Ultrasound-mediated delivery of doxorubicin to the brain results in immune modulation and improved responses to PD-1 blockade in gliomas

Víctor A. Arrieta; Andrew Gould; Kwang Soo Kim; Karl J. Habashy; Crismita Dmello; Gustavo I. Vázquez-Cervantes; Irina Palacín-Aliana; Graysen McManus; Christina Amidei; Cristal Gomez; Silpol Dhiantravan; Li Chen; Daniel Y. Zhang; Ruth Saganty; Meghan E. Cholak; Surya Pandey; Matthew McCord; Kathleen McCortney; Brandyn Castro; Rachel Ward; Miguel Muzzio; Guillaume Bouchoux; Carole Desseaux; Michael Canney; Alexandre Carpentier; Bin Zhang; Jason M. Miska; Maciej S. Lesniak; Craig M. Horbinski; Rimas V. Lukas; Roger Stupp; Catalina Lee-Chang; Adam M. Sonabend

doi:10.1038/s41467-024-48326-w

Ultrasound-mediated delivery of doxorubicin to the brain results in immune modulation and improved responses to PD-1 blockade in gliomas

Víctor A. Arrieta, Andrew Gould, Kwang Soo Kim, Karl J. Habashy, Crismita Dmello, Gustavo I. Vázquez-Cervantes, Irina Palacín-Aliana, Graysen McManus, Christina Amidei, Cristal Gomez, Silpol Dhiantravan, Li Chen, Daniel Y. Zhang, Ruth Saganty, Meghan E. Cholak, Surya Pandey, Matthew McCord, Kathleen McCortney, Brandyn Castro, Rachel WardMiguel Muzzio, Guillaume Bouchoux, Carole Desseaux, Michael Canney, Alexandre Carpentier, Bin Zhang, Jason M. Miska, Maciej S. Lesniak, Craig M. Horbinski, Rimas V. Lukas, Roger Stupp, Catalina Lee-Chang^*, Adam M. Sonabend^*

^*Corresponding author for this work

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

2 Scopus citations

Abstract

Given the marginal penetration of most drugs across the blood-brain barrier, the efficacy of various agents remains limited for glioblastoma (GBM). Here we employ low-intensity pulsed ultrasound (LIPU) and intravenously administered microbubbles (MB) to open the blood-brain barrier and increase the concentration of liposomal doxorubicin and PD-1 blocking antibodies (aPD-1). We report results on a cohort of 4 GBM patients and preclinical models treated with this approach. LIPU/MB increases the concentration of doxorubicin by 2-fold and 3.9-fold in the human and murine brains two days after sonication, respectively. Similarly, LIPU/MB-mediated blood-brain barrier disruption leads to a 6-fold and a 2-fold increase in aPD-1 concentrations in murine brains and peritumoral brain regions from GBM patients treated with pembrolizumab, respectively. Doxorubicin and aPD-1 delivered with LIPU/MB upregulate major histocompatibility complex (MHC) class I and II in tumor cells. Increased brain concentrations of doxorubicin achieved by LIPU/MB elicit IFN-γ and MHC class I expression in microglia and macrophages. Doxorubicin and aPD-1 delivered with LIPU/MB results in the long-term survival of most glioma-bearing mice, which rely on myeloid cells and lymphocytes for their efficacy. Overall, this translational study supports the utility of LIPU/MB to potentiate the antitumoral activities of doxorubicin and aPD-1 for GBM.

Original language	English (US)
Article number	4698
Journal	Nature communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-48326-w
State	Published - Dec 2024

Funding

This work was supported by the NIH grant 1R01NS110703-01A1 (AMS), NIH/NCI 1U19CA264338-01 (A.M.S. and R.S.), NIH/NCI 1R01CA245969-01A1 (A.M.S. and R.S,), P50CA221747 SPORE for Translational Approaches to Brain Cancer. Additionally, this work was supported by generous philanthropic support from the Moceri Family Foundation and the Panattoni family. V.A.A. is financially supported by the Mexican government through the Mexican National Council for Science and Technology (CONACYT) and the Plan of Combined Studies in Medicine (PECEM) of the National Autonomous University of Mexico (UNAM). M. McCord is supported by the F32 award 1F32CA264883. We thank J. Walshon, A. Steffens, and M. Santa Flowers from the Nervous System Tumor Bank supported by the P50CA221747 SPORE for Translational Approaches to Brain Cancer. Multiplex Immunofluorescence was performed at the Immunotherapy assessment core at Northwestern University. Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. This work was supported by the Northwestern University\u2014Flow Cytometry Core Facility supported by Cancer Center Support Grant (NCI CA060553). We thank B. Frederick, B. Shmaltsuyeva, and H. Fan at the Northwestern University Pathology Core Facility funded by the Cancer Center Support Grant (no. NCI CA060553). Most importantly, we thank the patients and their families for their contribution to this research.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Arrieta, V. A., Gould, A., Kim, K. S., Habashy, K. J., Dmello, C., Vázquez-Cervantes, G. I., Palacín-Aliana, I., McManus, G., Amidei, C., Gomez, C., Dhiantravan, S., Chen, L., Zhang, D. Y., Saganty, R., Cholak, M. E., Pandey, S., McCord, M., McCortney, K., Castro, B., ... Sonabend, A. M. (2024). Ultrasound-mediated delivery of doxorubicin to the brain results in immune modulation and improved responses to PD-1 blockade in gliomas. Nature communications, 15(1), Article 4698. https://doi.org/10.1038/s41467-024-48326-w

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title = "Ultrasound-mediated delivery of doxorubicin to the brain results in immune modulation and improved responses to PD-1 blockade in gliomas",

abstract = "Given the marginal penetration of most drugs across the blood-brain barrier, the efficacy of various agents remains limited for glioblastoma (GBM). Here we employ low-intensity pulsed ultrasound (LIPU) and intravenously administered microbubbles (MB) to open the blood-brain barrier and increase the concentration of liposomal doxorubicin and PD-1 blocking antibodies (aPD-1). We report results on a cohort of 4 GBM patients and preclinical models treated with this approach. LIPU/MB increases the concentration of doxorubicin by 2-fold and 3.9-fold in the human and murine brains two days after sonication, respectively. Similarly, LIPU/MB-mediated blood-brain barrier disruption leads to a 6-fold and a 2-fold increase in aPD-1 concentrations in murine brains and peritumoral brain regions from GBM patients treated with pembrolizumab, respectively. Doxorubicin and aPD-1 delivered with LIPU/MB upregulate major histocompatibility complex (MHC) class I and II in tumor cells. Increased brain concentrations of doxorubicin achieved by LIPU/MB elicit IFN-γ and MHC class I expression in microglia and macrophages. Doxorubicin and aPD-1 delivered with LIPU/MB results in the long-term survival of most glioma-bearing mice, which rely on myeloid cells and lymphocytes for their efficacy. Overall, this translational study supports the utility of LIPU/MB to potentiate the antitumoral activities of doxorubicin and aPD-1 for GBM.",

author = "Arrieta, {V{\'i}ctor A.} and Andrew Gould and Kim, {Kwang Soo} and Habashy, {Karl J.} and Crismita Dmello and V{\'a}zquez-Cervantes, {Gustavo I.} and Irina Palac{\'i}n-Aliana and Graysen McManus and Christina Amidei and Cristal Gomez and Silpol Dhiantravan and Li Chen and Zhang, {Daniel Y.} and Ruth Saganty and Cholak, {Meghan E.} and Surya Pandey and Matthew McCord and Kathleen McCortney and Brandyn Castro and Rachel Ward and Miguel Muzzio and Guillaume Bouchoux and Carole Desseaux and Michael Canney and Alexandre Carpentier and Bin Zhang and Miska, {Jason M.} and Lesniak, {Maciej S.} and Horbinski, {Craig M.} and Lukas, {Rimas V.} and Roger Stupp and Catalina Lee-Chang and Sonabend, {Adam M.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1038/s41467-024-48326-w",

language = "English (US)",

volume = "15",

journal = "Nature communications",

issn = "2041-1723",

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Arrieta, VA, Gould, A, Kim, KS, Habashy, KJ, Dmello, C, Vázquez-Cervantes, GI, Palacín-Aliana, I, McManus, G, Amidei, C, Gomez, C, Dhiantravan, S, Chen, L, Zhang, DY, Saganty, R, Cholak, ME, Pandey, S, McCord, M, McCortney, K, Castro, B, Ward, R, Muzzio, M, Bouchoux, G, Desseaux, C, Canney, M, Carpentier, A, Zhang, B , Miska, JM, Lesniak, MS, Horbinski, CM , Lukas, RV , Stupp, R , Lee-Chang, C & Sonabend, AM 2024, 'Ultrasound-mediated delivery of doxorubicin to the brain results in immune modulation and improved responses to PD-1 blockade in gliomas', Nature communications, vol. 15, no. 1, 4698. https://doi.org/10.1038/s41467-024-48326-w

TY - JOUR

T1 - Ultrasound-mediated delivery of doxorubicin to the brain results in immune modulation and improved responses to PD-1 blockade in gliomas

AU - Arrieta, Víctor A.

AU - Gould, Andrew

AU - Kim, Kwang Soo

AU - Habashy, Karl J.

AU - Dmello, Crismita

AU - Vázquez-Cervantes, Gustavo I.

AU - Palacín-Aliana, Irina

AU - McManus, Graysen

AU - Amidei, Christina

AU - Gomez, Cristal

AU - Dhiantravan, Silpol

AU - Chen, Li

AU - Zhang, Daniel Y.

AU - Saganty, Ruth

AU - Cholak, Meghan E.

AU - Pandey, Surya

AU - McCord, Matthew

AU - McCortney, Kathleen

AU - Castro, Brandyn

AU - Ward, Rachel

AU - Muzzio, Miguel

AU - Bouchoux, Guillaume

AU - Desseaux, Carole

AU - Canney, Michael

AU - Carpentier, Alexandre

AU - Zhang, Bin

AU - Miska, Jason M.

AU - Lesniak, Maciej S.

AU - Horbinski, Craig M.

AU - Lukas, Rimas V.

AU - Stupp, Roger

AU - Lee-Chang, Catalina

AU - Sonabend, Adam M.

PY - 2024/12

Y1 - 2024/12

N2 - Given the marginal penetration of most drugs across the blood-brain barrier, the efficacy of various agents remains limited for glioblastoma (GBM). Here we employ low-intensity pulsed ultrasound (LIPU) and intravenously administered microbubbles (MB) to open the blood-brain barrier and increase the concentration of liposomal doxorubicin and PD-1 blocking antibodies (aPD-1). We report results on a cohort of 4 GBM patients and preclinical models treated with this approach. LIPU/MB increases the concentration of doxorubicin by 2-fold and 3.9-fold in the human and murine brains two days after sonication, respectively. Similarly, LIPU/MB-mediated blood-brain barrier disruption leads to a 6-fold and a 2-fold increase in aPD-1 concentrations in murine brains and peritumoral brain regions from GBM patients treated with pembrolizumab, respectively. Doxorubicin and aPD-1 delivered with LIPU/MB upregulate major histocompatibility complex (MHC) class I and II in tumor cells. Increased brain concentrations of doxorubicin achieved by LIPU/MB elicit IFN-γ and MHC class I expression in microglia and macrophages. Doxorubicin and aPD-1 delivered with LIPU/MB results in the long-term survival of most glioma-bearing mice, which rely on myeloid cells and lymphocytes for their efficacy. Overall, this translational study supports the utility of LIPU/MB to potentiate the antitumoral activities of doxorubicin and aPD-1 for GBM.

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ER -

Ultrasound-mediated delivery of doxorubicin to the brain results in immune modulation and improved responses to PD-1 blockade in gliomas

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