Recurrent Glioblastoma Treated with Recombinant Poliovirus.
Recurrent Glioblastoma Treated with Recombinant Poliovirus.
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DOI：
10.1056/nejmoa1716435
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发表时间：
2018-07-12
期刊：
影响因子：
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通讯作者：
Bigner DD
中科院分区：
文献类型：
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作者：
Desjardins A;Gromeier M;Herndon JE 2nd;Beaubier N;Bolognesi DP;Friedman AH;Friedman HS;McSherry F;Muscat AM;Nair S;Peters KB;Randazzo D;Sampson JH;Vlahovic G;Harrison WT;McLendon RE;Ashley D;Bigner DD
复发的世界卫生组织(WHO)IV级恶性胶质瘤患者的预后很差，目前还没有有效的治疗方法。我们在这群患者中进行了剂量发现和毒性研究，评估对流增强的重组非致病性脊髓灰质炎-鼻病毒嵌合体(PVSRIPO)在肿瘤内的传递。PVSRIPO识别脊髓灰质炎病毒受体CD155，它广泛表达于实体瘤的肿瘤细胞和肿瘤微环境的主要组成部分。我们招募了连续的成年患者，他们有复发的WHO IV级恶性胶质瘤，经组织病理学检查证实，有可测量的疾病(最大直径为≥1 cm和≤5.5 cm的对比剂增强肿瘤)。这项研究评估了7种剂量，范围从107到1010 50%组织培养感染剂量(TCID50)，第一次处于剂量升级阶段，然后处于剂量扩大阶段。从2012年5月到2017年5月，共有61名患者入选并接受了一剂PVSRIPO。剂量水平−1(5.0×10 7TCID50)被确定为2期剂量。观察到一种剂量限制性毒性效应：一名患者在拔除导管后立即出现4级颅内出血，剂量水平为5(1010TCID50)。为了减轻长期使用糖皮质激素的肿瘤局部炎症，剂量水平5被降低到2期剂量。在剂量扩大阶段，19%的患者出现了与PVSRIPO相关的3级或更高级别的不良事件。接受PVSRIPO的患者的总存活率在24个月时达到21%的平台期(95%可信区间，11至33)，而持续到36个月。在复发的WHO IV级恶性胶质瘤患者中，瘤内注射PVSRIPO证实没有神经毒力潜力。接受PVSRIPO免疫治疗的患者在24个月和36个月的存活率高于历史对照组。
The prognosis of patients with recurrent World Health Organization (WHO) grade IV malignant glioma is dismal, and there is currently no effective therapy. We conducted a dose-finding and toxicity study in this population of patients, evaluating convection-enhanced, intratumoral delivery of the recombinant nonpathogenic polio–rhinovirus chimera (PVSRIPO). PVSRIPO recognizes the poliovirus receptor CD155, which is widely expressed in neoplastic cells of solid tumors and in major components of the tumor microenvironment. We enrolled consecutive adult patients who had recurrent supratentorial WHO grade IV malignant glioma, confirmed on histopathological testing, with measurable disease (contrast-enhancing tumor of ≥1 cm and ≤5.5 cm in the greatest dimension). The study evaluated seven doses, ranging between 107 and 1010 50% tissue-culture infectious doses (TCID50), first in a dose-escalation phase and then in a dose-expansion phase. From May 2012 through May 2017, a total of 61 patients were enrolled and received a dose of PVSRIPO. Dose level −1 (5.0×107 TCID50) was identified as the phase 2 dose. One dose-limiting toxic effect was observed; a patient in whom dose level 5 (1010 TCID50) was administered had a grade 4 intracranial hemorrhage immediately after the catheter was removed. To mitigate locoregional inflammation of the infused tumor with prolonged glucocorticoid use, dose level 5 was deescalated to reach the phase 2 dose. In the dose-expansion phase, 19% of the patients had a PVSRIPO-related adverse event of grade 3 or higher. Overall survival among the patients who received PVSRIPO reached a plateau of 21% (95% confidence interval, 11 to 33) at 24 months that was sustained at 36 months. Intratumoral infusion of PVSRIPO in patients with recurrent WHO grade IV malignant glioma confirmed the absence of neurovirulent potential. The survival rate among patients who received PVSRIPO immunotherapy was higher at 24 and 36 months than the rate among historical controls.