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Leukemia. 2017 Oct;31(10):2181-2190. doi: 10.1038/leu.2017.41. Epub 2017 Jan 25.

Frequency of regulatory T cells determines the outcome of the T-cell-engaging antibody blinatumomab in patients with B-precursor ALL.

Author information

1
Medizinische Klinik und Poliklinik II, Universitätsklinik Würzburg, Würzburg, Germany.
2
Bioinformatik, Biozentrum, Universität Würzburg, Würzburg, Germany.
3
Institute of Human Genetics, University of Würzburg, Würzburg, Germany.
4
Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
5
Institut für Pathologie, Universität Würzburg, Würzburg, Germany.
6
Comprehensive Cancer Center Mainfranken (CCC MF), Würzburg, Germany.

Abstract

Blinatumomab can induce a complete haematological remission in patients in 46.6% with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL) resulting in a survival benefit when compared with chemotherapy. Only bone marrow blast counts before therapy have shown a weak prediction of response. Here we investigated the role of regulatory T cells (Tregs), measured by CD4/CD25/FOXP3 expression, in predicting the outcome of immunotherapy with the CD19-directed bispecific T-cell engager construct blinatumomab. Blinatumomab responders (n=22) had an average of 4.82% Tregs (confidence interval (CI): 1.79-8.34%) in the peripheral blood, whereas non-responders (n=20) demonstrated 10.25% Tregs (CI: 3.36-65.9%). All other tested markers showed either no prediction value or an inferior prediction level including blast BM counts and the classical enzyme marker lactate dehydrogenase. With a cutoff of 8.525%, Treg enumeration can identify 100% of all blinatumomab responders and exclude 70% of the non-responders. The effect is facilitated by blinatumomab-activated Tregs, leading to interleukin-10 production, resulting in suppression of T-cell proliferation and reduced CD8-mediated lysis of ALL cells. Proliferation of patients' T cells can be restored by upfront removal of Tregs. Thus, enumeration of Treg identifies r/r ALL patients with a high response rate to blinatumomab. Therapeutic removal of Tregs may convert blinatumomab non-responders to responders.

PMID:
28119525
PMCID:
PMC5629361
DOI:
10.1038/leu.2017.41
[Indexed for MEDLINE]
Free PMC Article

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