RT Journal Article
SR Electronic
T1 Nano immunoconjugates crossing blood-brain barrier activate local brain tumor immune system for glioma treatment
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 466508
DO 10.1101/466508
A1 Anna Galstyan
A1 Antonella Chiechi
A1 Alan J. Korman
A1 Tao Sun
A1 Liron L. Israel
A1 Oliver Braubach
A1 Rameshwar Patil
A1 Ekaterina Shatalova
A1 Vladimir A. Ljubimov
A1 Janet Markman
A1 Zachary Grodzinski
A1 Keith L. Black
A1 Manuel L. Penichet
A1 Eggehard Holler
A1 Alexander V. Ljubimov
A1 Hui Ding
A1 Julia Y. Ljubimova
YR 2018
UL http://biorxiv.org/content/early/2018/11/09/466508.abstract
AB Treatment of brain gliomas 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 the blood-brain barrier (BBB). We describe a new generation of nano immunoconjugates (NICs) developed on natural biopolymer scaffold, poly(β-L-malic acid), with covalently attached a-CTLA-4 and/or a-PD-1 for delivery across the BBB and activation of local brain anti-tumor immune response in glioma-bearing mice. NIC treatment of mice bearing intracranial GL261 glioblastoma (GBM) resulted in an increase of CD8+ T-cells with a decrease of T regulatory cells (Tregs) in the brain tumor area. Survival of GBM-bearing mice treated with combination of NICs was significantly longer compared to animals treated by single checkpoint inhibitor-bearing NICs or free a-CTLA-4 and a-PD-1. Our study demonstrates trans-BBB delivery of nanopolymer-conjugated checkpoint inhibitors as an effective treatment of GBM via activation of both systemic and local brain tumor immune response.