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Disease progression in recurrent glioblastoma patients treated with the VEGFR inhibitor axitinib is associated with increased regulatory T cell numbers and T cell exhaustion

Abstract

Background

Recurrent glioblastoma is associated with a poor overall survival. Antiangiogenic therapy results in a high tumor response rate but has limited impact on survival. Immunotherapy has emerged as an efficient treatment modality for some cancers, and preclinical evidence indicates that anti-VEGF(R) therapy can counterbalance the immunosuppressive tumor microenvironment.

Methods

We collected peripheral blood mononuclear cells (PBMC) of patients with recurrent glioblastoma treated in a randomized phase II clinical trial comparing the effect of axitinib with axitinib plus lomustine and analyzed the immunophenotype of PBMC, the production of cytokines and expression of inhibitory molecules by circulating T cells.

Results

PBMC of 18 patients were collected at baseline and at 6 weeks after initiation of study treatment. Axitinib increased the number of naïve CD8+ T cells and central memory CD4+ and CD8+ T cells and reduced the TIM3 expression on CD4+ and CD8+ T cells. Patients diagnosed with progressive disease on axitinib had a significantly increased number of regulatory T cells and an increased level of PD-1 expression on CD4+ and CD8+ T cells. In addition, reduced numbers of cytokine-producing T cells were found in progressive patients as compared to patients responding to treatment.

Conclusion

Our results suggest that axitinib treatment in patients with recurrent glioblastoma has a favorable impact on immune function. At the time of acquired resistance to axitinib, we documented further enhancement of a preexisting immunosuppression. Further investigations on the role of axitinib as potential combination partner with immunotherapy are necessary.

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Abbreviations

6mPFS:

6-Month progression-free survival

CR:

Complete response

EGFRvIII:

Endothelial growth factor receptor variant III

GBM:

Glioblastoma

LAG3:

Lymphocyte-activation gene 3

ORR:

Objective response rate

PD:

Progressive disease

PDGFR:

Platelet-derived growth factor receptor

PR:

Partial response

SD:

Stable disease

TCM :

Central memory T cells

TEM :

Effector memory T cells

TIM3:

T cell immunoglobulin domain and mucin domain 3

TKI:

Tyrosine kinase inhibitor

Treg :

Regulatory T cells

VEGF:

Vascular endothelial growth factor

VEGFR:

Vascular endothelial growth factor receptor

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Acknowledgments

We would like to acknowledge the patients who consented to participate in this study, their families, and Pfizer Belgium for the provision of axitinib and a research grant for conducting the clinical trial. We would also like to thank the data manager Katrien Van den Bossche and Kathleen Mooren from the University Hospital Brussels (Universitair Ziekenhuis Brussel, UZ Brussel) for their help with the data collection, and Ludwig Van den Hove, PhD, Pfizer Belgium, for his support and critical review of the manuscript. Sarah K Maenhout and Stephanie Du Four are funded by a PhD grant from the Agency for Innovation by Science and Technology in Flanders (IWT). Brenda De Keersmaecker is funded by a research grant Emmanuel van der Schueren from the Flemish League against Cancer (Vlaamse Liga Tegen Kanker, VLK). This work is supported by a grant from the Research Foundation Flanders [Fonds voor Wetenschappelijk Onderzoek (FWO, G023411 N)] to Kris Thielemans and Joeri L Aerts. The FACSAria III cell sorter and the LSR Fortessa were purchased with support from the Hercules Foundation to Kris Thielemans and Joeri L Aerts (Grant UABR/09/002) and the Foundation against Cancer (Stichting Tegen Kanker), respectively. The clinical study was supported by a research grant from Pfizer.

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Correspondence to Joeri L. Aerts.

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Du Four, S., Maenhout, S.K., Benteyn, D. et al. Disease progression in recurrent glioblastoma patients treated with the VEGFR inhibitor axitinib is associated with increased regulatory T cell numbers and T cell exhaustion. Cancer Immunol Immunother 65, 727–740 (2016). https://doi.org/10.1007/s00262-016-1836-3

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Keywords

  • Glioblastoma
  • Antiangiogenesis
  • Axitinib
  • Regulatory T cells
  • Inhibitory molecules