Enhanced delivery of drugs to the brain could improve the outcomes for patients who develop brain metastases: that is the hope from an early proof-of-concept study.
“Failure of promising therapies to cross the blood–brain barrier (BBB) is an important cause of poor clinical response for a broad range of brain pathologies including cancer,” note the researchers, led by Ying Meng, PhD, Sunnybrook Research Institute, Toronto, Canada, and colleagues.
They showed, in a first-in-humans study, that magnetic resonance (MR)-guided focused ultrasound enhanced the delivery of the targeted monoclonal antibody trastuzumab (Herceptin) to the brain and thus allowed it to shrink tumors in women with HER2-positive brain metastases.
This study “sets the stage for a new means of delivering a wide array of large therapeutic molecules to the brain that otherwise cannot breach the BBB (blood–brain barrier),” the investigators assert.
The study was published online October 13 in Science Translational Medicine.
The study was conducted in four patients with primary HER2-positive breast cancer and intracranial disease. Three patients were on maintenance trastuzumab when they developed brain metastases, the authors note.
In the study, all patients underwent transcranial MRI-guided, focused ultrasound plus concomitant intravenous trastuzumab, both delivered as outpatient therapies.
Treatment took 138 minutes on average. Overall, the procedures were well tolerated with no serious adverse events, the team reports.
A radiopharmaceutical analog of trastuzumab allowed researchers to directly visualize enhanced trastuzumab distribution in the ultrasonicated regions of the brain. “The average relative increase in delayed signal was 101%…which indicates greater retention and binding of trastuzumab to HER2 where FUS [focused ultrasound] was delivered,” investigators report.
In contrast, the standardized uptake value ratio (SUVR) within normal tissues and non-sonicated lesions remained unchanged by treatment. Voxel-level analyses — a computational approach that measures differences in local concentrations of drugs in brain tissue — also showed that delayed SUVR increased as much as 450% compared with only 8% in control lesions, researchers add.
“All target tumors were either stable or reduced in size on the last follow-up MRI relative to baseline,” Meng notes.
Blood–brain-barrier permeability “was safely and transiently increased and reconstituted within 24 hours of the procedure,” the authors report.
There are several potential advantages to using MRI-guided focused ultrasound over other approaches to deliver drugs to the brain, the team asserts.
Firstly, focused ultrasound allows for selective targeting of either single or multiple brain lesions located at the extremes of the brain as well as those within deep central regions of the brain.
This means that lesions including those in the brainstem, cranial nerve nuclei, and cerebellum can be safely and precisely targeted with focused ultrasound, as the authors point out — all areas where radiation and surgery can have limited efficacy.
MRI-guided focused ultrasound can also be combined with other therapeutic agents with a favorable side effect profile, which could be safer and more tolerable for patients.
“Given the robust number of antibody-based biologics in therapeutic pipelines, our results should facilitate drug repurposing for neuro-oncological and neurological disorders not previously amenable to treatment because of low drug penetration,” researchers speculate.
“By demonstrating improved therapeutic binding and activity in four HER2-positive patients with progressive brain metastases, this study established a noninvasive image-guided method of delivering antibody therapy across the BBB,” they conclude.
The study was supported by the Focused Ultrasound Foundation, INSIGHTEC, Canadian Institutes of Health Research, Kavelman Foundation, the Canadian Breast Cancer Foundation, the Canadian Cancer Society, and the Harquail Centre for Neuromodulation. Meng has disclosed no relevant financial relationships. Several co-authors have disclosed relationships with industry. The full list of disclosures can be found with the original article.
Sci Transl Med. Published online October 13, 2021. Abstract
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