Interactions between Ibrutinib and Anti-CD20 Antibodies: Competing Effects on the Outcome of Combination Therapy.
Interactions between Ibrutinib and Anti-CD20 Antibodies: Competing Effects on the Outcome of Combination Therapy.
复制标题
DOI：
10.1158/1078-0432.ccr-15-1304
复制
发表时间：
2016-01-01
期刊：
影响因子：
--
通讯作者：
Wiestner A
中科院分区：
文献类型：
--
作者：
Skarzynski M;Niemann CU;Lee YS;Martyr S;Maric I;Salem D;Stetler-Stevenson M;Marti GE;Calvo KR;Yuan C;Valdez J;Soto S;Farooqui MZ;Herman SE;Wiestner A
伊曲替尼联合抗CD 20单克隆抗体（mAb）治疗慢性淋巴细胞白血病（CLL）的临床试验报告了令人鼓舞的结果。奇怪的是，在体外临床前研究中，报告了伊鲁替尼降低CD 20表达并抑制细胞效应机制。因此，我们着手研究可以解释这一悖论的体内伊鲁替尼治疗的效果。患者接受单药伊曲替尼（420毫克，每天）在一个激动剂启动的2期试验。在治疗前和治疗期间收集系列血液样品用于离体功能测定，以检查对抗CD 20 mAb对CLL细胞易感性的影响。我们证明，与基线相比，伊鲁替尼的CD 20表达迅速且持续下调（中位数降低74%，第28天，P<0.001）。同时，CD 20 mRNA降低，同时NF-κB信号传导减少。MS 4A 1（编码CD 20）启动子中的NF-κB结合位点和NF-κB抑制剂对CD 20的下调支持直接转录效应。离体情况下，与治疗前细胞相比，接受伊鲁替尼治疗的患者的肿瘤细胞对抗CD 20 mAb介导的补体依赖性细胞毒性的敏感性较低（中位数降低75%，P<0.001）;然而，补体蛋白C3 d（靶向吞噬细胞）的调理作用相对维持。衰变加速因子（CD 55）的表达在伊鲁替尼上降低，为保留的C3 d调理作用提供了可能的机制。此外，伊曲替尼显著抑制了胞间刺细胞增多，这是mAb治疗期间抗原丢失和肿瘤逃逸的主要原因。我们的数据表明，伊曲替尼促进了与抗CD 20 mAb的阳性和阴性相互作用，这表明成功利用这种组合的最大抗肿瘤作用需要进一步研究。
Clinical trials of ibrutinib combined with anti-CD20 monoclonal antibodies (mAbs) for chronic lymphocytic leukemia (CLL) report encouraging results. Paradoxically, in pre-clinical studies in vitro ibrutinib was reported to decrease CD20 expression and inhibits cellular effector mechanisms. We therefore set out to investigate effects of in vivo ibrutinib treatment that could explain this paradox. Patients received single agent ibrutinib (420mg daily) on an investigator-initiated phase 2 trial. Serial blood samples were collected pre-treatment and during treatment for ex vivo functional assays to examine the effects on CLL cell susceptibility to anti-CD20 mAbs. We demonstrate that CD20 expression on ibrutinib was rapidly and persistently down-regulated (median reduction 74%, day 28, P<0.001) compared to baseline. Concomitantly, CD20 mRNA was decreased concurrent with reduced NF-κB signaling. An NF-κB binding site in the promoter of MS4A1 (encoding CD20) and down-regulation of CD20 by NF-κB inhibitors support a direct transcriptional effect. Ex vivo, tumor cells from patients on ibrutinib were less susceptible to anti-CD20 mAb-mediated complement-dependent cytotoxicity than pre-treatment cells (median reduction 75%, P<0.001); however, opsonization by the complement protein C3d, which targets cells for phagocytosis, was relatively maintained. Expression of decay accelerating factor (CD55) decreased on ibrutinib, providing a likely mechanism for the preserved C3d opsonization. Additionally, ibrutinib significantly inhibited trogocytosis, a major contributor to antigen loss and tumor escape during mAb therapy. Our data indicate that ibrutinib promotes both positive and negative interactions with anti-CD20 mAbs, suggesting that successfully harnessing maximal anti-tumor effects of such combinations requires further investigation.