Opening of the blood–brain barrier using low-intensity pulsed ultrasound enhances responses to immunotherapy in preclinical glioma models

Aria Sabbagh, Kevin Beccaria, Xiaoyang Ling, Anantha Marisetty, Martina Ott, Hillary Caruso, Emily Barton, Ling Yuan Kong, Dexing Fang, Khatri Latha, Daniel Yang Zhang, Jun Wei, John DeGroot, Michael A. Curran, Ganesh Rao, Jian Hu, Carole Desseaux, Guillaume Bouchoux, Michael Canney, Alexandre CarpentierAmy B. Heimberger*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


Purpose: The blood–brain barrier (BBB) inhibits adequate dosing/penetration of therapeutic agents to malignancies in the brain. Low-intensity pulsed ultrasound (LIPU) is a safe therapeutic method of temporary BBB disruption (BBBD) to enhance chemotherapeutic delivery to the tumor and surrounding brain parenchyma for treatment of glioblastoma. Experimental Design: We investigated if LIPU could enhance therapeutic efficacy of anti–PD-1 in C57BL/6 mice bearing intracranial GL261 gliomas, epidermal growth factor receptor variant III (EGFRvIII) chimeric antigen receptor (CAR) T cells in NSG mice with EGFRvIII-U87 gliomas, and a genetically engineered antigen-presenting cell (APC)-based therapy producing the T-cell attracting chemokine CXCL10 in the GL261-bearing mice. Results: Mice treated with anti–PD-1 and LIPU-induced BBBD had a median survival duration of 58 days compared with 39 days for mice treated with anti–PD-1, and long-term survivors all remained alive after contralateral hemisphere rechallenge. CAR T-cell administration with LIPU-induced BBBD resulted in significant increases in CAR T-cell delivery to the CNS after 24 (P < 0.005) and 72 (P < 0.001) hours and increased median survival by greater than 129%, in comparison with CAR T cells alone. Local deposition of CXCL10-secreting APCs in the glioma microenvironment with LIPU enhanced T-cell glioma infiltration during the therapeutic window (P ¼ 0.004) and markedly enhanced survival (P < 0.05). Conclusions: LIPU increases immune therapeutic delivery to the tumor microenvironment with an associated increase in survival and is an emerging technique for enhancing novel therapies in the brain.

Original languageEnglish (US)
Pages (from-to)4325-4337
Number of pages13
JournalClinical Cancer Research
Issue number15
StatePublished - Aug 1 2021
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


Dive into the research topics of 'Opening of the blood–brain barrier using low-intensity pulsed ultrasound enhances responses to immunotherapy in preclinical glioma models'. Together they form a unique fingerprint.

Cite this