title: Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival.
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.
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Jonas
authors.initials: J
authors.lastname: Kloepper
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Lars
authors.initials: L
authors.lastname: Riedemann
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Zohreh
authors.initials: Z
authors.lastname: Amoozgar
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Giorgio
authors.initials: G
authors.lastname: Seano
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Katharina
authors.initials: K
authors.lastname: Susek
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Veronica
authors.initials: V
authors.lastname: Yu
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Nisha
authors.initials: N
authors.lastname: Dalvie
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Robin L
authors.initials: RL
authors.lastname: Amelung
authors.affiliation: Edwin 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;
authors.forename: Meenal
authors.initials: M
authors.lastname: Datta
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Song
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Vasileios
authors.initials: V
authors.lastname: Askoxylakis
authors.affiliation: Edwin 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;
authors.forename: Jennie W
authors.initials: JW
authors.lastname: Taylor
authors.affiliation: Edwin 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;
authors.forename: Christine
authors.initials: C
authors.lastname: Lu-Emerson
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Ana
authors.initials: A
authors.lastname: Batista
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Nathaniel D
authors.initials: ND
authors.lastname: Kirkpatrick
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Keehoon
authors.initials: K
authors.lastname: Jung
authors.affiliation: Edwin 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;
authors.forename: Matija
authors.initials: M
authors.lastname: Snuderl
authors.affiliation: Biostatistics Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Alona
authors.initials: A
authors.lastname: Muzikansky
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Munich, 82377 Penzberg, Germany;
authors.forename: Kay G
authors.initials: KG
authors.lastname: Stubenrauch
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Munich, 82377 Penzberg, Germany;
authors.forename: Oliver
authors.initials: O
authors.lastname: Krieter
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Wakimoto
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Lance L
authors.initials: LL
authors.lastname: Munn
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Dai
authors.initials: D
authors.lastname: Fukumura
authors.affiliation: Stephen 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.
authors.forename: Tracy T
authors.initials: TT
authors.lastname: Batchelor
authors.affiliation: Edwin 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.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000494:pharmacology*; D000912:Antibodies, Neoplasm / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012259:Ribonuclease, Pancreatic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; C467484:VEGFA protein, human; C555023:VPS51 protein, human; D042461:Vascular Endothelial Growth Factor A; D033921:Vesicular Transport Proteins; C467480:vascular endothelial growth factor A, mouse; C099439:Ang2 protein, mouse; D012259:Ribonuclease, Pancreatic
keywords: anti-angiogenic therapy; anti-tumor immunity; macrophage polarization; microglia reprogramming; tumor microenvironment