Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, 1500 Duarte Rd., Duarte, CA, 91010, USA.
Center for Gene Therapy, Department of Hematologic and Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, 91010, USA.
J Transl Med. 2018 Apr 26;16(1):110. doi: 10.1186/s12967-018-1483-x.
Pancreatic ductal adenocarcinoma (PDAC) has been increasing by 0.5% per year in the United States. PDAC portends a dismal prognosis and novel therapies are needed. This study describes the generation and characterization of a novel oncolytic chimeric orthopoxvirus for the treatment of pancreatic cancer.
After chimerization and high-throughput screening, CF33 was chosen from 100 new chimeric orthopoxvirus isolates for its ability to kill pancreatic cancer cells. In vitro cytotoxicity was assayed in six pancreatic cancer cell lines. In vivo efficacy and toxicity were evaluated in PANC-1 and MIA PaCa-2 xenograft models.
CF33 caused rapid killing of six pancreatic cancer cells lines in vitro, releasing damage-associated molecular patterns, and regression of PANC-1 injected and non-injected distant xenografts in vivo after a single low intratumoral dose of 10 plaque-forming units. Using luciferase imaging, CF33 was noted to preferentially replicate in tumors which corresponds to the low viral titers found in solid organs.
The low dose of CF33 required to treat pancreatic cancer in this preclinical study may ease the manufacturing and dosing challenges currently facing oncolytic viral therapy.
在美国，胰腺导管腺癌（PDAC）每年以 0.5%的速度增长。PDAC 的预后不佳，需要新的治疗方法。本研究描述了一种新型溶瘤嵌合正痘病毒的产生和特征，用于治疗胰腺癌。
经过嵌合和高通量筛选，从 100 种新的嵌合正痘病毒分离株中选择 CF33，因其能够杀伤胰腺癌细胞。在六种胰腺癌细胞系中进行体外细胞毒性测定。在 PANC-1 和 MIA PaCa-2 异种移植模型中评价体内疗效和毒性。
CF33 在体外迅速杀死六种胰腺癌细胞系，释放损伤相关分子模式，并在单次低瘤内剂量 10 噬菌斑形成单位后，体内消退 PANC-1 注射和未注射的远处异种移植物。使用荧光素酶成像，发现 CF33 优先在肿瘤中复制，这与在实体器官中发现的低病毒滴度相对应。
在这项临床前研究中，治疗胰腺癌所需的 CF33 低剂量可能会减轻目前溶瘤病毒治疗面临的制造和剂量挑战。
