The blood brain barrier (BBB) protects the central nervous system from foreign toxins and pathogens. However, this preservatory measure hinders otherwise effective therapeutics from acting on the brain. This is a key obstacle in neuro-oncology, where there is a rare number of cancer treatments that have poor long-term effectiveness. The development of strategies to safely render the BBB temporarily permeable to cancer therapeutics is an ongoing field of research. One of these strategies is the use of MR-guided focused ultrasound (MRgFUS) drug delivery to brain regions, a technique that has worked in animal studies but has yet to be proven safe and effective in humans. In the article by Meng et al., researchers used MRgFUS to deliver trastuzumab to brain metastases in patients with Her2-positive breast cancer (1) .

Four female patients ranging in age from 31-56 were enrolled in this single-arm open-labeled study. They were given a maximum of six combination treatments of MRgFUS overlapping the standard dosing regimen of trastuzumab-based therapies. Patient 1 had one infratentorial lesion. Patient 2 and 3 each had three lesions in the infratentorial and supratentorial regions respectively. Lastly patient 4 had one infratentorial and one supratentorial lesion. The primary outcome of this study was the characterization of treatment-related adverse events. The secondary outcome was the possibility of producing BBB permeability changes in intracranial metastatic disease as measured by contrast-enhanced T1-weighted MRI scans. The effect of MRgFUS BBB opening on the delivery of trastuzumab to the brain was measured using SPECT imaging with 111 In-BzDTPA- NLS-trastuzumab. Following MRgFUS, all sonicated regions had greater gadolinium contrast- enhancement in T1-weighted MRI scans, proving that the technique was able to disrupt the BBB. Patients tolerated this treatment well, as no significant adverse events were found in subsequent imaging.

The barrier was closed within 24 hours of the procedure. A radiotracer, 111 In-BzDTPA-NLS-trastuzumab, was used to observe tumor penetration of trastuzumab through SPECT imaging without MRgFUS delivery (baseline) and following MRgFUS delivery. MRgFUS delivery of the treatment resulted in an increased SPECT signal relative to the baseline imaging. The standardized uptake value ratio (SUVR) of MRgFUS-treated lesions increased by 101 ± 71%, compared to −18 ± 26% in control lesions. MRgFUS augmented drug uptake in 87 ± 17% of sonicated voxels (>20% increase in SUVR), with up to a 450% voxel-wise increase detected. Control lesions had 8 ± 8% voxels with >20% increase in SUVR. Unidimensional tumor measurements decreased by 19 ± 12% with treatment (1).

All patients enrolled in the study were shown to have either stable or reduced tumor size relative to baseline. The investigators also examined off target uptake of the drug in baseline imaging and with MRgFUS. They found that the sonication volume SUVR within unsonicated lesions and normal tissue were unchanged between baseline and MRgFUS therapy. This study, therefore, provides the first-in-human evidence that MRgFUS can safely deliver trastuzumab across the BBB.

The authors also highlighted some of the advantages that MRgFUS possesses over other strategies for drug delivery in the CNS. Firstly, MRgFUS offered the investigators a great deal of spatial and temporal control over drug delivery. The treatment modality allowed the researchers to demonstrate that the brainstem, cranial nerve nuclei and cerebellum were safe to target. Secondly, MRgFUS can be used in combination with a wide variety of drugs. Lastly, the bioavailability of other tumor medications may now be investigated with MRgFUS. There were also some limitations that were acknowledged by the authors. Firstly, the patient population was small, and the study was not blinded. Secondly, confirmation testing to ensure that the brain lesion retained the molecular status of the primary cancer was only done on one lesion. Thirdly, radiation necrosis or tumor progression related necrosis was not ruled out. Lastly, SPECT imaging had low spatial resolution. Despite these shortcomings, this study demonstrated that MRgFUS is a safe and effective method to deliver treatments across the BBB and paves the way for the use of this technique for other CNS diseases.

References
1. Meng Y, Reilly RM, Pezo RC, Trudeau M, Sahgal A, Singnurkar A, et al. MR-guided focused ultrasound enhances delivery of trastuzumab to Her2-positive brain metastases. Sci Transl Med. 2021 Oct 13;13(615):eabj4011.