Barton Kenneth N, Siddiqui Farzan, Pompa Robert, Freytag Svend O, Khan Gazala, Dobrosotskaya Irina, Ajlouni Munther, Zhang Yingshu, Cheng Jingfang, Movsas Benjamin, Kwon David
Department of Radiation Oncology, Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI 48202, USA.
Department of Gastroenterology, Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI 48202, USA.
Mol Ther Oncolytics. 2020 Dec 3;20:94-104. doi: 10.1016/j.omto.2020.11.006. eCollection 2021 Mar 26.
The safety of oncolytic adenovirus-mediated suicide and interleukin-12 ( ) gene therapy was evaluated in metastatic pancreatic cancer patients. In this phase I study, a replication-competent adenovirus (Ad5-yCD/TK -hIL-12) expressing yCD/TK (yeast cytidine deaminase/mutant S39R HSV-1 thymidine kinase) and human IL-12 ( ) was injected into tumors of 12 subjects with metastatic pancreatic cancer (T2N0M1-T4N1M1) at escalating doses (1 × 10, 3 × 10, or 1 × 10 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 , 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/TK -hIL-12 and oral 5-FC. Approximately 94% of the 121 adverse events observed were grade 1/2 requiring no medical intervention. Ad5-yCD/TK -hIL-12 DNA was detected in the blood of two patients. Elevated serum , IFNG, and CXCL10 levels were detected in 42%, 75%, and 92% of subjects, respectively. Analysis of immune cell populations indicated activation after Ad5-yCD/TK -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.
在转移性胰腺癌患者中评估了溶瘤腺病毒介导的自杀基因和白细胞介素-12（ ）基因治疗的安全性。在这项I期研究中，将表达酵母胞嘧啶脱氨酶/突变型S39R单纯疱疹病毒1型胸苷激酶（yCD/TK）和人白细胞介素-12（ ）的复制型腺病毒（Ad5-yCD/TK -hIL-12）以递增剂量（1×10、3×10或1×10病毒颗粒）注射到12例转移性胰腺癌（T2N0M1-T4N1M1）患者的肿瘤中。患者接受7天的5-氟胞嘧啶（5-FC）治疗，随后在腺病毒注射后21天开始化疗（FOLFIRINOX或吉西他滨/白蛋白结合型紫杉醇）。研究终点是至第21天的毒性。实验终点包括测量血清 、干扰素γ（IFNG）和CXCL10以评估免疫系统激活。通过流式细胞术分析外周血单个核细胞和增殖标志物。12例患者接受了Ad5-yCD/TK -hIL-12和口服5-FC。观察到的121例不良事件中约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/TK -hIL-12 DNA。分别在42%、75%和92%的受试者中检测到血清 、IFNG和CXCL10水平升高。免疫细胞群体分析表明，Ad5-yCD/TK -hIL-12给药后有激活。第三组患者的中位生存期为18.1（范围3.5-20.0）个月。未达到研究的最大耐受剂量（MTD）。
