Pai Chien-Chun Steven, Chen Mingyi, Mirsoian Annie, Grossenbacher Steven K, Tellez Joseph, Ames Erik, Sun Kai, Jagdeo Jared, Blazar Bruce R, Murphy William J, Abedi Mehrdad
Department of Dermatology and.
Department of Pathology, School of Medicine, University of California, Davis, Sacramento, CA;
Blood. 2014 Sep 4;124(10):1677-88. doi: 10.1182/blood-2014-02-554279. Epub 2014 Jul 9.
Chronic graft-versus-host disease (cGVHD) following allogeneic hematopoietic stem cell transplantation (HSCT) has emerged as a predominant complication following HSCT and has a distinct etiology. We and others have previously demonstrated that bortezomib, a proteasome inhibitor, can prevent but not treat acute GVHD in mice. To assess the effects of bortezomib on cGVHD, a mouse minor histocompatibility antigen-mismatched strain combination was used to mimic clinical cGVHD sclerodermatous pathogenesis and phenotype. Treatment of ongoing cGVHD with bortezomib ameliorated cutaneous lesions, which were also associated with a reduction in total numbers of germinal center B cells and lower B-cell activating factor gene expression levels in cutaneous tissues. Importantly, lymphoma-bearing mice receiving allogeneic HSCT with bortezomib preserved graft-versus-tumor (GVT) effects. Based on these animal studies, we initiated an intrapatient dose escalation clinical trial in patients with extensive steroid-intolerant, dependent, or resistant cGVHD. Marked clinical improvement was observed in patients, which was also associated with reductions of peripheral B cells and minimal toxicity. These results indicate that bortezomib can be of significant use in the treatment of cGVHD and may also allow for maintenance of GVT. This trial was registered at www.clinicaltrials.gov as #NCT01672229.
异基因造血干细胞移植（HSCT）后的慢性移植物抗宿主病（cGVHD）已成为HSCT后的主要并发症，且病因独特。我们和其他人之前已证明，蛋白酶体抑制剂硼替佐米可预防但不能治疗小鼠的急性移植物抗宿主病。为评估硼替佐米对cGVHD的影响，采用小鼠次要组织相容性抗原不匹配的品系组合来模拟临床cGVHD的硬皮病发病机制和表型。用硼替佐米治疗正在发生的cGVHD可改善皮肤病变，这也与生发中心B细胞总数减少以及皮肤组织中B细胞活化因子基因表达水平降低有关。重要的是，接受异基因HSCT并使用硼替佐米的荷淋巴瘤小鼠保留了移植物抗肿瘤（GVT）效应。基于这些动物研究，我们对患有广泛的类固醇不耐受、依赖或抵抗性cGVHD的患者启动了一项患者内剂量递增临床试验。在患者中观察到了明显的临床改善，这也与外周B细胞减少和最小毒性有关。这些结果表明，硼替佐米在cGVHD的治疗中可能具有重要用途，并且还可能有助于维持GVT。该试验已在www.clinicaltrials.gov上注册，编号为#NCT01672229。
