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重组脊髓灰质炎病毒治疗复发性胶质母细胞瘤
Recurrent Glioblastoma Treated with Recombinant Poliovirus


Annick Desjardins ... 肿瘤 • 2018.07.12
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• 重组脊髓灰质炎病毒治疗复发性胶质母细胞瘤

改造脊髓灰质炎病毒,治疗脑胶质瘤

 

马大程,谢震*

清华大学自动化系;清华大学合成与系统生物学研究中心;北京信息科学与技术国家研究中心

*通讯作者

 

2018年7月12日《新英格兰医学杂志》发表了题为《重组脊髓灰质炎病毒治疗复发性胶质母细胞瘤》(Recurrent Glioblastoma Treated with Recombinant Poliovirus)的临床试验1。来自美国杜克大学的Darell D. Bigner团队从2012年5月到2017年5月的5年时间内,共在61个确认为世界卫生组织(WHO)Ⅳ级恶性胶质瘤患者中开展临床试验。结果表明,这些患者的2年生存率实现21%,远高于历史数据的14%,同时,3年生存率维持了21%,而历史数据仅为4%。

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摘要


背景

复发性世界卫生组织(WHO)Ⅳ级恶性胶质瘤患者的预后极差,目前尚无有效的治疗方法。我们在这一患者人群中开展了一项剂量探索和毒性研究,对重组非致病性脊髓灰质炎-鼻病毒嵌合体(PVSRIPO)的对流增强(convection-enhanced)、肿瘤内给药进行了评估。PVSRIPO能够识别脊髓灰质炎病毒受体CD155,而CD155在实体瘤的肿瘤细胞和肿瘤微环境的主要成分中广泛表达。

 

方法

我们纳入患复发性幕上WHO Ⅳ级恶性胶质瘤的连续成人患者,肿瘤病变经组织病理学检查证实,大小可测量(造影增强的肿瘤最大尺寸≥1 cm并且≤5.5 cm)。本研究首先在剂量递增阶段,然后在剂量扩展阶段共评估了7种剂量,范围在107和1010半数组织培养感染剂量(TCID50)之间。

 

结果

从2012年5月至2017年5月,本研究共纳入61例患者,患者均接受了1剂PVSRIPO治疗。剂量水平-1(即5.0×107 TCID50)被确定为2期研究剂量。观察到1种剂量限制性毒性作用;接受剂量水平5(即1010 TCID50)治疗的1例患者在导管移除后立即发生4级颅内出血。为了通过糖皮质激素长时间用药来减轻输入病毒的肿瘤的局部区域炎症,剂量水平5逐渐降低至达到2期研究剂量。在剂量扩展阶段,19%的患者有PVSRIPO相关的3级或更高级别的不良事件。24个月时,接受PVSRIPO治疗的患者的总生存率达到了21%(95%置信区间[CI],11~33)这一平台水平,36个月时保持了这一总生存率。

 

结论

在复发性WHO Ⅳ级恶性胶质瘤患者瘤内输入PVSRIPO证实无神经毒性潜力。24和36个月时,接受PVSRIPO免疫治疗的患者的生存率高于历史对照的生存率(由脑瘤研究慈善机构[Brain Tumor Research Charity]等资助;在ClinicalTrials.gov注册号为NCT01491893)。





作者信息

Annick Desjardins, M.D., Matthias Gromeier, M.D., James E. Herndon, II, Ph.D., Nike Beaubier, M.D., Dani P. Bolognesi, Ph.D., Allan H. Friedman, M.D., Henry S. Friedman, M.D., Frances McSherry, M.A., Andrea M. Muscat, B.Sc., Smita Nair, Ph.D., Katherine B. Peters, M.D., Ph.D., Dina Randazzo, D.O., John H. Sampson, M.D., Ph.D., Gordana Vlahovic, M.D., William T. Harrison, M.D., Roger E. McLendon, M.D., David Ashley, M.B., B.S., Ph.D., and Darell D. Bigner, M.D., Ph.D.
From the Departments of Neurosurgery (A.D., M.G., A.H.F., H.S.F., K.B.P., D.R., J.H.S., G.V., D.A., D.D.B.), Biostatistics (J.E.H., F.M.), Surgery (D.P.B., S.N.), and Pathology (W.T.H., R.E.M.) and the Preston Robert Tisch Brain Tumor Center (A.D., M.G., J.E.H., D.P.B., A.H.F., H.S.F., F.M., S.N., K.B.P., D.R., J.H.S., G.V., W.T.H., R.E.M., D.A., D.D.B.), Duke University Medical Center, and Istari Oncology (D.P.B.) — all in Durham, NC; Tempus Labs, Chicago (N.B.); and the School of Medicine, Deakin University, Geelong, VIC, Australia (A.M.M.). Address reprint requests to Dr. Bigner at Duke University Medical Center, 177 MSRB, Box 3156, Research Dr., Durham, NC 27710, or at darell.bigner@duke.edu.

 

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