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

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

Research output: Contribution to journal › Article › peer-review

266 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 language	English
Article number	3850
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-11719-3
State	Published - 28 Aug 2019
Externally published	Yes

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.

Funders	Funder number
National Institutes of Health	CA188743, CA 206220, CA 230858, EY013431
National Cancer Institute	R01CA209921

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10.1038/s41467-019-11719-3

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Galstyan, A., Markman, J. L., Shatalova, E. S., Chiechi, A., Korman, A. J., Patil, R., Klymyshyn, D., Tourtellotte, W. G., Israel, L. L., Braubach, O., Ljubimov, V. A., Mashouf, L. A., Ramesh, A., Grodzinski, Z. B., Penichet, M. L., Black, K. L., Holler, E., Sun, T., Ding, H., ... Ljubimova, J. Y. (2019). Blood–brain barrier permeable nano immunoconjugates induce local immune responses for glioma therapy. Nature Communications, 10(1), Article 3850. https://doi.org/10.1038/s41467-019-11719-3

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title = "Blood–brain barrier permeable nano immunoconjugates induce local immune responses for glioma therapy",

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.",

author = "Anna Galstyan and Markman, \{Janet L.\} and Shatalova, \{Ekaterina S.\} and Antonella Chiechi and Korman, \{Alan J.\} and Rameshwar Patil and Dmytro Klymyshyn and Tourtellotte, \{Warren G.\} and Israel, \{Liron L.\} and Oliver Braubach and Ljubimov, \{Vladimir A.\} and Mashouf, \{Leila A.\} and Arshia Ramesh and Grodzinski, \{Zachary B.\} and Penichet, \{Manuel L.\} and Black, \{Keith L.\} and Eggehard Holler and Tao Sun and Hui Ding and Ljubimov, \{Alexander V.\} and Ljubimova, \{Julia Y.\}",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = aug,

day = "28",

doi = "10.1038/s41467-019-11719-3",

language = "אנגלית",

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Galstyan, A, Markman, JL, Shatalova, ES, Chiechi, A, Korman, AJ, Patil, R, Klymyshyn, D, Tourtellotte, WG, Israel, LL, Braubach, O, Ljubimov, VA, Mashouf, LA, Ramesh, A, Grodzinski, ZB, Penichet, ML, Black, KL, Holler, E, Sun, T, Ding, H, Ljubimov, AV & Ljubimova, JY 2019, 'Blood–brain barrier permeable nano immunoconjugates induce local immune responses for glioma therapy', Nature Communications, vol. 10, no. 1, 3850. https://doi.org/10.1038/s41467-019-11719-3

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T1 - Blood–brain barrier permeable nano immunoconjugates induce local immune responses for glioma therapy

AU - Galstyan, Anna

AU - Markman, Janet L.

AU - Shatalova, Ekaterina S.

AU - Chiechi, Antonella

AU - Korman, Alan J.

AU - Patil, Rameshwar

AU - Klymyshyn, Dmytro

AU - Tourtellotte, Warren G.

AU - Israel, Liron L.

AU - Braubach, Oliver

AU - Ljubimov, Vladimir A.

AU - Mashouf, Leila A.

AU - Ramesh, Arshia

AU - Grodzinski, Zachary B.

AU - Penichet, Manuel L.

AU - Black, Keith L.

AU - Holler, Eggehard

AU - Sun, Tao

AU - Ding, Hui

AU - Ljubimov, Alexander V.

AU - Ljubimova, Julia Y.

PY - 2019/8/28

Y1 - 2019/8/28

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-019-11719-3

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AN - SCOPUS:85071651368

SN - 2041-1723

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JO - Nature Communications

JF - Nature Communications

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M1 - 3850

ER -

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

Abstract

Bibliographical note

Funding

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