Vendors and Researchers Make Progress with Glioblastoma
by James Cavuoto, editor
May 2023 issue, BioElectRx Business Report
Glioblastoma, the deadly brain cancer that impacts about 12,000 people in the U.S. each year, remains one of the most significant unmet medical needs facing the healthcare industry. The five-year survival rate is under 10% and patients survive an average of 15 to 18 months after diagnosis.
Recently, several emerging bioelectronic medicine firms and research teams have reported progress at developing therapies for glioblastoma, though there is still a long road ahead for these efforts.
One promising bioelectronic medicine approach involves tumor-treating fields. In December, Novocure, the European manufacturer of oncology devices, announced that Health Canada approved its Optune system for the treatment of newly diagnosed and recurrent glioblastoma. Optune works by creating electric tumor treating fields that disrupt cancer cell division. The device delivers electrical therapy to the region of the tumor.
Last year, Alpheus Medical, Inc., a startup firm developing a novel sonodynamic therapy platform targeting solid body cancers, announced the treatment of the first three patients in the U.S.-based multi-center Phase 1 clinical trial evaluating the safety and optimal dosage of the company’s proprietary platform. Alpheus Medical’s investigational SDT treatment includes a noninvasive drug-device combination that targets cancer cells throughout the entire brain hemisphere using low-intensity, large-field ultrasound. The treatment can be done in an outpatient setting, allows for repeat treatment, and does not require the use of imaging, such as MRI.
One of the newest entrants in the market for glioblastoma is a British startup call Opto, co-founded by two former Cambridge University students Ben Woodington and Elise Jenkins. The startup launched with £1.85 million in pre-seed funding. Opto is seeking to deploy a procedure that would require no need for major surgery or an overnight stay in hospital. Using the latest round of investment, led by Blackbird Ventures (with additional support from Possible Ventures, Cambridge Engineering alumnus Amar Shah, co-founder of Wayve Technologies, and others), Opto will expand its engineering team and push towards validation of its core technology platform. “Glioblastoma is a horrendous disease, with a life expectancy of just 14 months from diagnosis. Patients, and the doctors who treat them, are desperate for tools that can help and lead to improved outcomes,” said Woodington. “We believe this is an area of medicine we can impact the fastest.”
A major impediment to treating glioblastoma has been that the most potent chemotherapy approaches can’t permeate the blood-brain barrier to reach the aggressive brain tumor. But a team of researchers at Northwestern Medicine scientists recently reported results of the first in-human clinical trial, published in The Lancet Oncology, in which they used a novel, skull-implantable ultrasound device to open the BBB and repeatedly permeate large, critical regions of the human brain to deliver chemotherapy that was injected intravenously.
The four-minute procedure to open the BBB 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 BBB opening on the concentrations of chemotherapy in the human brain. Opening the BBB led to an approximately four- to six-fold increase in drug concentrations in the human brain, the results showed.
The investigators observed this increase with two different chemotherapy drugs, paclitaxel and carboplatin. The drugs are not used to treat these patients because they do not cross the BBB in normal circumstances.
In addition, this is the first study to describe how quickly the BBB closes after sonication. Most of the BBB restoration happens in the first 30 to 60 minutes after sonication, they 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 Adam Sonabend, associate professor of neurological surgery and a Northwestern Medicine neurosurgeon. Temozolomide, the current chemotherapy used for glioblastoma, does cross the BBB, but is a weak drug, he said.
The BBB 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.
The research team 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,” said Sonabend, also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Previous human studies showed that the BBB 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.
The study reports that using a novel skull-implantable grid of nine ultrasound emitters designed by French biotech company Carthera opens the BBB 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 the removal of glioblastoma tumors.
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.
The Northwestern team 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 BBB was visualized and mapped in the operating room using a fluorescent dye 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.