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

Ko Ting Chen; Wen Yen Chai; Ya Jui Lin; Chia Jung Lin; Pin Yuan Chen; Hong Chieh Tsai; Chiung Yin Huang; John S. Kuo; Hao Li Liu; Kuo-Chen Cheng Wei

doi:10.1126/sciadv.abd0772

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

Ko Ting Chen, Wen Yen Chai, Ya Jui Lin, Chia Jung Lin, Pin Yuan Chen, Hong Chieh Tsai, Chiung Yin Huang, John S. Kuo, Hao Li Liu, Kuo-Chen Cheng Wei^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal Article › peer-review

128 Scopus citations

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.

Original language	English
Article number	eabd0772
Journal	Science Advances
Volume	7
Issue number	6
DOIs	https://doi.org/10.1126/sciadv.abd0772
State	Published - 05 02 2021

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Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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title = "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.",

author = "Chen, {Ko Ting} and Chai, {Wen Yen} and Lin, {Ya Jui} and Lin, {Chia Jung} and Chen, {Pin Yuan} and Tsai, {Hong Chieh} and Huang, {Chiung Yin} and Kuo, {John S.} and Liu, {Hao Li} and Wei, {Kuo-Chen Cheng}",

note = "Publisher Copyright: Copyright {\textcopyright} 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).",

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AU - Chen, Ko Ting

AU - Chai, Wen Yen

AU - Lin, Ya Jui

AU - Lin, Chia Jung

AU - Chen, Pin Yuan

AU - Tsai, Hong Chieh

AU - Huang, Chiung Yin

AU - Kuo, John S.

AU - Liu, Hao Li

AU - Wei, Kuo-Chen Cheng

N1 - Publisher Copyright: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

PY - 2021/2/5

Y1 - 2021/2/5

N2 - 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.

AB - 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.

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

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