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@ARTICLE{DiTacchio:148865,
author = {M. Di Tacchio$^*$ and J. Macas and J. Weissenberger and K.
Sommer and O. Bähr$^*$ and J. P. Steinbach$^*$ and C.
Senft$^*$ and V. Seifert$^*$ and M. Glas$^*$ and U.
Herrlinger and D. Krex$^*$ and M. Meinhardt and A.
Weyerbrock and M. Timmer and R. Goldbrunner and M. Deckert
and A. H. Scheel and R. Büttner and O. M. Grauer and J.
Schittenhelm and G. Tabatabai$^*$ and P. Harter$^*$ and S.
Günther and K. Devraj and K. H. Plate$^*$ and Y. Reiss$^*$},
title = {{T}umor {V}essel {N}ormalization, {I}mmunostimulatory
{R}eprogramming, and {I}mproved {S}urvival in {G}lioblastoma
with {C}ombined {I}nhibition of {PD}-1, {A}ngiopoietin-2,
and {VEGF}.},
journal = {Cancer immunology research},
volume = {7},
number = {12},
issn = {2326-6074},
address = {Philadelphia, Pa.},
publisher = {AACR},
reportid = {DKFZ-2020-00057},
pages = {1910 - 1927},
year = {2019},
abstract = {Glioblastoma (GBM) is a non-T-cell-inflamed cancer
characterized by an immunosuppressive microenvironment that
impedes dendritic cell maturation and T-cell cytotoxicity.
Proangiogenic cytokines such as VEGF and angiopoietin-2
(Ang-2) have high expression in glioblastoma in a
cell-specific manner and not only drive tumor angiogenesis
and vascular permeability but also negatively regulate
T-lymphocyte and innate immune cell responses. Consequently,
the alleviation of immunosuppression might be a prerequisite
for successful immune checkpoint therapy in GBM. We here
combined antiangiogenic and immune checkpoint therapy and
demonstrated improved therapeutic efficacy in syngeneic,
orthotopic GBM models. We observed that blockade of VEGF,
Ang-2, and programmed cell death protein-1 (PD-1)
significantly extended survival compared with vascular
targeting alone. In the GBM microenvironment, triple therapy
increased the numbers of CTLs, which inversely correlated
with myeloid-derived suppressor cells and regulatory T
cells. Transcriptome analysis of GBM microvessels indicated
a global vascular normalization that was highest after
triple therapy. Our results propose a rationale to overcome
tumor immunosuppression and the current limitations of VEGF
monotherapy by integrating the synergistic effects of
VEGF/Ang-2 and PD-1 blockade to reinforce antitumor immunity
through a normalized vasculature.},
cin = {L501 / L401 / L301 / L801},
ddc = {610},
cid = {I:(DE-He78)L501-20160331 / I:(DE-He78)L401-20160331 /
I:(DE-He78)L301-20160331 / I:(DE-He78)L801-20160331},
pnm = {899 - ohne Topic (POF3-899)},
pid = {G:(DE-HGF)POF3-899},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:31597643},
doi = {10.1158/2326-6066.CIR-18-0865},
url = {https://inrepo02.dkfz.de/record/148865},
}