Proapoptotic and immunomodulatory effects of SYK inhibitor entospletinib in combination with obinutuzumab in patients with chronic lymphocytic leukaemia
Proapoptotic and immunomodulatory effects of SYK inhibitor entospletinib in combination with obinutuzumab in patients with chronic lymphocytic leukaemia
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DOI：
10.1111/bcp.14962
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发表时间：
2021-07-19
影响因子：
3.4
通讯作者：
Danilov, Alexey V.
中科院分区：
文献类型：
--
作者：
Lam, Vi;Best, Scott;Danilov, Alexey V.
脾酪氨酸激酶（SYK）在B细胞受体信号传导中是不可或缺的。SYK抑制剂entospletinib在慢性淋巴细胞白血病（CLL）患者中显示出临床疗效。然而，对CLL细胞中SYK抑制的药效学作用和CLL患者中B细胞受体信号传导抑制剂的免疫调节作用知之甚少。我们在17例复发/难治性CLL患者中进行了entospletinib联合obinutuzumab（一种抗CD 20抗体）的2期试验。药效学分析表明，用entospletinib治疗导致CLL细胞中pSTAT 3和抗凋亡蛋白MCL 1的快速下调。与此同时，6个月的联合治疗伴随着CD 4（+）T细胞中干扰素-γ分泌的减少和衰竭表型的逆转，正如PD-1的下调所证明的那样。因此，SYK抑制下调MCL-1并部分恢复CLL中的T细胞免疫。试验注册号NCT 03010358。
Spleen tyrosine kinase (SYK) is indispensable in B-cell receptor signalling. SYK inhibitor entospletinib demonstrated clinical efficacy in patients with chronic lymphocytic leukaemia (CLL). However, pharmacodynamic effects of SYK inhibition in CLL cells and immunomodulatory effects of B-cell receptor-signalling inhibitors in patients with CLL are poorly understood. We conducted a phase 2 trial of entospletinib in combination with obinutuzumab, an anti-CD20 antibody, in 17 patients with relapsed/refractory CLL. Pharmacodynamic analysis demonstrated that treatment with entospletinib led to rapid downmodulation of pSTAT3 and the anti-apoptotic protein MCL1 in CLL cells. Meanwhile, 6 months of combination therapy was accompanied by a reduction in interferon-gamma secretion in CD4(+) T-cells and a reversal of exhausted phenotype, as evidenced by downregulation of PD-1. Thus, SYK inhibition downmodulates MCL-1 and partially restores T-cell immunity in CLL. Trial registration number NCT03010358.