Evaluation of vecabrutinib as a model for noncovalent BTK/ITK inhibition for treatment of chronic lymphocytic leukemia
Evaluation of vecabrutinib as a model for noncovalent BTK/ITK inhibition for treatment of chronic lymphocytic leukemia
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DOI：
10.1182/blood.2021011516
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发表时间：
2022-02-10
期刊：
影响因子：
20.3
通讯作者：
Stilgenbauer, Stephan
中科院分区：
文献类型：
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作者：
Jebaraj, Billy Michael Chelliah;Mueller, Annika;Stilgenbauer, Stephan
共价布鲁顿酪氨酸激酶 (BTK) 抑制剂，例如依鲁替尼，已被证明对治疗慢性淋巴细胞白血病 (CLL) 非常有益。有趣的是，依鲁替尼对 IL-2 诱导性 T 细胞激酶 (ITK) 的脱靶抑制也可能在调节肿瘤微环境中发挥作用，从而可能增强治疗效果。然而，由于 BTK (C481S) 的半胱氨酸 481 发生突变，可能会产生对共价结合 BTK 抑制剂的耐药性，从而阻止药物的不可逆结合。在本研究中，我们对 vecabrutinib 进行了临床前表征，vecabrutinib 是一种下一代非共价 BTK 抑制剂，具有与 ibrutinib 类似的 ITK 抑制特性。与 ibrutinib 和其他共价 BTK 抑制剂不同，vecabrutinib 在体外表现出对 C481S BTK 突变体的抑制作用，与野生型 BTK 相似。在小鼠 E mu-TCL1 过继转移模型中，维卡替尼减轻了肿瘤负荷并显着提高了生存率。 Vecabrutinib治疗导致CD8(+)效应细胞和记忆T细胞数量减少，而初始细胞数量增加。重要的是，vecabrutinib 治疗显着降低了体内调节性 CD4(+) T 细胞的频率。与 ibrutinib（依鲁替尼）不同，vecabrutinib（维卡替尼）治疗对分离 T 细胞的激活和增殖的不利影响极小。最后，vecabrutinib 和 Venetoclax 的联合治疗增强了治疗效果，显着提高了生存率，并导致小鼠 E mu-TCL1 模型中微环境的有利重编程。因此，非共价 BTK/ITK 抑制剂（例如维卡替尼）可能对 C481S BTK 突变型 CLL 有效，同时保留依鲁替尼的 T 细胞免疫调节功能。
Covalent Bruton tyrosine kinase (BTK) inhibitors, such as ibrutinib, have proven to be highly beneficial in the treatment of chronic lymphocytic leukemia (CLL). Interestingly, the off-target inhibition of IL-2-inducible T-cell kinase (ITK) by ibrutinib may also play a role in modulating the tumor microenvironment, potentially enhancing the treatment benefit. However, resistance to covalently binding BTK inhibitors can develop as the result of a mutation in cysteine 481 of BTK (C481S), which prevents irreversible binding of the drugs. In the present study we performed preclinical characterization of vecabrutinib, a nextgeneration noncovalent BTK inhibitor that has ITK-inhibitory properties similar to those of ibrutinib. Unlike ibrutinib and other covalent BTK inhibitors, vecabrutinib showed retention of the inhibitory effect on C481S BTK mutants in vitro, similar to that of wild-type BTK. In the murine E mu-TCL1 adoptive transfer model, vecabrutinib reduced tumor burden and significantly improved survival. Vecabrutinib treatment led to a decrease in CD8(+) effector and memory T-cell populations, whereas the naive populations were increased. Of importance, vecabrutinib treatment significantly reduced the frequency of regulatory CD4(+) T cells in vivo. Unlike ibrutinib, vecabrutinib treatment showed minimal adverse impact on the activation and proliferation of isolated T cells. Lastly, combination treatment with vecabrutinib and venetoclax augmented treatment efficacy, significantly improved survival, and led to favorable reprogramming of the microenvironment in the murine E mu-TCL1 model. Thus, noncovalent BTK/ITK inhibitors, such as vecabrutinib, may be efficacious in C481S BTK mutant CLL while preserving the T-cell immunomodulatory function of ibrutinib.