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.

T lymphocytes as therapeutic arsenal for patients with hematological malignancies

“…Both events can be treated with drug interruption, high-dose steroids and some patients may require tocilizumab [78 & ]. Treatment resistance and relapse after blinatumomab correlates with leukemia burden, extramedullary ALL, PD-L1 blast expression [82] and circulating regulatory T cells [83]. The immunological pressure drives CD19À relapses in 10-20% of patients, due to CD19 expression loss or disrupted membrane trafficking [84], selection of preexisting CD19À clones [85] or lineage switch [86], indicating the need to carefully monitor escape variants.…”

Immunologic approaches for the treatment of multiple myeloma

“…The main disadvantage however of this backbone approach is the in situ activation of autologous T cells. Recent analysis suggests unwanted stimulation of immune suppressive Tregs, which also carry the CD3 molecule, leading to therapy resistance particularly in patients with baseline increased Treg numbers [93]. Of note, Treg frequencies are generally increased in MM [16].…”

Blinatumomab: enlisting serial killer T-cells in the war against hematologic malignancies

“…Prior studies have suggested that increased marrow disease burden (>50% blasts) [37], multiple previous relapses [28], or relapsed disease after prior alloSCT [36] are all associated with worse response rates to blinatumomab. In addition, higher regulatory T cell counts and elevated lactate dehydrogenase may also predict poor response [59]. To date, analyses of T cell numbers and cytokine kinetics show no correlation to response rate [9].…”