title: Immune modulation associated with vascular endothelial growth factor (VEGF) blockade in patients with glioblastoma.
abstract: BACKGROUND
  Vascular endothelial growth factor (VEGF), in addition to being pro-angiogenic, is an immunomodulatory cytokine systemically and in the tumor microenvironment. We previously reported the immunomodulatory effects of radiation and temozolomide (TMZ) in newly diagnosed glioblastoma. This study aimed to assess changes in peripheral blood mononuclear cell (PBMC) populations, plasma cytokines, and growth factor concentrations following treatment with radiation, TMZ, and bevacizumab (BEV).
  
  
  METHODS
  Eleven patients with newly diagnosed glioblastoma were treated with radiation, TMZ, and BEV, following surgery. We measured immune-related PBMC subsets using multi-parameter flow cytometry and plasma cytokine and growth factor concentrations using electrochemiluminescence-based multiplex analysis at baseline and after 6 weeks of treatment.
  
  
  RESULTS
  The absolute number of peripheral blood regulatory T cells (Tregs) decreased significantly following treatment. The lower number of peripheral Tregs was associated with a CD4+ lymphopenia, and thus, the ratio of Tregs to PBMCs was unchanged. The addition of bevacizumab to standard radiation and temozolomide led to the decrease in the number of circulating Tregs when compared with our prior study. There was a significant decrease in CD8+ cytotoxic and CD4+ recent thymic emigrant T cells, but no change in the number of myeloid-derived suppressor cells. Significant increases in plasma VEGF and placental growth factor (PlGF) concentrations were observed.
  
  
  CONCLUSIONS
  Treatment with radiation, TMZ, and BEV decreased the number but not the proportion of peripheral Tregs and increased the concentration of circulating VEGF. This shift in the peripheral immune cell profile may modulate the tumor environment and have implications for combining immunotherapy with anti-angiogenic therapy.
authors.affiliation: University of Vermont College of Medicine and University of Vermont Cancer Center, Burlington, VT, USA.
authors.forename: Alissa A
authors.initials: AA
authors.lastname: Thomas
authors.affiliation: Geisel School of Medicine at Dartmouth and The Norris Cotton Cancer Center at Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.
authors.forename: Jan L
authors.initials: JL
authors.lastname: Fisher
authors.affiliation: Geisel School of Medicine at Dartmouth and The Norris Cotton Cancer Center at Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Hampton
authors.affiliation: Geisel School of Medicine at Dartmouth and The Norris Cotton Cancer Center at Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.
authors.forename: Brock C
authors.initials: BC
authors.lastname: Christensen
authors.affiliation: Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Tsongalis
authors.affiliation: Geisel School of Medicine at Dartmouth and The Norris Cotton Cancer Center at Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.
authors.forename: Gilbert J
authors.initials: GJ
authors.lastname: Rahme
authors.affiliation: Geisel School of Medicine at Dartmouth and The Norris Cotton Cancer Center at Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.
authors.forename: Chery A
authors.initials: CA
authors.lastname: Whipple
authors.affiliation: Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Steel
authors.affiliation: Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Davis
authors.affiliation: Geisel School of Medicine at Dartmouth and The Norris Cotton Cancer Center at Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.
authors.forename: Arti B
authors.initials: AB
authors.lastname: Gaur
authors.affiliation: Geisel School of Medicine at Dartmouth and The Norris Cotton Cancer Center at Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.
authors.forename: Lionel D
authors.initials: LD
authors.lastname: Lewis
authors.affiliation: Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Ernstoff
authors.affiliation: Division of Neuro-Oncology, Department of Neurology, University of Virginia School of Medicine, P.O. Box 800432, Charlottesville, VA, 22908, USA. CEF3W@virginia.edu.
authors.forename: Camilo E
authors.initials: CE
authors.lastname: Fadul
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D001932:Brain Neoplasms / Q000097:blood / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D059248:Chemoradiotherapy; D016207:Cytokines / Q000097:blood; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000097:blood / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000528:radiation effects; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000528:radiation effects; D000077204:Temozolomide; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D016207:Cytokines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D003606:Dacarbazine; D000077204:Temozolomide
keywords: Bevacizumab; Glioblastoma; Immune modulation; Tregs; VEGF