溶瘤病毒对抗脑瘤!临床1期显示:显著延长患者生存期
2018/02/27
“一种常见的感冒病毒经过‘改造’后,能够攻击致命的脑瘤,延长患者的生存期”——这是一项发表在《Journal of Clinical Oncology》期刊上的最新成果。来自于德克萨斯大学MD安德森癌症中心的研究人员刚刚完成了临床Ⅰ期试验,并获得喜人的成绩。


图片来源: Min Yu (Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC),USC Norris Comprehensive Cancer Center

带来这一惊喜的溶瘤腺病毒(oncolytic adenovirus)被命名为“DNX-2401”(Delta-24-RGD),不仅仅可以特异性靶向肿瘤细胞,还具备较强的复制能力,能够进一步刺激宿主的抗肿瘤免疫反应。

来自于MD安德森癌症中心的科学家们针对DNX-2401启动了临床Ⅰ期试验,结果显示,该病毒能够显著延长胶质母细胞瘤复发患者的生存期,其中20%的患者生存期达到3年。通常,胶质母细胞瘤复发的患者只有6个月的中位生存期。这无疑是个好消息。


图片来源:Journal of Clinical Oncology(DOI: 10.1200/JCO.2017.75.8219

72%的患者生存期延长

他们共招募37名复发性恶性胶质瘤患者,并分成两组:A组(25人)接受病毒注射,用于评估安全性和有效性;B组(12人)患者在接受病毒注射14天后,将被采集肿瘤样本,用于分析腺病毒的作用机制。

结果显示,A组中有18例患者(72%)的肿瘤减小,总体生存期达到9.5个月。同时,有3名患者的肿瘤得到了95%的减少,且无进展生存期超过3年(其中2名患者的无进展生存期分别达到42.5个月、36.4个月)。

B组结果表明,DNX-2401被证实能够特异性攻击癌细胞,并在肿瘤组织内复制、扩散。而且,这一疗法毒性较小,只有两名患者出现了与治疗相关的轻度副作用。

腺病毒刺激免疫反应

临床试验表明,腺病毒感染可以激活免疫系统攻击肿瘤。

通常,胶质母细胞瘤不会引起免疫系统的注意,几乎没有T细胞能够穿透肿瘤。现在,溶瘤腺病毒可以通过杀死肿瘤细胞,瓦解肿瘤对于免疫系统的逃逸机制,从而为后者提供多个抗原靶点,最终完全摧毁肿瘤。

研究团队正在优化这一方案,为病毒添加新的因素,从而进一步刺激免疫系统。他们还试图将“智能病毒炸弹”与其他治疗方法结合,例如“DNX-2401+Keytruda”(一款热门的免疫检查点抑制剂),以此评估这一联合增强免疫反应的效果。

参考资料:

Smart bomb virus shows promise as brain tumor immunotherapy

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  • Phase I Study of DNX-2401 (Delta-24-RGD) Oncolytic Adenovirus: Replication and Immunotherapeutic Effects in Recurrent Malignant Glioma

    Purpose DNX-2401 (Delta-24-RGD; tasadenoturev) is a tumor-selective, replication-competent oncolytic adenovirus. Preclinical studies demonstrated antiglioma efficacy, but the effects and mechanisms of action have not been evaluated in patients. Methods A phase I, dose-escalation, biologic-end-point clinical trial of DNX-2401 was conducted in 37 patients with recurrent malignant glioma. Patients received a single intratumoral injection of DNX-2401 into biopsy-confirmed recurrent tumor to evaluate safety and response across eight dose levels (group A). To investigate the mechanism of action, a second group of patients (group B) underwent intratumoral injection through a permanently implanted catheter, followed 14 days later by en bloc resection to acquire post-treatment specimens. Results In group A (n = 25), 20% of patients survived > 3 years from treatment, and three patients had a ≥ 95% reduction in the enhancing tumor (12%), with all three of these dramatic responses resulting in > 3 years of progression-free survival from the time of treatment. Analyses of post-treatment surgical specimens (group B, n = 12) showed that DNX-2401 replicates and spreads within the tumor, documenting direct virus-induced oncolysis in patients. In addition to radiographic signs of inflammation, histopathologic examination of immune markers in post-treatment specimens showed tumor infiltration by CD8+ and T-bet+ cells, and transmembrane immunoglobulin mucin-3 downregulation after treatment. Analyses of patient-derived cell lines for damage-associated molecular patterns revealed induction of immunogenic cell death in tumor cells after DNX-2401 administration. Conclusion Treatment with DNX-2401 resulted in dramatic responses with long-term survival in recurrent high-grade gliomas that are probably due to direct oncolytic effects of the virus followed by elicitation of an immune-mediated antiglioma response.

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