A major impediment to the treatment of glioblastoma, a deadly brain cancer, has been that the most potent chemotherapy cannot penetrate the blood-brain barrier to reach the aggressive brain tumor.
But now, Northwestern Medicine scientists are reporting the results of the first-in-human clinical trial in which they used a novel skull-implantable ultrasound device to open the blood-brain barrier and repeatedly penetrate large critical regions of the human brain to deliver chemotherapy that was injected. intravenously.
The four-minute procedure to open the blood-brain barrier is performed while the patient is awake, and patients go home after a few hours. The results show that the treatment is safe and well tolerated, with some patients receiving up to six cycles of treatment.
This is the first study to successfully quantify the effect of ultrasound-based blood-brain barrier opening on chemotherapy concentrations in the human brain. Opening of the blood-brain barrier led to an approximately four- to six-fold increase in drug concentrations in the human brain, the results showed.
Scientists observed this increase with two different powerful chemotherapy drugs, paclitaxel and carboplatin. Drugs are not used to treat these patients because they do not cross the blood-brain barrier under normal circumstances.
Furthermore, this is the first study to describe how quickly the blood-brain barrier closes after sonication. Most of the blood-brain barrier restoration occurs in the first 30 to 60 minutes after sonication, the scientists found. The findings will allow optimization of the drug delivery sequence and ultrasound activation to maximize drug penetration into the human brain, the authors said.
“This is potentially a breakthrough for patients with glioblastoma,” said lead investigator Dr. Adam Sonabend, an associate professor of neurological surgery at Northwestern University Feinberg School of Medicine and a neurosurgeon at Northwestern Medicine.
Temozolomide, the current chemotherapy used for glioblastoma, crosses the blood-brain barrier, but it is a weak drug, Sonabend said.
The article will be published on May 2 in Lancet oncology.
The blood-brain barrier is a microscopic structure that protects the brain from the vast majority of drugs in circulation. As a result, the repertoire of drugs that can be used to treat brain diseases is very limited. Brain cancer patients cannot be treated with most drugs that are otherwise effective for cancer in other parts of the body, as these do not cross the blood-brain barrier. The effective repurposing of drugs to treat brain pathology and cancer requires their delivery to the brain.
In the past, studies that injected paclitaxel directly into the brains of patients with these tumors have seen promising signs of efficacy, but direct injection has been associated with toxicity such as brain irritation and meningitis, Sonabend said.
The blood-brain barrier closes again after one hour
The scientists found that the use of ultrasound and microbubble-based opening of the blood-brain barrier is transient, with most blood-brain barrier integrity restored within an hour after this procedure in humans.
“There is a critical time window after sonication when the brain is permeable to drugs circulating in the bloodstream,” Sonabend said.
Previous studies in humans have shown that the blood-brain barrier is fully restored 24 hours after sonication of the brain, and based on some animal studies, the field has assumed that the blood-brain barrier is open for the first six hours or so. The Northwestern study shows that this time window could be shorter.
In another first, the study reports that the use of a new nine-emitter skull-implantable grid designed by French biotech company Carthera opens the blood-brain barrier in a brain volume that is nine times larger than the initial device. (a small device of a single device). ultrasonic emitting implant). This is important because to be effective, this approach requires coverage of a large region of the brain adjacent to the cavity left in the brain after removal of glioblastoma tumors.
Clinical trial for patients with recurrent glioblastoma
The study findings are the basis of an ongoing Phase 2 clinical trial that scientists are conducting for patients with recurrent glioblastoma. The aim of the trial, in which participants receive a combination of paclitaxel and carboplatin delivered to the brain using ultrasound technique, is to investigate whether this treatment prolongs survival in these patients. A combination of these two drugs is used in other types of cancer, which is the basis for combining them in the phase 2 trial.
In the phase 1 clinical trial reported herein, patients underwent surgery for resection of their tumors and implantation of the ultrasound device. They began treatment within a few weeks of implantation.
The scientists increased the dose of paclitaxel administered every three weeks with ultrasound-based opening of the blood-brain barrier. In subgroups of patients, studies were performed during surgery to investigate the effect of this ultrasound device on drug concentrations. The blood-brain barrier was visualized and mapped in the operating room using a fluorescent die called fluorescein and by MRI obtained after ultrasound therapy.
“While we have focused on brain cancer (for which there are approximately 30,000 gliomas in the US), this opens the door to investigate new drug-based treatments for millions of patients suffering from various brain diseases. Sonabend said.
Other Northwestern authors include: A. Gould, C. Amidei, R. Ward, KA Schmidt, DY Zhang, C. Gomez, JF Bebawy, BP Liu, IB Helenowski, RV Lukas, K. Dixit, P. Kumthekar, VA Arrieta . Lesniak, H. Zhang, and R. Stupp.
This work is supported by grants 1R01CA245969-01A1 and P50CA221747 from the National Cancer Institute of the National Institutes of Health and SPORE support from the Moceri Family Foundation and the Panattoni family.
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