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Immune modulation associated with vascular endothelial growth factor (VEGF) blockade in patients with glioblastoma

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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.

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Abbreviations

ACD:

Acid, citrate, dextrose

BEV:

Bevacizumab

bFGF:

Beta-fibroblast growth factor

CBC:

Complete blood count

CD:

Cluster of differentiation

CTCAE:

Common terminology criteria for adverse events

CTEP:

Cancer therapy evaluation program

DC:

Dendritic cell

FDA:

Federal Drug Administration

FOXP3:

Forkhead box P3

GMCSF:

Granulocyte–monocyte colony-stimulating factor

HIF:

Hypoxia-inducible factor

HLA:

Human leukocyte antigen

IgG:

Immunoglobulin G

IL:

Interleukin

KPS:

Karnofsky performance scale

L/D:

Live/dead

MDSC:

Myeloid-derived suppressor cell

MSD:

MESO Scale Discovery

NCI:

National Cancer Institute

OS:

Overall survival

PBMC:

Peripheral blood mononuclear cell

PBS:

Phosphate buffered saline

PFS:

Progression-free survival

PlGF:

Placental growth factor

RT:

Radiation therapy

SDF-1α:

Stromal cell-derived factor 1-alpha

sFlt-1:

Soluble fms-like tyrosine kinase 1

STAT3:

Signal transducer and activator of transcription

TMZ:

Temozolomide

TNFα:

Tumor necrosis factor alpha

Tregs:

Regulatory T cells

VEGF:

Vascular endothelial growth factor

VEGFR:

Vascular endothelial growth factor receptor

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Acknowledgements

We would like to thank DartLab: Immunoassay and Flow Cytometry Shared Resource at The Norris Cotton Cancer Center and Geisel School of Medicine at Dartmouth, for the use of the MacsQuant10 flow cytometer and the MSD Sector Imager 2400 instrument. The DartLab is supported in part by the National Cancer Institute (NCI, 5 P30 CA023108-36) and the National Institute of General Medical Sciences (NIGMS, 8 P30 GM103415-14) Grants awarded to the Norris Cotton Cancer Center. This work was supported by grants to Camilo Fadul from Genentech and the Norris Cotton Cancer Center Brain Tumor Research Fund. Lionel Lewis was supported in part by the National Cancer Institute (NCI, 5 P30 CA023108-36) and by the National Center for Advancing Translational Sciences (NCATS, U10 CA151662-03) through the National Institutes of Health. Thomas Hampton was supported in part by the National Institutes of Health (NIH, RO1 HL074175).

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Authors and Affiliations

  1. University of Vermont College of Medicine and University of Vermont Cancer Center, Burlington, VT, USA

    Alissa A. Thomas

  2. Geisel School of Medicine at Dartmouth and The Norris Cotton Cancer Center at Dartmouth Hitchcock Medical Center, Lebanon, NH, USA

    Jan L. Fisher, Thomas H. Hampton, Brock C. Christensen, Gilbert J. Rahme, Chery A. Whipple, Arti B. Gaur & Lionel D. Lewis

  3. Dartmouth Hitchcock Medical Center, Lebanon, NH, USA

    Gregory J. Tsongalis, Sandra E. Steel & Melissa C. Davis

  4. Roswell Park Cancer Institute, Buffalo, NY, USA

    Marc S. Ernstoff

  5. Division of Neuro-Oncology, Department of Neurology, University of Virginia School of Medicine, P.O. Box 800432, Charlottesville, VA, 22908, USA

    Camilo E. Fadul

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  1. Alissa A. Thomas
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  2. Jan L. Fisher
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Correspondence to Camilo E. Fadul.

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Thomas, A.A., Fisher, J.L., Hampton, T.H. et al. Immune modulation associated with vascular endothelial growth factor (VEGF) blockade in patients with glioblastoma. Cancer Immunol Immunother 66, 379–389 (2017). https://doi.org/10.1007/s00262-016-1941-3

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