Nov 9, 2018

Nano immunoconjugates crossing blood-brain barrier activate local brain tumor immune system for glioma treatment

BioRxiv : the Preprint Server for Biology
Anna GalstyanJulia Y Ljubimova

Abstract

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(beta-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.

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Mentioned in this Paper

Study
Immune Response
Immune System
Blood - Brain Barrier Anatomy
T-Lymphocyte
Immune Response to Tumor Cell
Brain
MALIC ACID, L-
Cytotoxic T-Lymphocytes
Ir1

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