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

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.

Interaction of regulatory T cells with antigen-presenting cells in health and disease.

Among antigen-presenting cells (APCs), dendritic cells as well as monocytes acquire immunostimulatory capacity only after appropriate maturation. Therefore, blockade of the maturation/activation results in a steady state or alternatively activated phenotype, which induces tolerance rather than immunity. Functional analyses revealed recently that steady-state dendritic cells and alternatively activated macrophages, respectively, actively induce regulatory T cells (Tregs) in the periphery of the body. Thus, production of Tregs does not rely exclusively on thymic development. Vice versa, Tregs respond to APCs by several means. Recent lines of evidence indicate that Tregs prevent terminal differentiation of subpopulations of APCs or lead to upregulation of surface expression of immunosuppressive molecules. Thus, Tregs foster an environment that further promotes their development. In conclusion, the mutual interaction of Tregs and APCs enables Tregs to sustain their immunosuppressive function(s), which in healthy individuals may be crucial for the maintenance of peripheral tolerance. Since macrophages bridge the innate and the acquired immune system, Tregs are able to gain influence on the innate immune system by interacting with macrophages beyond the mere interaction with effector T cells.