Blood-brain barrier permeable nano immunoconjugates induce local immune responses for glioma therapy.

Autor:	Galstyan A; Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, AHSP, Los Angeles, CA, 90048, USA., Markman JL; Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, AHSP, Los Angeles, CA, 90048, USA., Shatalova ES; Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, AHSP, Los Angeles, CA, 90048, USA., Chiechi A; Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, AHSP, Los Angeles, CA, 90048, USA., Korman AJ; Bristol-Myers Squibb, 700 Bay Road, Redwood City, CA, 94063, USA., Patil R; Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, AHSP, Los Angeles, CA, 90048, USA., Klymyshyn D; Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, AHSP, Los Angeles, CA, 90048, USA., Tourtellotte WG; Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd., ST 8719, West Hollywood, CA, 90048, USA.; Department of Biomedical Sciences, Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, AHSP, Los Angeles, CA, 90048, USA.; Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA., Israel LL; Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, AHSP, Los Angeles, CA, 90048, USA., Braubach O; Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, AHSP, Los Angeles, CA, 90048, USA., Ljubimov VA; Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, AHSP, Los Angeles, CA, 90048, USA., Mashouf LA; Harvard Medical School, 25 Shattuck Street, Boston, MA, 02115, USA., Ramesh A; University of California, Los Angeles (UCLA), 621 Charles E Young Dr S, Los Angeles, CA, 90095, USA., Grodzinski ZB; Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, AHSP, Los Angeles, CA, 90048, USA., Penichet ML; Division of Surgical Oncology, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles (UCLA), 10833 Le Conte Ave, Los Angeles, CA, 90095, USA.; Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA, USA.; Jonsson Comprehensive Cancer Center, University of California, Los Angeles (UCLA), 10833 Le Conte Ave, Los Angeles, CA, 90095, USA.; The Molecular Biology Institute, University of California, Los Angeles (UCLA), 611 Charles E Young Dr E, Los Angeles, CA, 90095, USA.; AIDS Institute, University of California, Los Angeles (UCLA), 10940 Wilshire Blvd Suite 960, Los Angeles, CA, 90024, USA.; The California NanoSystems Institute, University of California, Los Angeles (UCLA), 570 Westwood Plaza Building 114, Los Angeles, CA, 90095, USA., Black KL; Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, AHSP, Los Angeles, CA, 90048, USA., Holler E; Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, AHSP, Los Angeles, CA, 90048, USA.; Institut für Biophysik und Physikalische Biochemie, Universität Regensburg, Regensburg, D-93040, Germany., Sun T; Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, AHSP, Los Angeles, CA, 90048, USA., Ding H; Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, AHSP, Los Angeles, CA, 90048, USA., Ljubimov AV; Department of Biomedical Sciences, Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, AHSP, Los Angeles, CA, 90048, USA., Ljubimova JY; Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, AHSP, Los Angeles, CA, 90048, USA. Ljubimovaj@cshs.org.; Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA. Ljubimovaj@cshs.org.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2019 Aug 28; Vol. 10 (1), pp. 3850. Date of Electronic Publication: 2019 Aug 28.
DOI:	10.1038/s41467-019-11719-3
Abstrakt:	Brain glioma treatment with checkpoint inhibitor antibodies to cytotoxic T-lymphocyte-associated antigen 4 (a-CTLA-4) and programmed cell death-1 (a-PD-1) was largely unsuccessful due to their inability to cross blood-brain barrier (BBB). Here we describe targeted nanoscale immunoconjugates (NICs) on natural biopolymer scaffold, poly(β-L-malic acid), with covalently attached a-CTLA-4 or a-PD-1 for systemic delivery across the BBB and activation of local brain anti-tumor immune response. NIC treatment of mice bearing intracranial GL261 glioblastoma (GBM) results in an increase of CD8+ T cells, NK cells and macrophages with a decrease of regulatory T cells (Tregs) in the brain tumor area. Survival of GBM-bearing mice treated with NIC combination is significantly longer compared to animals treated with single checkpoint inhibitor-bearing NICs or free a-CTLA-4 and a-PD-1. Our study demonstrates trans-BBB delivery of tumor-targeted polymer-conjugated checkpoint inhibitors as an effective GBM treatment via activation of both systemic and local privileged brain tumor immune response.
Databáze:	MEDLINE
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