title: Frequency of regulatory T cells determines the outcome of the T-cell-engaging antibody blinatumomab in patients with B-precursor ALL.
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.
authors.affiliation: Medizinische Klinik und Poliklinik II, Universitätsklinik Würzburg, Würzburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Duell
authors.affiliation: Bioinformatik, Biozentrum, Universität Würzburg, Würzburg, Germany.|Institute of Human Genetics, University of Würzburg, Würzburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Dittrich
authors.affiliation: Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Bedke
authors.affiliation: Bioinformatik, Biozentrum, Universität Würzburg, Würzburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Mueller
authors.affiliation: Medizinische Klinik und Poliklinik II, Universitätsklinik Würzburg, Würzburg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Eisele
authors.affiliation: Institut für Pathologie, Universität Würzburg, Würzburg, Germany.|Comprehensive Cancer Center Mainfranken (CCC MF), Würzburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Rosenwald
authors.affiliation: Medizinische Klinik und Poliklinik II, Universitätsklinik Würzburg, Würzburg, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Rasche
authors.affiliation: Institut für Pathologie, Universität Würzburg, Würzburg, Germany.|Comprehensive Cancer Center Mainfranken (CCC MF), Würzburg, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Hartmann
authors.affiliation: Bioinformatik, Biozentrum, Universität Würzburg, Würzburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Dandekar
authors.affiliation: Medizinische Klinik und Poliklinik II, Universitätsklinik Würzburg, Würzburg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Einsele
authors.affiliation: Medizinische Klinik und Poliklinik II, Universitätsklinik Würzburg, Würzburg, Germany.
authors.forename: M S
authors.initials: MS
authors.lastname: Topp
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018033:Antibodies, Bispecific / Q000276:immunology / Q000627:therapeutic use*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D003602:Cytotoxicity, Immunologic; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007167:Immunotherapy; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000628:therapy*; D011379:Prognosis; D012074:Remission Induction; D016879:Salvage Therapy; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: D018033:Antibodies, Bispecific; D000945:Antigens, Differentiation, T-Lymphocyte; C508609:IL10 protein, human; D016753:Interleukin-10; C510808:blinatumomab