Phase I Study of DNX-2401 (Delta-24-RGD) Oncolytic Adenovirus: Replication and Immunotherapeutic Effects in Recurrent Malignant Glioma
Phase I Study of DNX-2401 (Delta-24-RGD) Oncolytic Adenovirus: Replication and Immunotherapeutic Effects in Recurrent Malignant Glioma
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DOI：
10.1200/jco.2017.75.8219
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发表时间：
2018-05-10
影响因子：
45.3
通讯作者：
Fueyo, Juan
中科院分区：
文献类型：
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作者：
Lang, Frederick F.;Conrad, Charles;Fueyo, Juan
目的DNX-2401（Delta-24-RGD; tasadenoturev）是一种具有肿瘤选择性、增殖能力的溶瘤腺病毒。临床前研究表明，抗胶质瘤的疗效，但作用的效果和机制尚未在patients.MethodsA I期，剂量递增，生物终点临床试验DNX-2401进行了37例复发性恶性胶质瘤。患者接受单次瘤内注射DNX-2401至活检证实的复发肿瘤中，以评估八个剂量水平的安全性和反应（A组）。为了研究作用机制，第二组患者（B组）通过永久植入导管进行瘤内注射，14天后进行整块切除以获得治疗后标本。结果在A组（n = 25）中，20%的患者从治疗后存活> 3年，3名患者的增强肿瘤缩小了95%（12%），所有这三种显著的反应导致从治疗时起> 3年的无进展存活。对治疗后手术标本（组B，n = 12）的分析显示，DNX-2401在肿瘤内复制和扩散，记录了患者中的直接病毒诱导的溶瘤作用。除了炎症的放射学体征外，治疗后标本中免疫标志物的组织病理学检查显示肿瘤浸润有CD 8（+）和T-bet（+）细胞，治疗后跨膜免疫球蛋白粘蛋白-3下调。损伤相关的分子模式的患者来源的细胞系的分析显示诱导免疫原性细胞死亡后，肿瘤细胞DNX-2401 administration.ConclusionTreatment与DNX-2401导致显着的反应与长期生存的复发性高级别胶质瘤，这可能是由于直接溶瘤作用的病毒，然后通过激发免疫介导的抗胶质瘤反应。
PurposeDNX-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.MethodsA 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.ResultsIn 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.ConclusionTreatment 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.