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; Julia Y Ljubimova

doi:10.1038/s41467-019-11719-3

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

Nat Commun. 2019 Aug 28;10(1):3850. doi: 10.1038/s41467-019-11719-3.

Authors

Anna Galstyan¹, Janet L Markman¹, Ekaterina S Shatalova¹, Antonella Chiechi¹, Alan J Korman², Rameshwar Patil¹, Dmytro Klymyshyn¹, Warren G Tourtellotte^{3

4

5}, Liron L Israel¹, Oliver Braubach¹, Vladimir A Ljubimov¹, Leila A Mashouf⁶, Arshia Ramesh⁷, Zachary B Grodzinski¹, Manuel L Penichet^{8

9

10

11

12

13}, Keith L Black¹, Eggehard Holler^{1

14}, Tao Sun¹, Hui Ding¹, Alexander V Ljubimov⁴, Julia Y Ljubimova^{15

16}

Affiliations

¹ Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, AHSP, Los Angeles, CA, 90048, USA.
² Bristol-Myers Squibb, 700 Bay Road, Redwood City, CA, 94063, USA.
³ Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd., ST 8719, West Hollywood, CA, 90048, USA.
⁴ Department of Biomedical Sciences, Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, AHSP, Los Angeles, CA, 90048, USA.
⁵ Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA.
⁶ Harvard Medical School, 25 Shattuck Street, Boston, MA, 02115, USA.
⁷ University of California, Los Angeles (UCLA), 621 Charles E Young Dr S, Los Angeles, CA, 90095, USA.
⁸ 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.
⁹ Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
¹⁰ Jonsson Comprehensive Cancer Center, University of California, Los Angeles (UCLA), 10833 Le Conte Ave, Los Angeles, CA, 90095, USA.
¹¹ The Molecular Biology Institute, University of California, Los Angeles (UCLA), 611 Charles E Young Dr E, Los Angeles, CA, 90095, USA.
¹² AIDS Institute, University of California, Los Angeles (UCLA), 10940 Wilshire Blvd Suite 960, Los Angeles, CA, 90024, USA.
¹³ The California NanoSystems Institute, University of California, Los Angeles (UCLA), 570 Westwood Plaza Building 114, Los Angeles, CA, 90095, USA.
¹⁴ Institut für Biophysik und Physikalische Biochemie, Universität Regensburg, Regensburg, D-93040, Germany.
¹⁵ Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, AHSP, Los Angeles, CA, 90048, USA. Ljubimovaj@cshs.org.
¹⁶ Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA. Ljubimovaj@cshs.org.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Antineoplastic Agents, Immunological / administration & dosage*
Antineoplastic Agents, Immunological / pharmacokinetics
Biopolymers / chemistry
Blood-Brain Barrier / metabolism
Brain Neoplasms / drug therapy*
Brain Neoplasms / immunology
Brain Neoplasms / pathology
CTLA-4 Antigen / antagonists & inhibitors
CTLA-4 Antigen / immunology
Cell Line, Tumor / transplantation
Disease Models, Animal
Female
Glioma / drug therapy*
Glioma / immunology
Glioma / pathology
Humans
Immunoconjugates / administration & dosage*
Immunoconjugates / chemistry
Immunoconjugates / pharmacokinetics
Malates / chemistry
Mice
Nanoconjugates / chemistry*
Permeability
Physarum polycephalum / chemistry
Polymers / chemistry
Programmed Cell Death 1 Receptor / antagonists & inhibitors
Programmed Cell Death 1 Receptor / immunology
Treatment Outcome

Substances

Antineoplastic Agents, Immunological
Biopolymers
CTLA-4 Antigen
Ctla4 protein, mouse
Immunoconjugates
Malates
Nanoconjugates
Pdcd1 protein, mouse
Polymers
Programmed Cell Death 1 Receptor
poly(malic acid)

Abstract

Publication types

MeSH terms

Substances

Grants and funding