Frequency of regulatory T cells determines the outcome of the T-cell-engaging antibody blinatumomab in patients with B-precursor ALL
Frequency of regulatory T cells determines the outcome of the T-cell-engaging antibody blinatumomab in patients with B-precursor ALL
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DOI：
10.1038/leu.2017.41
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发表时间：
2017-10-01
期刊：
影响因子：
11.4
通讯作者：
Topp, M. S.
中科院分区：
文献类型：
--
作者：
Duell, J.;Dittrich, M.;Topp, M. S.
与化疗相比，博纳吐单抗可以使 46.6% 的复发/难治性 B 前体急性淋巴细胞白血病 (r/r ALL) 患者获得完全血液学缓解，从而提高生存率。只有治疗前的骨髓原始细胞计数显示出对反应的预测较弱。在这里，我们研究了通过 CD4/CD25/FOXP3 表达测量的调节性 T 细胞 (Treg) 在预测 CD19 导向的双特异性 T 细胞接合器构建体 blinatumomab 免疫治疗结果中的作用。博纳吐单抗应答者 (n = 22) 外周血中的 Tregs 平均为 4.82%（置信区间 (CI)：1.79-8.34%），而无应答者 (n = 20) 的 Treg 为 10.25%（CI：3.36-65.9%）。所有其他测试的标记物要么没有预测价值，要么预测水平较低，包括原始细胞 BM 计数和经典酶标记物乳酸脱氢酶。 Treg 计数的截止值为 8.525%，可以识别 100% 的所有 blinatumomab 应答者，并排除 70% 的无应答者。 blinatumomab 激活的 Tregs 促进了这种作用，导致白细胞介素 10 的产生，从而抑制 T 细胞增殖并减少 CD8 介导的 ALL 细胞裂解。通过预先去除 Tregs 可以恢复患者 T 细胞的增殖。因此，Treg 的计数可识别出对 blinatumomab 有高反应率的 r/r ALL 患者。治疗性去除 Tregs 可能会将 blinatumomab 无反应者转变为反应者。
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.