Neuronavigation-guided focused ultrasound for transcranial blood-brain barrier opening and immunostimulation in brain tumors

Abstract

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.

Focused Ultrasound Combined with Microbubbles in Central Nervous System Applications

“…For a clinically safe BBBO parameter (0.63 mechanical index (MI)), the immune cell population did not change noticeably; however, at a higher but still safe dosage (0.81 MI, which caused minimal RBC extravasation), noticeable increases in CD4 + and CD8 + TILs were observed. These observations support the possibility of fine tuning the FUS parameters to induce an appropriate anticancer immune response while simultaneously maintaining the treatment safety [74].…”

“…An advantage of this system is its relatively low integration complexity, with it being feasible to incorporate the FUS apparatus with currently commercially available neuronavigation systems. This also means that the system could deliver treatments even in the outpatient setting, and a recent study found that the overall procedure can be accomplished within half an hour [ 74 ]. However, a major concern is that the guidance relies on perfect ballistic beam projection offered from numerical treatment planning without actual beam deposition.…”

Molecular Mechanisms of Drug Resistance in Glioblastoma

“…The non-invasive approaches suggest the usage of chemical modification of drugs such as lipidization [28], substrates for carrier-mediated transcytosis [29], substrates for receptor-mediated transcytosis, virus-mediated bloodbrain barrier delivery [30,31], and exosome-mediated blood-brain barrier delivery [32]. There are also several methods different from the above two approaches: the intranasal delivery route [33], the modulation of the blood-brain barrier permeability by hyperosmotic agents [34], and the use of focused ultrasound [35].…”

Ultrasound-mediated disruption of the blood tumor barrier for improved therapeutic delivery

“…A recent study evaluated BTB disruption using FUS with adjuvant temozolomide and showed accurate and safe opening in patients for six sonication cycles at the same targeted sites [ 74 ]. Another recent investigation reported feasibility of BBB opening within peri-enhancing regions of the brain in six patients with recurrent GBM, using the NaviFUS system with concomitant Sonovue microbubbles [ 79 ]. This analysis suggests a dose-dependent BBB permeability effect of FUS, based on DCE kinetic parameter analysis (K trans and V e ) [ 79 ].…”

“…Another recent investigation reported feasibility of BBB opening within peri-enhancing regions of the brain in six patients with recurrent GBM, using the NaviFUS system with concomitant Sonovue microbubbles [ 79 ]. This analysis suggests a dose-dependent BBB permeability effect of FUS, based on DCE kinetic parameter analysis (K trans and V e ) [ 79 ].…”