复发性神经胶质瘤的重组脊髓灰质炎病毒治疗。
Recurrent Glioblastoma Treated with Recombinant Poliovirus.
机构信息
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.).
出版信息
N Engl J Med. 2018 Jul 12;379(2):150-161. doi: 10.1056/NEJMoa1716435. Epub 2018 Jun 26.
BACKGROUND
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.
METHODS
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 10 and 10 50% tissue-culture infectious doses (TCID), first in a dose-escalation phase and then in a dose-expansion phase.
RESULTS
From May 2012 through May 2017, a total of 61 patients were enrolled and received a dose of PVSRIPO. Dose level -1 (5.0×10 TCID) was identified as the phase 2 dose. One dose-limiting toxic effect was observed; a patient in whom dose level 5 (10 TCID) 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.
CONCLUSIONS
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. (Funded by the Brain Tumor Research Charity and others; ClinicalTrials.gov number, NCT01491893 .).
背景
世界卫生组织（WHO）四级恶性胶质瘤患者的预后较差，目前尚无有效的治疗方法。我们在该人群中进行了剂量发现和毒性研究，评估了重组非致病性脊髓灰质炎-鼻病毒嵌合体（PVSRIPO）的经皮腔内瘤内输送。PVSRIPO 识别广泛表达于实体瘤肿瘤细胞和肿瘤微环境主要成分的脊髓灰质炎病毒受体 CD155。
方法
我们纳入了连续的成年患者，这些患者患有经组织病理学证实的复发性幕上 WHO 四级恶性胶质瘤，且有可测量的疾病（增强对比的肿瘤直径≥1cm 且≤5.5cm）。该研究评估了 7 个剂量，范围在 10 到 10 50%组织培养感染剂量（TCID）之间，首先在剂量递增阶段，然后在剂量扩展阶段进行。
结果
2012 年 5 月至 2017 年 5 月，共有 61 名患者入组并接受了 PVSRIPO 剂量。确定剂量水平-1（5.0×10 TCID）为 2 期剂量。观察到 1 例剂量限制性毒性作用；在接受 5 剂量（10 TCID）的患者中，导管取出后立即出现 4 级颅内出血。为了减轻局部炎症，减少糖皮质激素的使用，将 5 剂量降低到达到 2 期剂量。在剂量扩展阶段，19%的患者出现 3 级或更高级别的与 PVSRIPO 相关的不良事件。接受 PVSRIPO 治疗的患者总生存在 24 个月时达到 21%（95%置信区间，11 至 33）的平台，并在 36 个月时保持稳定。
结论
在复发性 WHO 四级恶性胶质瘤患者中，经皮腔内瘤内输注 PVSRIPO 证实了其无神经毒性潜力。接受 PVSRIPO 免疫治疗的患者在 24 个月和 36 个月时的生存率高于历史对照。（由脑肿瘤研究慈善机构等资助；ClinicalTrials.gov 编号，NCT01491893）。
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