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

• Published in: Leukemia Vol. 31; no. 10; pp. 2181 - 2190
• Main Authors: Duell, J, Dittrich, M, Bedke, T, Mueller, T, Eisele, F, Rosenwald, A, Rasche, L, Hartmann, E, Dandekar, T, Einsele, H, Topp, M S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2017; Nature Publishing Group
• Subjects: 13/1; 13/21; 13/31; 14/1; 631/250/1619/554/1898/1271; 631/250/251; 631/67/1059/2325; 631/67/1990/283/2125; 692/308/575; 692/699/67/580; Acute lymphoblastic leukemia; Acute lymphocytic leukemia; Adolescent; Adult; Aged; Antibodies, Bispecific - immunology; Antibodies, Bispecific - therapeutic use; Antigens, Differentiation, T-Lymphocyte - analysis; Bone marrow; Cancer Research; Care and treatment; CD19 antigen; CD25 antigen; CD4 antigen; CD8 antigen; Cell Line, Tumor; Cell proliferation; Chemotherapy; Clinical Trials as Topic; Confidence intervals; Critical Care Medicine; Cytotoxicity, Immunologic; Development and progression; Enumeration; Female; Foxp3 protein; Genetic aspects; Health aspects; Hematology; Humans; Immunophenotyping; Immunoregulation; Immunotherapy; Intensive; Interleukin 10; Interleukin-10 - biosynthesis; Interleukin-10 - genetics; Internal Medicine; L-Lactate dehydrogenase; Lactate dehydrogenase; Lactic acid; Leukemia; Lymphatic leukemia; Lymphocyte Activation; Lymphocyte Count; Lymphocytes; Lymphocytes T; Lysis; Male; Medicine; Medicine & Public Health; Middle Aged; Monoclonal antibodies; Oncology; Original; original-article; Patients; Peripheral blood; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - therapy; Predictions; Prognosis; Remission; Remission Induction; Salvage Therapy; T cell receptors; T cells; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Regulatory - immunology; Targeted cancer therapy; Treatment Outcome
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2017.41

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.