Noninvasive Blood-Brain Barrier Disruption to Directly Deliver Chemotherapies to Glioblastoma
The team that was first to offer a clinical trial in the United States opening the blood-brain barrier (BBB) with MRI-guided, focused ultrasound is now using the approach to direct chemotherapy into high-grade glioma tumors such as glioblastoma (GBM) and recurrent GBM (rGBM). Currently, two clinical trials at the University of Maryland Medical Center’s Brain Tumor Treatment and Research Center at the UM Marlene and Stewart Greenebaum Comprehensive Cancer Center (UMGCCC) are combining the strategy of using low-frequency (220 kHz) focused ultrasound and lipid-encased, gas-filled microbubbles to disrupt the BBB, allowing for the penetration of chemotherapeutic agents into tumor-infiltrated brain tissues. The portfolio of clinical trials at the University of Maryland now also includes a newly opened trial for rGBM exploring the use of carboplatin – a chemotherapy that might demonstrate improved efficacy against malignant brain tumor cells once the BBB is overcome.
“We are pleased to be among the first in the world to be exploring ways of treating GBM that were impossible before recent advances in focused ultrasound,” says Graeme F. Woodworth, MD, FACS, Professor and Chair of the Department of Neurosurgery at the University of Maryland School of Medicine and director of the Brain Tumor Treatment and Research Center at UMGCCC. “Blood brain barrier disruption is a major opportunity for treating numerous neurological conditions, including Parkinson’s disease and Alzheimer’s disease,” he continues. “However, as this treatment strategy has the potential to improve drug treatment and survival for patients with aggressive brain tumors, applying it to that end is one of our top priorities.”
GBM is thought to have a poor prognosis in large part because of the diffuse way glioma cells invade healthy brain tissue. Even after primary tumor resection, traces of GBM remain at the margins of the tumor bed, unable to be removed safely and not even visible on contrast-enhanced MRI. The standard of care for primary GBM includes a six-week course of concurrent radiotherapy and chemotherapy in the form of oral temozolomide (TMZ) is followed by an adjuvant course of TMZ one week a month for six months. However, even after TMZ was added this protocol – which increased median survival from 9–12 months to 14.6 months – recurrence is inevitable, and 5-year survival rates for GBM are less than 5 percent.
To potentially find better treatments for GBM, it is anticipated that the two trials will provide evidence that serial temporary blood-brain barrier disruption (BBBD), through the use of low-frequency focused ultrasound and the stable oscillation of circulating microbubbles, is a safe and feasible way to administer localized chemotherapy drugs in the residual tumor-invaded brain regions or in the setting of recurrent GBM tumors.
The Logistics of Opening the Blood-Brain Barrier
The BBB protects the brain from neurotoxins and viral infections through tightly connected, specialized endothelial cells supported by a complex network of astrocytes, pericytes and microglia; without intervention, this protective quality also makes it impenetrable to all but small lipophilic molecules less than 400 Daltons, severely limiting therapeutic options.
Woodworth and others from the University of Maryland and Mayo Clinic Arizona have reviewed the various strategies for opening the BBB to treat GBM more directly1, perhaps with lower, safer chemotherapeutic doses. Focused ultrasound combined with microbubbles to mechanically disrupt the blood-brain barrier – an application that UM researchers described in a 2016 paper2. The team believes this is a particularly promising approach for the following reasons:
- Noninvasive – The technology is applied transcranially
- Safe – Gas-filled microbubbles allow for focused ultrasound sonication efficacy at a lower frequency that does not heat tissues and cause treatment-related side effects
- Temporary – After the application of focused ultrasound with microbubbles, the BBB remains open for 4–6 hours before closing up again
- Targetable – BBBD can be limited to the regions of the brain near the tumor bed
- Closed Feedback Loop Control – The focused ultrasound treatments are monitored and controlled in real-time via acoustic emission monitoring systems
BBBD is achieved through harnessing the Exablate 4000 Type 2.0/2.1 transcranial focused ultrasound technology (Insightec; Tirat Carmel, Israel) and intravenous contrast DEFINITY® microbubbles (Lantheus Medical Imaging; Billerica, MA). Sonication by the ultrasound transducer produces acoustical, non-inertial cavitation of the 1–5 m microbubbles in the blood-brain barrier capillaries, temporarily opening the junctions between the endothelial cells in the BBB.
Glioblastoma Trials at UMGCCC Exploring BBBD-enhanced Chemotherapy
Woodworth is the principal investigator for three Insightec-sponsored BBBD treatment protocols open at the Brain Tumor Treatment and Research Center at UMGCCC:
- A prospective, single-arm, open-label feasibility study, Exablate Blood Brain Barrier Disruption (BBBD) for Planned Surgery in Suspected Infiltrating Glioma (NCT03322813) was the first in the United States to assess the safety and feasibility of disrupting the blood-brain barrier in gliomas using focused ultrasound. The approach is used to mark brain tumor regions immediately prior to planned surgical intervention.
- A prospective, multi-center, single-arm study, Assessment of Safety and Feasibility of Exablate Blood-Brain Barrier Disruption for the Treatment of High-Grade Glioma in Patients Undergoing Standard Chemotherapy (NCT03551249), is currently enrolling patients with primary GBM. Patients will follow the Stupp protocol of tumor resection and concomitant radiation therapy and treatment with TMZ and can enroll in the trial at any point up until adjuvant TMZ treatment begins. The treatment protocol consists of six sessions of BBBD sonication, each administered on the first day of the monthly, one-week course of treatment with TMZ. Exablate BBBD will be administered to a target 3 cm margin around the resected tumor bed approximately two hours before the patient receives oral TMZ. The study’s primary outcome is assessment of the safety of repeated BBBD sonication sessions, as measured by follow-up MRI scans and reporting of adverse events. Feasibility will be measured by comparing contrast-enhanced MRI images pre- and post-sonication. Other secondary measures are progression-free survival and overall survival.
- The phase 1/2, open-label, prospective, multi-center, single-arm Exablate Blood-Brain Barrier Disruption for the Treatment of rGBM in Subjects Undergoing Carboplatin Monotherapy (NCT04417088) safety and feasibility study gives researchers an opportunity to study two levels of BBBD treatment volumes to assess tolerability. The study will begin with three subjects enrolled at a 30 cc treatment volume and escalate to subjects enrolled at 65 cc if the lower treatment volume is well tolerated by the first subjects. Trial enrollees must already be planned to receive carboplatin, which demonstrates promise for the treatment of glioma cells in the lab, but to date has shown limited benefits for patients because of the BBB. However, this particular trial is designed to provide the basis for a pivotal study and will not itself determine the efficacy of Exablate BBBD for the delivery of carboplatin to tumor cells. The treatment protocol involves administering Exablate BBBD approximately an hour before each planned carboplatin infusion cycle, which are four weeks apart. Enrollees will receive up to six sessions of Exablate BBBD. Prior to each session, the tumor will be imaged so that the BBBD is applied to the regions of advancing tumor growth.
For information about the BBBD trials for GBM at UMGCCC, contact Kaitlyn Henry at 410-328-0939.
- Blood Brain Barrier Disruption for Direct Delivery of Agents to Tumors
- MRI-Guided Focused Ultrasound for Essential Tremor at UMMC
- Press Release: University of Maryland Scientists to Conduct First FDA Approved Study of Focused Ultrasound to Open Blood-Brain Barrier
- UMMC Brain Tumor Treatment and Research Center at UMGCCC
1Harder BG, Blomquist MR, Wang J, Kim AJ, et al. Developments in blood-brain barrier penetrance and drug repurposing for improved treatment of glioblastoma. Front Oncol. 2018;8:462. doi: 10.3389/fonc.2018.00462
2Hersch DS, Kim AJ, Winkles JA, Eisenberg HM, et al. Emerging applications of therapeutic ultrasound in neuro-oncology: moving beyond tumor ablation. Neurosurgery. 2016;79(5):643-654. Doi: 10.1227/NEU.0000000000001339