Neuronavigation-guided focused ultrasound for transcranial blood-brain barrier opening and immunostimulation in brain tumors.
Authors: Chen KT, Chai WY, Lin YJ, Lin CJ, Chen PY, Tsai HC, Huang CY, Kuo JS, Liu HL, Wei KC
Focused ultrasound (FUS) in the presence of microbubbles can transiently open the blood-brain barrier (BBB) to increase therapeutic agent penetration at the targeted brain site to benefit recurrent glioblastoma (rGBM) treatment. This study is a dose-escalating pilot trial using a device combining neuronavigation and a manually operated frameless FUS system to treat rGBM patients. The safety and feasibility were established, while a dose-dependent BBB-opening effect was observed, which reverted to baseline within 24 hours after treatment. No immunological response was observed clinically under the applied FUS level in humans; however, selecting a higher level in animals resulted in prolonged immunostimulation, as confirmed preclinically by the recruitment of lymphocytes into the tumor microenvironment (TME) in a rat glioma model. Our findings provide preliminary evidence of FUS-induced immune modulation as an additional therapeutic benefit by converting the immunosuppressive TME into an immunostimulatory TME via a higher but safe FUS dosage.
Introduction
Purpose
Drug delivery with BBB opening
Study Objective
To evaluate the safety and feasibility of dose-escalated frameless focused ultrasound with microbubbles to transiently open the blood–brain barrier and assess dose-dependent BBB opening and immune modulation in patients with recurrent glioblastoma.
Animal model / Human subject
Rat (glioma model); strain None; age None; sex None
Disease model
Recurrent glioblastoma (rGBM); rat glioma model
MRI or image guidance method
Neuronavigation (manually operated frameless FUS system)
Targeted brain region(s)
Recurrent Glioblastoma (Tumor Site / Tumor Microenvironment)
Outcomes and Safety
Summary of Outcomes
NaviFUS safely and transiently opened the blood–brain barrier in recurrent GBM patients in a dose‑dependent manner (estimated ceiling MI ≈ 0.48, 0.58, 0.68) with permeability returning to baseline within 24 h and no clinical immune response at those doses; in a rat glioma model, a higher FUS level (0.81 MI) induced prolonged immunostimulation and lymphocyte recruitment to the tumor microenvironment, whereas 0.63 MI (comparable to the highest human dose) did not.
Duration of biological effect
7 days
Safety-related matter
In this clinical pilot, NaviFUS was determined safe and tolerable up to the tested ceiling (<0.68 MI) with no procedure-related adverse events, no deaths, hemorrhages, brain swelling, neurologic deficits, or dose-limiting toxicity; two serious adverse events (hyponatremia and hypernatremia) occurred but were judged definitely not related to FUS or microbubbles. Preclinical/animal data indicate higher FUS exposures (≈0.8–0.85 MI) can cause asymptomatic red blood cell extravasation and cellular apoptosis, suggesting potential side effects at higher doses.
Brain Region
Ultrasound Parameters
Focal Characteristics
Focal depth: None; Focal length: None; Aperture size: None
Treatment frequency
Single session
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