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



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.



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.



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.
Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel, Laarbeeklaan 103E, 1090, Brussels, Belgium.
Stephanie
S
Du Four
Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel, Laarbeeklaan 103E, 1090, Brussels, Belgium.
Sarah K
SK
Maenhout
Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel, Laarbeeklaan 103E, 1090, Brussels, Belgium.
Daphné
D
Benteyn
Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel, Laarbeeklaan 103E, 1090, Brussels, Belgium.
Brenda
B
De Keersmaecker
Department of Neurosurgery, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium.
Johnny
J
Duerinck
Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel, Laarbeeklaan 103E, 1090, Brussels, Belgium.
Kris
K
Thielemans
Department of Medical Oncology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium.
Bart
B
Neyns
Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel, Laarbeeklaan 103E, 1090, Brussels, Belgium. Joeri.Aerts@vub.ac.be.
Joeri L
JL
Aerts
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015703:Antigens, CD / Q000378:metabolism; D000077784:Axitinib; D015415:Biomarkers; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D000072597:Hepatitis A Virus Cellular Receptor 2 / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007156:Immunologic Memory; D056747:Immunomodulation / Q000187:drug effects; D016130:Immunophenotyping; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use*; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D000093322:Lymphocyte Activation Gene 3 Protein
D020533:Angiogenesis Inhibitors; D015703:Antigens, CD; D015415:Biomarkers; D016207:Cytokines; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D007093:Imidazoles; D007191:Indazoles; D061026:Programmed Cell Death 1 Receptor; D047428:Protein Kinase Inhibitors; D000077784:Axitinib; D040262:Receptors, Vascular Endothelial Growth Factor; D000093322:Lymphocyte Activation Gene 3 Protein; C000720326:Lag3 protein, human
Antiangiogenesis; Axitinib; Glioblastoma; Inhibitory molecules; Regulatory T cells