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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

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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

References

  1. Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996

    Article  CAS  PubMed  Google Scholar 

  2. Lamborn KR, Chang SM, Prados MD (2004) Prognostic factors for survival of patients with glioblastoma: recursive partitioning analysis. Neuro Oncol 6:227–235

    Article  PubMed  PubMed Central  Google Scholar 

  3. Friedman HS, Prados MD, Wen PY et al (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27:4733–4740

    Article  CAS  PubMed  Google Scholar 

  4. Stupp R, Hegi ME, Gorlia T et al (2014) Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 15:1100–1108

    Article  CAS  PubMed  Google Scholar 

  5. Hutterer M, Nowosielski M, Haybaeck J et al (2014) A single-arm phase II Austrian/German multicenter trial on continuous daily sunitinib in primary glioblastoma at first recurrence (SURGE 01-07). Neuro Oncol 16:92–102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lee EQ, Kuhn J, Lamborn KR et al (2012) Phase I/II study of sorafenib in combination with temsirolimus for recurrent glioblastoma or gliosarcoma: North American Brain Tumor Consortium study 05-02. Neuro Oncol 14:1511–1518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Batchelor TT, Mulholland P, Neyns B et al (2013) Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol 31:3212–3218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Neyns B, Duerinck J, Du Four S et al (2014) Randomized phase II study of axitinib versus standard of care in patients with recurrent glioblastoma. ASCO Meet Abstr 32:2018

    Google Scholar 

  9. Duerinck J, Du Four S, Bouttens F, Neyns B (2016) Randomized phase II study of axitinib versus physicians best alternative choice of therapy in patients with recurrent glioblastoma. J Neurooncol. doi:10.1007/s11060-016-2092-2

  10. Taal W, Oosterkamp HM, Walenkamp AME et al (2014) Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol 15:943–953

    Article  CAS  PubMed  Google Scholar 

  11. Huang Y, Goel S, Duda DG et al (2013) Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res 73:2943–2948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Du Four S, Maenhout SK, De Pierre K et al (2015) Axitinib increases the infiltration of immune cells and reduces the suppressive capacity of monocytic MDSCs in an intracranial mouse melanoma model. Oncoimmunology 4:e998107. doi:10.1080/2162402X.2014.998107

    Article  PubMed  PubMed Central  Google Scholar 

  13. Jackson CM, Lim M, Drake CG (2014) Immunotherapy for brain cancer: recent progress and future promise. Clin Cancer Res 20:3651–3659. doi:10.1158/1078-0432.CCR-13-2057

    Article  PubMed  PubMed Central  Google Scholar 

  14. Reardon DA, Schuster J, Tran DD et al (2015) ReACT: overall survival from a randomized phase II study of rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma. ASCO Meet Abstr 33:2009

    Google Scholar 

  15. Chung AS, Wu X, Zhuang G et al (2013) An interleukin-17-mediated paracrine network promotes tumor resistance to anti-angiogenic therapy. Nat Med 19:1114–1123

    Article  CAS  PubMed  Google Scholar 

  16. Doloff JC, Waxman DJ (2012) VEGF receptor inhibitors block the ability of metronomically dosed cyclophosphamide to activate innate immunity-induced tumor regression. Cancer Res 72:1103–1115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Stehle F, Schulz K, Fahldieck C et al (2013) Reduced immunosuppressive properties of axitinib in comparison with other tyrosine kinase inhibitors. J Biol Chem 288:16334–16347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gattinoni L, Klebanoff CA, Palmer DC et al (2005) Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8 + T cells. J Clin Invest 115:1616–1626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Klebanoff Christopher, Gattoni Luca, Restifo N (2012) Sorting through subsets: which T cell populations mediate highly effective adoptive immunotherapy? J Immunother 35:651–660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fourcade J, Sun Z, Pagliano O et al (2012) CD8 + T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1. Cancer Res 72:887–896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Fourcade J, Sun Z, Pagliano O et al (2014) PD-1 and Tim-3 regulate the expansion of tumor antigen-specific CD8 + T cells induced by melanoma vaccines. Cancer Res 74:1045–1055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Clary S, Nagarkatti PS, Nagarkatti M (1990) Immunomodulatory effects of nitrosoureas on the phenotype and functions of T cells in the thymus and periphery. Immunopharmacology 20:153–164

    Article  CAS  PubMed  Google Scholar 

  23. Nguyen LT, Ohashi PS (2015) Clinical blockade of PD1 and LAG3—potential mechanisms of action. Nat Rev Immunol 15:45–56. doi:10.1038/nri3790

    Article  CAS  PubMed  Google Scholar 

  24. Goldberg MV, Drake CG (2011) LAG-3 in cancer immunotherapy. Curr Top Microbiol Immunol 344:269–278

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Wei B, Wang L, Zhao X et al (2014) The upregulation of programmed death 1 on peripheral blood T cells of glioma is correlated with disease progression. Tumor Biol 35:2923–2929

    Article  CAS  Google Scholar 

  26. Ozao-Choy J, Ma G, Kao J et al (2009) The novel role of Tyrosine Kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Res 69:2514–2522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chen ML, Yan BS, Lu WC et al (2014) Sorafenib relieves cell-intrinsic and cell-extrinsic inhibitions of effector T cells in tumor microenvironment to augment antitumor immunity. Int J Cancer 134:319–331

    Article  PubMed  Google Scholar 

  28. Guislain A, Gadiot J, Kaiser A et al (2015) Sunitinib pretreatment improves tumor—infiltrating lymphocyte expansion by reduction in intratumoral content of myeloid—derived suppressor cells in human renal cell carcinoma. Cancer Immunol Immunother 64:1241–1250

    Article  CAS  PubMed  Google Scholar 

  29. Curiel TJ, Coukos G, Zou L et al (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942–949

    Article  CAS  PubMed  Google Scholar 

  30. Choi BD, Fecci PE, Sampson JH (2012) Regulatory T cells move in when gliomas say “I DO”. Clin Cancer Res 18:6086–6088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Fecci PE, Mitchell DA, Whitesides JF et al (2006) Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res 66:3294–3302

    Article  CAS  PubMed  Google Scholar 

  32. Thomas AA, Fisher JL, Rahme GJ et al (2015) Regulatory T cells are not a strong predictor of survival for patients with glioblastoma. Neuro Oncol 17:801–809

    Article  PubMed  Google Scholar 

  33. Wainwright DA, Chang AL, Dey M et al (2014) Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors. Clin Cancer Res 20:5290–5301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Motz GT, Santoro SP, Wang L-P et al (2014) Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat Med 20:607–615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Batchelor TT, Reardon DA, de Groot JF et al (2014) Antiangiogenic therapy for glioblastoma: current status and future prospects. Clin Cancer Res 20:5612–5619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Franchimont D (2004) Overview of the actions of glucocorticoids on the immune response: a good model to characterize new pathways of immunosuppression for new treatment strategies. Ann N Y Acad Sci 1024:124–137

    Article  CAS  PubMed  Google Scholar 

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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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Authors and Affiliations

  1. Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel, Laarbeeklaan 103E, 1090, Brussels, Belgium

    Stephanie Du Four, Sarah K. Maenhout, Daphné Benteyn, Brenda De Keersmaecker, Kris Thielemans & Joeri L. Aerts

  2. Department of Medical Oncology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium

    Bart Neyns

  3. Department of Neurosurgery, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium

    Johnny Duerinck

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  1. Stephanie Du Four
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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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