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. LjubimovJulia Y. Ljubimova

Research output: Contribution to journalArticlepeer-review

203 Scopus citations

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.

Original languageEnglish
Article number3850
JournalNature Communications
Volume10
Issue number1
DOIs
StatePublished - 28 Aug 2019
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2019, The Author(s).

Funding

This work was supported by NIH R01 Grants CA188743, CA 206220, CA 230858 (J.Y. L.), CA 209921 (E.H.), and EY013431 (A.V.L.). The authors thank Gene Arvan (Vir8 Studio Inc, Los Angeles, CA, USA) and Yuliy Vishnevskiy (Los Angeles, CA, USA) for Supplementary Movie 1 representing the treatment technology.

FundersFunder number
National Institutes of HealthCA188743, CA 206220, CA 230858, EY013431
National Cancer InstituteR01CA209921

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