Phase I trial of oncolytic adenovirus-mediated cytotoxic and interleukin-12 gene therapy for the treatment of metastatic pancreatic cancer.
Phase I trial of oncolytic adenovirus-mediated cytotoxic and interleukin-12 gene therapy for the treatment of metastatic pancreatic cancer.
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溶瘤腺病毒介导的细胞毒性和白细胞介素-12 基因疗法治疗转移性胰腺癌的 I 期试验。
DOI：
10.1016/j.omto.2020.11.006
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发表时间：
2021-03-26
期刊：
影响因子：
--
通讯作者：
Kwon D
中科院分区：
文献类型：
--
作者：
Barton KN;Siddiqui F;Pompa R;Freytag SO;Khan G;Dobrosotskaya I;Ajlouni M;Zhang Y;Cheng J;Movsas B;Kwon D
在转移性胰腺癌患者中评估了溶瘤腺病毒介导的自杀和白介素 12 (IL12) 基因治疗的安全性。在这项 I 期研究中，将表达 yCD/mutTKSR39（酵母胞苷脱氨酶/突变型 S39R HSV-1 胸苷激酶）和人 IL-12 (IL12) 的具有复制能力的腺病毒 (Ad5-yCD/mutTKSR39rep-hIL-12) 注射到 12 名转移性胰腺癌受试者 (T2N0M1-T4N1M1) 的肿瘤中。剂量递增（1 × 1011、3 × 1011 或 1 × 1012 病毒颗粒）。受试者接受 5-氟胞嘧啶 (5-FC) 治疗 7 天，然后在腺病毒注射后 21 天开始接受化疗（FOLFIRINOX 或吉西他滨/白蛋白结合紫杉醇）。研究终点是第 21 天的毒性。实验终点包括血清 IL12、干扰素 γ (IFNG) 和 CXCL10 的测量，以评估免疫系统的激活。通过流式细胞仪分析外周血单核细胞和增殖标志物。 12 名患者接受 Ad5-yCD/mutTKSR39rep-hIL-12 和口服 5-FC。在观察到的 121 起不良事件中，大约 94% 为 1/2 级，无需医疗干预。在两名患者的血液中检测到 Ad5-yCD/mutTKSR39rep-hIL-12 DNA。分别有 42%、75% 和 92% 的受试者检测到血清 IL12、IFNG 和 CXCL10 水平升高。免疫细胞群分析表明 Ad5-yCD/mutTKSR39rep-hIL-12 施用后激活。第三组患者的中位生存期为 18.1（范围，3.5-20.0）个月。未达到研究最大耐受剂量（MTD）。进行了一项 I 期剂量递增研究，以证明溶瘤腺病毒介导的自杀和白细胞介素 12 基因治疗联合化疗对转移性胰腺癌患者的安全性。我们的方法被证明是安全的，并且有迹象表明对接受最高腺病毒剂量的患者有效。
The safety of oncolytic adenovirus-mediated suicide and interleukin-12 (IL12) gene therapy was evaluated in metastatic pancreatic cancer patients. In this phase I study, a replication-competent adenovirus (Ad5-yCD/mutTKSR39rep-hIL-12) expressing yCD/mutTKSR39 (yeast cytidine deaminase/mutant S39R HSV-1 thymidine kinase) and human IL-12 (IL12) was injected into tumors of 12 subjects with metastatic pancreatic cancer (T2N0M1-T4N1M1) at escalating doses (1 × 1011, 3 × 1011, or 1 × 1012 viral particles). Subjects received 5-fluorocytosine (5-FC) therapy for 7 days followed by chemotherapy (FOLFIRINOX or gemcitabine/albumin-bound paclitaxel) starting 21 days after adenovirus injection. The study endpoint was toxicity through day 21. Experimental endpoints included measurements of serum IL12, interferon gamma (IFNG), and CXCL10 to assess immune system activation. Peripheral blood mononuclear cells and proliferation markers were analyzed by flow cytometry. Twelve patients received Ad5-yCD/mutTKSR39rep-hIL-12 and oral 5-FC. Approximately 94% of the 121 adverse events observed were grade 1/2 requiring no medical intervention. Ad5-yCD/mutTKSR39rep-hIL-12 DNA was detected in the blood of two patients. Elevated serum IL12, IFNG, and CXCL10 levels were detected in 42%, 75%, and 92% of subjects, respectively. Analysis of immune cell populations indicated activation after Ad5-yCD/mutTKSR39rep-hIL-12 administration. The median survival of patients in the third cohort is 18.1 (range, 3.5–20.0) months. The study maximum tolerated dose (MTD) was not reached. A phase I dose-escalation study was conducted to demonstrate the safety of oncolytic adenovirus-mediated suicide and interleukin-12 gene therapy combined with chemotherapy in metastatic pancreatic cancer patients. Our approach was shown to be safe, and there are indications of efficacy in patients who received the highest adenovirus dose.
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12.4
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