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In the first in-human clinical trial, scientists used a novel, skull-implantable ultrasound device to open the blood-brain barrier and repeatedly permeate large, critical regions of the human brain to deliver chemotherapy that was injected intravenously. This is potentially a huge advance for glioblastoma patients because the most potent chemotherapy can't permeate the blood-brain barrier to reach the aggressive and deadly brain tumor. A major impediment to treating the deadly brain cancer glioblastoma has been that the most potent chemotherapy can't permeate the blood-brain barrier to reach the aggressive brain tumor. But now Northwestern Medicine scientists report 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 permeate 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 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 getting up to six cycles of treatment. This is the first study to successfully quantify the effect of ultrasound-based blood-brain barrier opening on the concentrations of chemotherapy in the human brain. Opening 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. The drugs are not used to treat these patients because they do not cross blood-brain barrier in normal circumstances. In addition, this is the first study to describe how quickly the blood-brain barrier closes after sonication. Most of the blood-brain barrier restoration happens in the first 30 to 60 minutes after sonication, the scientists discovered. The findings will allow optimization of the sequence of drug delivery and ultrasound activation to maximize the drug penetration into the human brain, the authors said. "This is potentially a huge advance for glioblastoma patients," said lead investigator Dr. Adam Sonabend, an associate professor of neurological surgery at Northwestern University Feinberg School of Medicine and a Northwestern Medicine neurosurgeon. Temozolomide, the current chemotherapy used for glioblastoma, does cross the blood-brain barrier, but is a weak drug, Sonabend said. The paper will be published May 2 in The Lancet Oncology. The blood-brain barrier is a microscopic structure that shields the brain from the vast majority of circulating drugs. As a result, the repertoire of drugs that can be used to treat brain diseases is very limited. Patients with brain cancer cannot be treated with most drugs that are otherwise effective for cancer elsewhere in the body, as these do not cross the blood-brain barrier. Effective repurposing of drugs to treat brain pathology and cancer require their delivery to the brain. In the past, studies that injected paclitaxel directly into the brain of patients with these tumors observed promising signs of efficacy, but the direct injection was associated with toxicity such as brain irritation and meningitis, Sonabend said. Blood-brain barrier recloses after an hour The scientists discovered that the use of ultrasound and microbubble-based opening of the blood-brain barrier is transient, and most of the blood-brain barrier integrity is restored within one hour after this procedure in humans. "There is a critical time window after sonification when the brain is permeable to drugs circulating in the bloodstream," Sonabend said. Previous human studies showed that the blood-brain barrier is completely restored 24 hours after brain sonication, and based on some animal studies, the field assumed that the blood-brain barrier is open for the first six hours or so. The Northwestern study shows that this time window might be shorter. In another first, the study reports that using a novel skull-implantable grid of nine ultrasound emitters designed by French biotech company Carthera opens the blood-brain barrier in a volume of brain that is nine times larger than the initial device (a small single-ultrasound emitter implant). This is important because to be effective, 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. Clinical trial for patients with recurrent glioblastoma The findings of the study are the basis for an ongoing phase 2 clinical trial the scientists are conducting for patients with recurrent glioblastoma. The objective of the trial -- in which participants receive a combination of paclitaxel and carboplatin delivered to their brain with the ultrasound technique -- is to investigate whether this treatment prolongs survival of these patients. A combination of these two drugs is used in other cancers, which is the basis for combining them in the phase 2 trial. In the phase 1 clinical trial reported in this paper, patients underwent surgery for resection of their tumors and implantation of the ultrasound device. They started treatment within a few weeks after the implantation. Scientists escalated the dose of paclitaxel delivered every three weeks with the accompanying ultrasound-based blood-brain barrier opening. In subsets 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 U.S.), this opens the door to investigate novel drug-based treatments for millions of patients who suffer from various brain diseases," Sonabend said. Other Northwestern authors include: A. Gould, C. Amidei, R. Ward, K. A. Schmidt, D.Y. Zhang, C. Gomez, J.F. Bebawy, B.P. Liu, I.B. Helenowski, R.V. Lukas, K. Dixit, P. Kumthekar, V. A. Arrieta. Lesniak, H. Zhang and R. Stupp. This work is funded by the 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.

WEDNESDAY, May 3, 2023 -- Brain cancers are notoriously difficult to treat because most chemotherapy drugs can’t breach the blood-brain barrier, a microscopic layer of cells that protect the brain from toxins. But researchers now say they can temporarily open that barrier and get more chemo to brain tumors, using an experimental ultrasound device. The technology led to a four- to sixfold increase in chemo drug concentrations within the brains of patients. The researchers observed this increase with two different powerful chemotherapy drugs, paclitaxel and carboplatin. These drugs aren’t typically used to treat brain tumors because they normally can’t cross the blood-brain barrier. For this study, doctors surgically removed patients’ glioblastoma — the most common malignant brain tumor in adults — and then implanted a grid of nine ultrasound emitters in their skulls. Within a few weeks of surgery, patients started chemo treatment to kill any residual cancer cells in their brains. The experimental emitter grid, designed by French biotech company Carthera, opened the blood-brain barrier at large, critical regions of the brain. This allowed the intravenous chemo drug paclitaxel to seep into the brain. The ultrasound procedure takes about four minutes and is performed with the patient awake, the researchers reported. Patients go home after a few hours. The blood-brain barrier quickly reestablishes itself following the procedure, with most of its integrity restored within one hour, the study authors said. The report was published May 2 in The Lancet Oncology journal. “There is a critical time window after sonification when the brain is permeable to drugs circulating in the bloodstream,” said lead researcher Dr. Adam Sonabend , an associate professor of neurological surgery at Northwestern University Feinberg School of Medicine, in Chicago. The doctors escalated the dose of paclitaxel delivered every three weeks, using the ultrasound implant to make sure the chemo got to the brain. The treatment was safe and well-tolerated, the researchers said. Some patients got up to six chemo treatment cycles for their brain tumors. The findings of this study have formed the basis for a clinical trial in which patients will receive a combination of paclitaxel and carboplatin to their brains, to see if the treatment prolongs their survival. Glioblastomas are the fastest-growing brain tumors, and they are nearly always advanced when detected. Five-year survival rates are 22% for people aged 20 to 44, 9% for adults 45 to 54, and 6% for those aged 55 to 64, according to the American Cancer Society. The researchers said the ultrasound technique could be used to help deliver many different types of medication to the brain. “While we have focused on brain cancer (for which there are approximately 30,000 gliomas in the U.S.), this opens the door to investigate novel drug-based treatments for millions of patients who suffer from various brain diseases,” Sonabend said in a university news release. Sources Northwestern University, news release, May 2, 2023 Posted May 2023

Paris-based Carthera designed SonoCloud-9 for implantation in a skull window below the skin. Once in place, the device becomes invisible and, when activated for a few minutes using a transdermal needle connection to an external control unit, it uses low-intensity pulsed ultrasound to temporarily disrupt the blood-brain barrier (BBB). SonoCloud-9 disrupts the BBB for several hours, offering a window during which drug therapies can be administered, allowing the therapeutics to reach the brain in higher and more effective concentrations, according to a news release. Carthera said SonoCloud allows for the therapeutic efficacy of new and existing therapies to be unlocked and harnessed to improve the treatment of a wide range of brain diseases, including glioblastoma. “There is a significant unmet need for new treatments for glioblastoma patients, who have very few available therapeutic options,” Carthera Chief Scientific Officer Michael Canney said in the release. “We’re excited that the FDA has acknowledged the innovative potential of the SonoCloud approach through the granting of this breakthrough designation.” Carthera said the breakthrough nod will offer access to priority review, more intensive FDA interaction to help build an efficient device development program and commitment from experts and senior managers with the FDA who will assist the company along during the premarket review phase. “Following the recent successful completion of our phase 1/2 trial in recurrent glioblastoma, this Breakthrough Device Designation is another important milestone supporting the potential of SonoCloud,” Carthera CEO Frédéric Sottilini said. “This step forward is also a strong signal for investors who have joined our next round of financing and for those who are considering joining. I am confident that we will soon close our Series B round, which will allow us to start our pivotal clinical trial in early 2023.” Another disease SonoCloud may help treat is mild Alzheimer’s Disease, as the company announced positive results from a trial evaluating the safety and efficacy of the use of the technology in the treatment of Alzheimer’s in March.