Tolerability and safety of EUS-injected adenovirus-mediated double-suicide gene therapy with chemotherapy in locally advanced pancreatic cancer: a phase 1 trial
Tolerability and safety of EUS-injected adenovirus-mediated double-suicide gene therapy with chemotherapy in locally advanced pancreatic cancer: a phase 1 trial
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DOI：
10.1016/j.gie.2020.02.012
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发表时间：
2020-11-01
影响因子：
7.7
通讯作者：
Hwang, Jin-Hyeok
中科院分区：
文献类型：
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作者：
Lee, Jong-Chan;Shin, Dong Woo;Hwang, Jin-Hyeok
背景和目标：局部晚期胰腺癌（LAPC）具有挑战性。在这里，我们的目的是评估 Ad5-yCD/mutTK(SR39)rep-ADP (Ad5-DS)（一种具有复制能力的腺病毒介导的双自杀基因疗法）与吉西他滨联合治疗 LAPC 患者的耐受性和安全性。 方法：新诊断的 LAPC 患者被纳入这项单中心、开放标签、3 + 3 剂量递增的 1 期试验。使用 EUS 引导的细针将 Ad5-DS 注射到胰腺肿块中，并结合口服 5-氟胞嘧啶和缬更昔洛韦，以及标准剂量的静脉注射吉西他滨。第 1 至第 3 组中 Ad5-DS 的剂量分别为 1 x 10(11)、3 x 10(11) 和 1 x 10(12) 病毒颗粒 (vp)/mL。 Ad5-DS 注射后观察患者剂量限制毒性 (DLT) 8 周。还评估了12周内的毒性、12周内的肿瘤反应、6.5个月内的疾病进展以及8周内的腺病毒DNA颗粒检测。结果：在11名入组患者中，9名完成评估期，2名撤回同意。没有报告 DLT；因此，未达到最大耐受剂量。 9 至 12 周内没有报告额外的毒性。 12 周时，1 名患者出现部分缓解，8 名患者病情稳定。两名患者在 6.5 个月时出现疾病进展（中位无进展生存期为 11.4 个月）。 8周时，4名患者（中位时间为55天）检测到血清腺病毒DNA颗粒。结论：瘤内注射Ad5-DS和吉西他滨的组合对于LAPC患者是安全的且耐受性良好。这需要在更大规模的临床试验中进行进一步研究。
Background and Aims: Locally advanced pancreatic cancer (LAPC) is challenging. Here, we aimed to evaluate the tolerability and safety of Ad5-yCD/mutTK(SR39)rep-ADP (Ad5-DS), a replication-competent adenovirus-mediated double-suicide gene therapy in combination with gemcitabine in patients with LAPC.Methods: Patients with newly diagnosed LAPC were enrolled in this single-center, open-label, 3 + 3 dose-escalation phase 1 trial. Ad5-DS was injected into the pancreatic mass with EUS-guided fine needles combined with oral 5-fluorocytosine and valganciclovir, and a standard dose of intravenous gemcitabine. The doses of Ad5-DS in cohorts 1 to 3 were 1 x 10(11), 3 x 10(11), and 1 x 10(12) viral particles (vp)/mL, respectively. Patients were observed for dose-limiting toxicity (DLT) for 8 weeks after Ad5-DS injection. Toxicity within 12 weeks, tumor response in 12 weeks, disease progression in 6.5 months, and detection of adenoviral DNA particles in 8 weeks were also assessed.Results: Among the 11 enrolled patients, 9 completed the evaluation period and 2 withdrew their consent. No DLT was reported; thus, the maximum tolerated dose was not reached. No additional toxicity was reported in 9 to 12 weeks. One patient showed a partial response and 8 showed stable disease at 12 weeks. Two patients showed disease progression at 6.5 months (median progression-free survival, 11.4 months). At 8 weeks, serum adenoviral DNA particles were detected in 4 patients (median, 55 days).Conclusion: A combination of intratumoral Ad5-DS and gemcitabine is safe and well tolerated in patients with LAPC. This warrants further investigation in a larger clinical trial.