The inability of even the strongest chemotherapy to cross the blood-brain barrier and reach the tumors has been a significant obstacle to treating the deadliest and most aggressive brain cancer glioblastoma.
Now, however, researchers from Northwestern Medicine have released the findings of the first in-person clinical trial in which they broke down the blood-brain barrier by using a cutting-edge ultrasound device that can be implanted in the skull to continuously deliver chemotherapy typically administered intravenously.
Patients undergo the 4-minute-long procedure to break down the blood-brain barrier while they are still conscious, and then they are sent home a few hours later.
Considering some patients received up to 6 cycles of treatment, the results demonstrate the treatment’s safety and tolerability.
The impact of opening the blood-brain barrier using ultrasound has never been accurately measured before.
The results demonstrated that doing this increased drug concentrations in the brain by a factor of four to six.
With the help of the powerful chemotherapy drugs paclitaxel and carboplatin, researchers were able to detect this rise.
Because the medications do not normally cross the blood-brain barrier, they aren’t typically used to treat such patients.
Additionally, this is the first ever study to outline how quickly sonication causes the blood-brain barrier to close.
The majority of blood-brain barrier restoration occurs within the first 30-60 minutes following sonication, the researchers found.
Dr. Adam Sonabend, the study’s lead investigator, said that “This is potentially a huge advance for glioblastoma patients.”
The existing chemotherapy procedure for glioblastoma, temozolomide, is able to cross the blood-brain barrier but Sonabend noted that it’s still very much a weak medication.
The microscopic barrier protects the brain from the vast majority of drugs out there. As a result, there’s a very small selection of medications that can be used to treat brain illnesses.
In other words, most medications that are effective for cancer elsewhere in the body, remain unable to cross the blood-brain barrier in order to target brain cancer.
Sonabend stated that although earlier studies that injected paclitaxel into the brains of patients directly showed encouraging results, the direct injection was also linked to toxicity such as meningitis as well as brain irritation.
The researchers found that the barrier can be temporarily opened in humans using ultrasound and microbubble technology, and that most of its integrity returns an hour later.
Sonabend noted that “There’s a critical time window after sonification when the brain is quite permeable to drugs circulating in the bloodstream.”
The blood-brain barrier is fully restored no more than 24 hours after brain sonication, according to previous studies.
However, based on some animal focused research, the field had previously assumed the barrier is open for the first 6 to 8 hours.
This window may be smaller, according to the Northwestern study.
Another first is the opening of the blood-brain barrier in a brain volume 9 times larger than the original device using a new grid of 9 ultrasound emitters that can be implanted into the skull.
This device was created by the French biotech company Carthera.
This is crucial because the strategy needs to cover a sizable area of the brain close to the cavity left behind after glioblastoma tumors have been removed in order to be effective.
The study’s conclusions served as the foundation for a phase two clinical trial that researchers are currently running for patients suffering from recurrent glioblastoma.
The goal of the trial is to determine whether this treatment increases the number of patients who survive. Participants in the trial receive a mixture of paclitaxel and carboplatin supplied to their brains using ultrasound technology.
The reason for combining these two treatments in the phase 2 trial is that they have previously been used in combination to treat other cancers.
Patients in the phase 1 clinical trial described in the study underwent surgery to have their tumors removed and to have the ultrasound device implanted.
A few weeks after the implantation, they began their treatment.
The blood-brain barrier opening associated with the three-weekly administration of paclitaxel was increased by researchers.
Studies were carried out on specific patient populations during surgery to look into how this ultrasound device affected drug concentrations. Fluorescein, a fluorescent dye, was used in the operating room to visualize and map the barrier, and an MRI taken after ultrasound therapy was also used.
Sonabend concluded that “While we’ve focused on brain cancer, this opens the door to investigate novel drug-based treatments for millions of patients who suffer from various brain diseases.”