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

Anna Galstyan, Janet L. Markman, Ekaterina S. Shatalova, Antonella Chiechi, Alan J. Korman, Rameshwar Patil, Dmytro Klymyshyn, Warren G. Tourtellotte, Liron L. Israel, Oliver Braubach, Vladimir A. Ljubimov, Leila A. Mashouf, Arshia Ramesh, Zachary B. Grodzinski, Manuel L. Penichet, Keith L. Black, Eggehard Holler, Tao Sun, Hui Ding, Alexander V. Ljubimov and Julia Y. Ljubimova ()
Additional contact information
Anna Galstyan: Cedars-Sinai Medical Center
Janet L. Markman: Cedars-Sinai Medical Center
Ekaterina S. Shatalova: Cedars-Sinai Medical Center
Antonella Chiechi: Cedars-Sinai Medical Center
Alan J. Korman: Bristol-Myers Squibb
Rameshwar Patil: Cedars-Sinai Medical Center
Dmytro Klymyshyn: Cedars-Sinai Medical Center
Warren G. Tourtellotte: Cedars-Sinai Medical Center
Liron L. Israel: Cedars-Sinai Medical Center
Oliver Braubach: Cedars-Sinai Medical Center
Vladimir A. Ljubimov: Cedars-Sinai Medical Center
Leila A. Mashouf: Harvard Medical School
Arshia Ramesh: University of California, Los Angeles (UCLA)
Zachary B. Grodzinski: Cedars-Sinai Medical Center
Manuel L. Penichet: David Geffen School of Medicine at University of California, Los Angeles (UCLA)
Keith L. Black: Cedars-Sinai Medical Center
Eggehard Holler: Cedars-Sinai Medical Center
Tao Sun: Cedars-Sinai Medical Center
Hui Ding: Cedars-Sinai Medical Center
Alexander V. Ljubimov: Cedars-Sinai Medical Center
Julia Y. Ljubimova: Cedars-Sinai Medical Center

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-11719-3

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