Department of Experimental Immunology and Hematology.
Janssen R&D, Spring House, PA; and.
Blood Adv. 2021 Dec 14;5(23):5410-5414. doi: 10.1182/bloodadvances.2021004861.
The covalent inhibitor of Bruton's tyrosine kinase ibrutinib and the specific Bcl-2 inhibitor venetoclax are both highly efficacious single-agent drugs in the treatment of chronic lymphocytic leukemia (CLL). Based on their complementary modes of action, ibrutinib and venetoclax are hypothesized to act in a synergistic fashion. Currently, it is unclear whether combined treatment is indeed superior to continuous single-agent treatment and what mechanisms underlie the resistance to combination treatment. In addition, the effects of such treatment on the skewed T-cell compartment characteristic of CLL are as yet unknown. In the murine Eµ-TCL1 adoptive transfer model resembling aggressive CLL, we found that combined treatment resulted in the deepest responses, with the longest duration related to a combination of decreased proliferation and increased induction of apoptosis. In addition, alterations in T-cell subsets were most prominent after combination treatment, with increased naive cells and reduced effector memory cells. Remarkably, effects of single agents but also combination treatment were eventually interrupted by relapse, and we found downregulation of BIM expression as a plausible cause of acquired drug resistance. Nevertheless, in this murine model, the combination of venetoclax and ibrutinib has increased efficacy over single agents, accompanied by a restoration of the T-cell compartment.
布鲁顿酪氨酸激酶共价抑制剂伊布替尼和特异性 Bcl-2 抑制剂维奈托克均为治疗慢性淋巴细胞白血病（CLL）的高效单药。基于其互补的作用模式，伊布替尼和维奈托克被假设以协同方式发挥作用。目前尚不清楚联合治疗是否确实优于连续单药治疗，以及联合治疗耐药的机制是什么。此外，这种治疗对 CLL 特征性的偏向性 T 细胞区室的影响尚不清楚。在类似于侵袭性 CLL 的 Eµ-TCL1 过继转移模型中，我们发现联合治疗导致了最深的反应，与增殖减少和凋亡诱导增加相关的持续时间最长。此外，在联合治疗后 T 细胞亚群的改变最为明显，幼稚细胞增加，效应记忆细胞减少。值得注意的是，单药治疗和联合治疗的效果最终都因复发而中断，我们发现 BIM 表达下调是获得性耐药的一个合理原因。然而，在这种小鼠模型中，维奈托克和伊布替尼的联合使用比单药治疗更有效，同时 T 细胞区室也得到了恢复。
