Evidence map›Paper›PMID 27044098›Full record

ArticleProceedings of the National Academy of Sciences of the United States of America2016

Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival.

Jonas Kloepper, Lars Riedemann, Zohreh Amoozgar, Giorgio Seano, Katharina Susek, Veronica Yu, Nisha Dalvie, Robin L Amelung, Meenal Datta, Jonathan W Song and 17 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 213 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
213citing papers in PubMed, 2 pooled it
19.4field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

213 citing papers in PubMed, 2 syntheses or guidelines pooled it, 351 citations in OpenAlex.

  1. Pooled it
  2. Targeting autophagy for combating chemoresistance and radioresistance in glioblastoma.Apoptosis : an international journal on programmed cell death · 2018
    Pooled it
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  11. Physiologically based pharmacokinetic model for CAR-T cell delivery and efficacy in solid tumors.Proceedings of the National Academy of Sciences of the United States of America · 2025
    Article
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  17. Wnt inhibition alleviates resistance to anti-PD1 therapy and improves antitumor immunity in glioblastoma.Proceedings of the National Academy of Sciences of the United States of America · 2025
    Article
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  20. Solid Stress Estimations via Intraoperative 3D Navigation in Patients with Brain Tumors.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025
    Article

153 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

27 authors at 4 institutions in 2 countries.

Jonas KloepperEdwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
Lars RiedemannEdwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
Zohreh AmoozgarEdwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
Giorgio SeanoEdwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
Katharina SusekEdwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
Veronica YuEdwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
Nisha DalvieEdwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
Robin L AmelungEdwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
Meenal DattaEdwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; Department of Chemical and Biological Engineering, Tufts University, Medford, MA 02155;
Jonathan W SongEdwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
Vasileios AskoxylakisEdwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
Jennie W TaylorEdwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; Stephen E. and Catherine Pappas Center for Neuro-Oncology, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
Christine Lu-EmersonEdwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; Stephen E. and Catherine Pappas Center for Neuro-Oncology, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
Ana BatistaEdwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
Nathaniel D KirkpatrickEdwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
Keehoon JungEdwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
Matija SnuderlEdwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
Alona MuzikanskyBiostatistics Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
Kay G StubenrauchRoche Pharma Research and Early Development, Roche Innovation Center Munich, 82377 Penzberg, Germany;
Oliver KrieterRoche Pharma Research and Early Development, Roche Innovation Center Munich, 82377 Penzberg, Germany;
Hiroaki WakimotoDepartment of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
Lei Xu
Lance L MunnEdwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
Dan G DudaEdwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
Dai FukumuraEdwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
Tracy T BatchelorStephen E. and Catherine Pappas Center for Neuro-Oncology, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; tbatchelor@mgh.harvard.edu jain@steele.mgh.harvard.edu.
Rakesh K JainEdwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; tbatchelor@mgh.harvard.edu jain@steele.mgh.harvard.edu.
Massachusetts General Hospital · USHarvard University · USRoche Pharma AG (Germany) · DECenter for Neuro-Oncology · US

Funding

Vascular Normalization: Rolse of Perivascular CellsP01CA080124 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI JAIN, RAKESH K. · 2000 to 2016
$35.0M
Targeting the Vasular SystemP50CA165962 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI Benjamin Harris Kann · 2013 to 2026
$33.5M
Training Program in Nervous System TumorsK12CA090354 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI PLOTKIN, SCOTT R · 2001 to 2025
$16.3M
Probing Tumor Microenvironment Using NanotechnologyR01CA126642 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI JAIN, RAKESH K. · 2008 to 2012
$8.3M
Dissecting Pediatric Brain Tumor Microenvironment to Improve TreatmentR35CA197743 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI JAIN, RAKESH K. · 2015 to 2020
$5.7M
NO in Tumor Angiogenesis,Microcirculation &Rad.TherapyR01CA096915 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI FUKUMURA, DAI · 2002 to 2012
$3.0M
Training Program in Pathophysiology of Solid TumorsT32CA073479 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI JAIN, RAKESH K. · 1998 to 2012
$3.0M
Clinical and Molecular Studies of Novel Therapeutics in Malignant Brain TumorsK24CA125440 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI BATCHELOR, TRACY T · 2007 to 2016
$1.9M
Role of SDF1a pathway in prostate cancer relapse and metastasis post-radiotherapyR01CA159258 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI DUDA, DAN GABRIEL · 2011 to 2015
$1.6M
Encouraging anastomosis of engrafted vascular networksR01HL106584 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI MUNN, LANCE L. · 2012 to 2015
$1.3M
Doppler Optical Frequency Domain Imaging InstrumentS10RR027070 · NCRR · MASSACHUSETTS GENERAL HOSPITAL · PI FUKUMURA, DAI · 2010 to 2010
$260k
NCI NIH HHS K12 CA090354NCI NIH HHS K12CA090354NCI NIH HHS K24 CA125440NCI NIH HHS P01 CA080124NCI NIH HHS P01CA080124NCI NIH HHS P50 CA165962NCI NIH HHS P50CA165962NCI NIH HHS R01 CA096915NCI NIH HHS R01CA096915NCI NIH HHS R01 CA126642NCI NIH HHS R01CA126642NCI NIH HHS R01 CA159258NCI NIH HHS R01CA159258NCI NIH HHS R35 CA197743NCI NIH HHS R35CA197743NCI NIH HHS T32 CA073479NCI NIH HHS T32-CA073479NCRR NIH HHS S10 RR027070NCRR NIH HHS S10-RR027070NHLBI NIH HHS R01 HL106584NHLBI NIH HHS R01HL106584PHS HHS KCA125440
6 · The paper itself

Abstract

Inhibition of the vascular endothelial growth factor (VEGF) pathway has failed to improve overall survival of patients with glioblastoma (GBM). We previously showed that angiopoietin-2 (Ang-2) overexpression compromised the benefit from anti-VEGF therapy in a preclinical GBM model. Here we investigated whether dual Ang-2/VEGF inhibition could overcome resistance to anti-VEGF treatment. We treated mice bearing orthotopic syngeneic (Gl261) GBMs or human (MGG8) GBM xenografts with antibodies inhibiting VEGF (B20), or Ang-2/VEGF (CrossMab, A2V). We examined the effects of treatment on the tumor vasculature, immune cell populations, tumor growth, and survival in both the Gl261 and MGG8 tumor models. We found that in the Gl261 model, which displays a highly abnormal tumor vasculature, A2V decreased vessel density, delayed tumor growth, and prolonged survival compared with B20. In the MGG8 model, which displays a low degree of vessel abnormality, A2V induced no significant changes in the tumor vasculature but still prolonged survival. In both the Gl261 and MGG8 models A2V reprogrammed protumor M2 macrophages toward the antitumor M1 phenotype. Our findings indicate that A2V may prolong survival in mice with GBM by reprogramming the tumor immune microenvironment and delaying tumor growth.

Indexed as

AnimalsAntibodies, BispecificAntibodies, NeoplasmAntineoplastic AgentsCell Line, TumorGlioblastomaHumansMacrophagesMiceNeoplasm ProteinsNeoplasms, ExperimentalRibonuclease, PancreaticVascular Endothelial Growth Factor AVesicular Transport ProteinsXenograft Model Antitumor AssaysAng2 protein, mouseAntibodies, BispecificAntibodies, NeoplasmAntineoplastic AgentsNeoplasm ProteinsRibonuclease, PancreaticVascular Endothelial Growth Factor Avascular endothelial growth factor A, mouseVEGFA protein, humanVesicular Transport ProteinsVPS51 protein, humananti-angiogenic therapyanti-tumor immunitymacrophage polarizationmicroglia reprogrammingtumor microenvironment

Identifiers

PMID27044098
PMCPMC4843473
OpenAlexW2326749252

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.