Crossing the Barrier
By Beth W. Orenstein
Radiology Today
Vol. 23 No. 2 P. 10

Focused ultrasound shows promise as a way to deliver treatment for cancer of the brain.

More than 24,500 people in the United States were diagnosed with brain cancer in 2021, according to the Centers for Disease Control and Prevention (CDC). The CDC also estimates that 18,600 Americans died of brain cancer last year. Those numbers, however, don’t factor in the many types of cancer that can metastasize to the brain. Any type of cancer can spread to the brain, but lung, breast, colon, kidney, and melanoma are the most likely to cause brain metastases.

In recent years, promising new therapies have been developed for treating all types of cancer. One of these treatments is monoclonal antibodies, which harness the body’s own immune system to attack cancer cells. However, this promising treatment poses a particular challenge in the event of brain cancer and other cancers that have spread to the brain; the problem has been the blood-brain barrier.

The blood-brain barrier is made up of a thin layer of cells that line blood vessels. This barrier is meant to keep bacteria, viruses, and other toxins from harming the brain. However, at the same time, it prevents helpful antibody therapies from crossing and entering the region.

That’s what makes new research—the first in humans—using focused ultrasound to noninvasively deliver cancer drugs directly into the brain tumor so exciting, says neuroradiologist Suzanne LeBlang, MD, director of clinical relationships at the Focused Ultrasound Foundation in Charlottesville, Virginia.

Researchers at Sunnybrook Research Institute in Toronto, Canada, recently used MR–guided focused ultrasound to deliver trastuzumab (Herceptin), a common monoclonal antibody treatment, to the brains of four of 10 patients with a type of metastatic breast cancer. Trastuzumab is 100 times larger than the typical compound that can enter the brain across the blood-brain barrier. However, focused ultrasound can open the blood-brain barrier and allow medications to permeate it.

Although their study was small, the results were encouraging, says lead author Nir Lipsman, MD, PhD, director at Sunnybrook’s Harquail Centre for Neuromodulation. “Although our work is preliminary, we were able to show that we can in fact get the drug in the brain with this method and that it is safe,” Lipsman says.

Metastatic, or stage IV, breast cancer starts in the breast and spreads to other areas—possibly the bone, liver, other organs, and the brain. About 20% to 30% of patients with HER2-positive breast cancer develop brain metastases, which are associated with greater morbidity and mortality despite therapeutic advances. Treatment for breast metastases may include a combination of open neurosurgery, radiation, and chemotherapy. Options for surgery and radiation can be limited, depending on the location of the metastases, and both treatments are associated with significant risks and side effects.

Work Sets the Stage
LeBlang says, “I’m absolutely thrilled they are researching the ability to increase the delivery of therapies directly to the brain metastases in a noninvasive manner for the first time in breast cancer patients. If we can get targeted drug therapy in patients, it could potentially improve their outcome and allow us to obviate radiation therapy or use it later in the course of treatment. The focused ultrasound procedure is really encouraging to deliver specific therapeutics for various other types of brain cancers.”

Lipsman says their work sets the stage for the possibility of delivering a host of both established and novel therapies to not just brain cancer and metastases but also other neurological conditions where access to the brain is critical for treatment, such as Parkinson’s and Alzheimer’s diseases and amyotrophic lateral sclerosis.

The Canadian researchers’ phase I clinical study, which was published in Science Translational Medicine in October 2021, is the first visual confirmation that focused ultrasound can improve delivery of targeted antibody therapy across the blood-brain barrier, Lipsman says. Their findings, he adds, are the culmination of nearly 20 years of research initiated by focused ultrasound innovator Kullervo Hynynen, PhD, vice president of research and innovation at Sunnybrook Research Institute. Lipsman says his group is fortunate to have Hynynen as a collaborator. “He was behind a lot of the early work in the early 2000s, looking at this technique,” Lipsman says. As early as the 1950s, researchers studying animals had started to notice that ultrasound could be used to less invasively access the brain. Hynynen studied the early research and discovered that the technique could also be used to overcome the blood-brain barrier by using microbubbles to temporarily open it without inflicting damage.

The intent of their most recent study was to determine whether focused ultrasound could temporarily open the blood-brain barrier and allow the antibody therapy to pass into the tumor tissue. MRI and a helmetlike focused ultrasound device developed by InSightec was used to direct the ultrasound waves precisely to the areas of the brain where the tumors were seen on the imaging scans. The focused ultrasound opening the blood-brain barrier was performed while the patients were in the MRI machine.

The MRI was a pivotal part of the research, Lipsman notes. “Under MRI guidance, we could visualize the tumor in this case and plan our targeting on the intraoperatively obtained images. We were then able to personalize and tailor our delivery of the drug to the patients’ tumor or tumors,” he says.

The researchers made sure to target each axial slice in order to encompass the entire lesion, Lipsman says. “We were able to extend the blood-brain barrier opening a centimeter or two beyond what we could see on the MRI to be sure we got the border around it.” The group used a 3T research MRI scanner. No modifications to the scanner were necessary, Lipsman notes.

Tagging Drugs
The researchers were able to confirm that the drug was delivered by “tagging” the antibody therapy with a special compound that could be seen using SPECT imaging. Raymond Reilly, PhD, of the Centre for Pharmaceutical Oncology at the Leslie Dan Faculty of Pharmacy at the University of Toronto, led the team that developed the radiopharmaceutical drug used as a “tag.”

Developing the tracer was costly, “both in absolute cost but also in human resources to get to the point where we were injecting it in a human patient,” Lipsman says. “This was the first time it was done in a clinical population, and it took years of background work to demonstrate the technical feasibility and preclinical evidence. We needed to prove its safety and efficacy and to get it through the regulatory process and our ethics board. It took years of work and operational costs associated with this.”

The patients in the study were scanned before and after their procedure. “Two weeks before focused ultrasound, in conjunction with the patients’ chemotherapy [regimen], we injected them with radiolabeled trastuzumab and looked at their brain scans,” Lipsman says. “We saw very little uptake of the drug at baseline.” However, the scans after focused ultrasound showed that they had significant uptake of the antibody therapy. “This indicated to us that we were able to enhance delivery of at least this specific radioactive-labeled trastuzumab and, with it, hopefully all trastuzumab can be increased to this part of the brain. We were able to visually confirm that focused ultrasound improved the delivery of targeted antibody therapy across the blood-brain barrier.”

Rossanna Pezo, MD, PhD, FRCPC, a medical oncologist in the Odette Cancer Centre at Sunnybrook, reports that the patients’ tumors shrank in size after the focused ultrasound. Results varied for patients between 7% and 31%, with an average of 21%. Pezo says that while the reduction in tumor size is promising, it “should be interpreted with caution, as further research on a larger scale is needed.”

The patients went home the same day as their MRI-guided focused ultrasound and were followed after 24 hours, one month, three months, and one year. By following the patients, the researchers were able to conclude that the procedure was safe and that the patients could tolerate it well, Lipsman says.

Lipsman says this early work is a “major coup” because, although what they showed has been theorized, until now it hadn’t been confirmed. Of course, Lipsman says, the question remains as to whether this technique works “across the board” for all therapeutics and all indications. “How translatable is this to other medications? It remains to be seen, but I think it is,” Lipsman says. “I think we’re describing a physical phenomenon, something that is agnostic to the therapeutic being delivered. Much more work needs to be done to determine whether opening the blood-brain barrier with microbubbles and ultrasound is the future for the delivery of new treatments.”

More Research Is Needed
Next on the researchers’ agenda is to test the technique on more patients. “We’ve demonstrated a proof of concept at this stage, and we got these important data to suggest that we could potentially enhance chemotherapy delivery,” Lipsman says. “The next step is treating more patients to better characterize the patient profile and establish whether we truly are seeing an effect on the progression of these tumors.” Lipsman says they also plan more research on the technical parameters to determine what will lead to enhanced delivery of chemotherapy and other compounds. “We are looking at the delivery technology as well as what it is we are delivering,” he says.

Lipsman expects in time they will be able “to make the procedure more efficient, streamlined, and more tailored, including determining what ultrasound parameters should be used to optimize the effect.”

Lipsman says the field is evolving, leading researchers to approach highly complex diseases in multifaceted ways.

Work is underway by his group to look at opening the blood-brain barrier to treat glioblastoma. “In 2015, we got the first proof-of-concept data that opening the blood-brain barrier in glioblastoma patients is safe and feasible, and have expanded that to a larger trial,” he says.

LeBlang says in another trial of medications used to treat glioblastoma, researchers used contrast-enhanced MRI to determine whether they had opened the blood-brain barrier; the medication they were testing couldn’t be tagged. Besides, LeBlang says, it would be too costly to tag every new medication to see whether it crossed the blood-brain barrier. That’s why, she says, trials like the Canadians’ are important and could be a game-changer.

Real-time MRI guidance is just one way to deliver medications with focused ultrasound; another is using neuro-navigation. “With neuro-navigation, the patient is not inside the MRI scanner during the procedure. MRI scans are loaded into a computer and with the patient in a separate location, the images guide a separate ultrasound-guided device to open the blood-brain barrier,” LeBlang says.

According to the Focused Ultrasound Foundation’s 2021 report on the state of the field, “there are currently 152 clinical indications in various stages of research and development, and the number is increasing rapidly. Most are early stage. Worldwide, 34 indications have regulatory approval; in the United States, seven have been approved by the FDA.

“Focused ultrasound is not for every patient or every disorder. Much work remains to determine where this technology provides significant therapeutic and cost-effective value.”

— Beth W. Orenstein, of Northampton, Pennsylvania, is a freelance medical writer and regular contributor to Radiology Today.