Oncolytic H-1 Parvovirus Shows Safety and Signs of Immunogenic Activity in a First Phase I/IIa Glioblastoma Trial.
Oncolytic H-1 Parvovirus Shows Safety and Signs of Immunogenic Activity in a First Phase I/IIa Glioblastoma Trial.
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DOI：
10.1016/j.ymthe.2017.08.016
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发表时间：
2017-12-06
期刊：
影响因子：
--
通讯作者：
Rommelaere J
中科院分区：
文献类型：
--
作者：
Geletneky K;Hajda J;Angelova AL;Leuchs B;Capper D;Bartsch AJ;Neumann JO;Schöning T;Hüsing J;Beelte B;Kiprianova I;Roscher M;Bhat R;von Deimling A;Brück W;Just A;Frehtman V;Löbhard S;Terletskaia-Ladwig E;Fry J;Jochims K;Daniel V;Krebs O;Dahm M;Huber B;Unterberg A;Rommelaere J
溶瘤病毒治疗可能是改善恶性脑肿瘤预后不良的一种手段。大鼠H-1细小病毒（H-1 PV）通过直接溶瘤和刺激抗癌免疫反应抑制临床前胶质瘤模型中的肿瘤。这是ParvOryx 01的基础，ParvOryx 01是溶瘤细小病毒在复发性胶质母细胞瘤患者中的第一个I/IIa期临床试验。H-1 PV（递增剂量）通过瘤内或静脉注射给药。治疗后9天切除肿瘤，并在切除腔周围重新施用病毒。主要终点是安全性和耐受性、病毒分布和最大耐受剂量（MTD）。还研究了无进展生存期和总生存期以及肿瘤和外周血中病毒和免疫标志物的水平。H-1 PV治疗安全且耐受性良好，未达到MTD。病毒可以穿过血脑/肿瘤屏障，并通过肿瘤广泛传播。它显示出有利的药代动力学，以剂量依赖性方式诱导抗体形成，并触发特异性T细胞应答。病毒复制，小胶质细胞/巨噬细胞活化，细胞毒性T细胞浸润的标志物在感染的肿瘤中被检测到，这表明H-1 PV可能引发免疫原性刺激。与最近的荟萃分析相比，中位生存期延长。总之，ParvOryx 01的结果为进一步的H-1 PV临床开发提供了动力。通过在复发性胶质母细胞瘤患者中进行的早期临床试验，Geletneky等人表明溶瘤H-1细小病毒是安全的、耐受性良好的，并且能够建立免疫原性肿瘤微环境。与历史对照相比，血脑/肿瘤交叉和有利的存活率使该病毒成为进一步临床开发的有趣候选者。
Oncolytic virotherapy may be a means of improving the dismal prognosis of malignant brain tumors. The rat H-1 parvovirus (H-1PV) suppresses tumors in preclinical glioma models, through both direct oncolysis and stimulation of anticancer immune responses. This was the basis of ParvOryx01, the first phase I/IIa clinical trial of an oncolytic parvovirus in recurrent glioblastoma patients. H-1PV (escalating dose) was administered via intratumoral or intravenous injection. Tumors were resected 9 days after treatment, and virus was re-administered around the resection cavity. Primary endpoints were safety and tolerability, virus distribution, and maximum tolerated dose (MTD). Progression-free and overall survival and levels of viral and immunological markers in the tumor and peripheral blood were also investigated. H-1PV treatment was safe and well tolerated, and no MTD was reached. The virus could cross the blood-brain/tumor barrier and spread widely through the tumor. It showed favorable pharmacokinetics, induced antibody formation in a dose-dependent manner, and triggered specific T cell responses. Markers of virus replication, microglia/macrophage activation, and cytotoxic T cell infiltration were detected in infected tumors, suggesting that H-1PV may trigger an immunogenic stimulus. Median survival was extended in comparison with recent meta-analyses. Altogether, ParvOryx01 results provide an impetus for further H-1PV clinical development. Through an early-phase clinical trial in recurrent glioblastoma patients, Geletneky et al. show that the oncolytic H-1 parvovirus is safe, well tolerated, and able to establish an immunogenic tumor microenvironment. Blood-brain/tumor crossing and favorable survival compared with historical controls make this virus an interesting candidate for further clinical development.
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