First-in-man Phase 1 Clinical Trial of Gene Therapy for Advanced Pancreatic Cancer: Safety, Biodistribution, and Preliminary Clinical Findings
First-in-man Phase 1 Clinical Trial of Gene Therapy for Advanced Pancreatic Cancer: Safety, Biodistribution, and Preliminary Clinical Findings
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DOI：
10.1038/mt.2015.1
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发表时间：
2015-04-01
影响因子：
12.4
通讯作者：
Cordelier, Pierre
中科院分区：
文献类型：
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作者：
Buscail, Louis;Bournet, Barbara;Cordelier, Pierre
这项1期试验旨在确定CyL-02的安全性、药代动力学和初步临床活性，这是一种使胰腺癌细胞对化疗敏感的非病毒基因治疗产品。22名同时接受化疗(吉西他滨)的胰腺癌患者使用内窥镜超声对Cyl-02进行治疗。最大耐受量(MTD)超过了CyL-02的最大可行剂量，未确定。与治疗相关的毒性反应轻微，没有严重的不良反应。药代动力学分析显示，血液和肿瘤中的CyL-02 DNA暴露呈剂量依赖性增加，而在肿瘤中检测到治疗性RNA。没有观察到客观反应，但9名患者在治疗后6个月内病情稳定，其中2名患者获得了长期生存。一组血浆microRNAs和蛋白质被确定为预测基因治疗效果。我们证明，CYL-02非病毒基因治疗具有良好的安全性和患者的耐受性。我们研究了CyL-02在肿瘤中的生物分布，并展示了治疗性基因的表达。接受治疗的患者经历了疾病的稳定，并确定了治疗反应的预测生物标记物。这些有希望的结果值得在第二阶段临床试验中进一步评估。
This phase 1 trial was aimed to determine the safety, pharmacokinetics, and preliminary clinical activity of CYL-02, a nonviral gene therapy product that sensitizes pancreatic cancer cells to chemotherapy. CYL-02 was administrated using endoscopic ultrasound in 22 patients with pancreatic cancer that concomitantly received chemotherapy (gemcitabine). The maximum-tolerated dose (MTD) exceeded the maximal feasible dose of CYL-02 and was not identified. Treatment-related toxicities were mild, without serious adverse events. Pharmacokinetic analysis revealed a dose-dependent increase in CYL-02 DNA exposure in blood and tumors, while therapeutic RNAs were detected in tumors. No objective response was observed, but nine patients showed stable disease up to 6 months following treatment and two of these patients experienced long-term survival. Panels of plasmatic microRNAs and proteins were identified as predictive of gene therapy efficacy. We demonstrate that CYL-02 nonviral gene therapy has a favorable safety profile and is well tolerated in patients. We characterize CYL-02 biodistribution and demonstrate therapeutic gene expression in tumors. Treated patients experienced stability of disease and predictive biomarkers of response to treatment were identified. These promising results warrant further evaluation in phase 2 clinical trial.