human brain.
Opening the blood-brain barrier with sonification has led to a 4- to 6-fold increase in drug concentrations reaching the brain, the results showed.
In the study, scientists increased the dose of paclitaxel delivered every three weeks with the accompanying ultrasound-based blood-brain barrier opening. In subsets of patients, studies were also performed during surgery to investigate the effect of this ultrasound device on drug concentrations.
Ongoing clinical trial
The four-minute procedure to open the blood-brain barrier can be performed with the patient awake, and patients go home after a few hours. The results show the treatment is safe and well tolerated, with some patients receiving up to six cycles of treatment.
The estimated primary completion date of the trial is August 2024, while the estimated study completion date is September 2025. In the meantime, the scientists will continue to evaluate patient survival, safety, tolerance, tumor shrinkage, circulating tumor DNA and the timeline associated with the opening of the blood-brain barrier.
“While we have focused on brain cancer—for which there are approximately 30,000 gliomas in the U.S.—these results open the door to investigate novel drug-based treatments for millions of patients who suffer from various brain diseases,” said Sonabend.