@article{b053b7b310ec46cf92dbbcce255e2098,
title = "Opening of the blood–brain barrier using low-intensity pulsed ultrasound enhances responses to immunotherapy in preclinical glioma models",
abstract = "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.",
author = "Aria Sabbagh and Kevin Beccaria and Xiaoyang Ling and Anantha Marisetty and Martina Ott and Hillary Caruso and Emily Barton and Kong, {Ling Yuan} and Dexing Fang and Khatri Latha and Zhang, {Daniel Yang} and Jun Wei and John DeGroot and Curran, {Michael A.} and Ganesh Rao and Jian Hu and Carole Desseaux and Guillaume Bouchoux and Michael Canney and Alexandre Carpentier and Heimberger, {Amy B.}",
note = "Funding Information: The authors acknowledge graphic designer Quentin Beccaria for his help in creating Fig. 6, as well as Laura Russell, ELS and Audria Patrick for editorial and administrative support. Funding was provided by the ReMission Alliance Against Brain Tumors, Traver Walsh Foundation, the Anne C. Brooks and Anthony D. Bullock Foundation, the MD Anderson Cancer Center Provost Fund, and NIH/NCI P30CA016672. Funding was not provided by CarThera for this study. Funding Information: K. Beccaria reports a patent for Apparatus for the treatment of brain affections and method implementing thereof issued. H. Caruso reports personal fees from Intrexon Corporation and Ziopharm Oncology during the conduct of the study; personal fees from Intrexon Corporation and Ziopharm Oncology outside the submitted work; in addition, H. Caruso has a patent for US20170158749A1 pending to Intrexon Corporation and Ziopharm Oncology. J.F. de Groot reports grants from CarThera, HaiHe Pharma, and Taiho Pharma, other support from Ziopharm Oncology, WuXi Biologics, and Gilead, personal fees from Del Mar Pharmaceuticals (BC) Ltd, Samus Therapeutics, Inc., Insightec, Bioasis Technologies, Inc., Magnolia Innovation, LLC, Monteris Medical Corporation, Karyopharm Therapeutics Inc., Mundipharma Research Limited, Prelude Therapeutics, Kiyatec, Cure Brain Cancer Foundation, Merck Sharp & Dohme Co., Sapience Therapeutics, GlaxoSmithKline LLC (GSK), ResTORbio, Inc., Roche, GenomiCare, Tocagen, Voyager Therapeutics, Angios, AbbVie, Kairos Venture Investments, Deciphera Pharmaceuticals, Taiho Pharmaceutical Company, Inc., Janssen Global Services, Novartis, Debiopharm Therapeutics, Inc., Novella Clinical, and Blue Earth Diagnostics outside the submitted work; and spouse employed by Ziopharm Oncology; participated in DSMB: VBI Vaccines, Inc [Glioblastoma (VBI-1901)]. M.A. Curran reports grants and personal fees from ImmunoGenesis, Inc., and ImmunoMet, personal fees from Agenus, Inc., Alligator Bioscience, Inc., ImmunOs, Inc., Oncoresponse, Inc., Pieris, Inc., Nurix, Inc., Aptevo, Inc., Servier, Inc., Kineta, Inc., Salarius, Inc., Xencor, Inc., and Amunix, Inc. outside the submitted work; in addition, M.A. Curran has a patent for Methods and Composition for Localized Secretion of anti–CTLA-4 antibodies issued to multiple licensees and a patent for dual specificity antibodies that bind both PD-L1 and PD-L2 and prevent their binding to PD-1 pending to ImmunoGenesis, Inc. C. Desseaux reports other support from CarThera outside the submitted work. M. Canney reports other support from CarThera during the conduct of the study; in addition, M. Canney has a patent submitted pending. A. Carpentier reports personal fees from CarThera outside the submitted work; in addition, A. Carpentier has a patent for SonoCloud issued and licensed to To CarThera. A.B. Heimberger reports nonfinancial support from CarThera during the conduct of the study; other support from Caris Life Sciences, WCG Oncology Advisory Board (Western IRB), Moleculin, DNAtrix, and Celldex Therapeutics, and grants from Codiak Life Sciences and Celularity outside the submitted work; in addition, A.B. Heimberger has a patent for genetically Publisher Copyright: {\textcopyright} 2021 The Authors; Published by the American Association for Cancer Research.",
year = "2021",
month = aug,
day = "1",
doi = "10.1158/1078-0432.CCR-20-3760",
language = "English (US)",
volume = "27",
pages = "4325--4337",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "15",
}