Phase I trial of a pathotropic retroviral vector expressing a cytocidal cyclin G1 construct (rexin-G) in patients with advanced pancreatic cancer
Phase I trial of a pathotropic retroviral vector expressing a cytocidal cyclin G1 construct (rexin-G) in patients with advanced pancreatic cancer
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DOI：
10.1038/mt.2008.29
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发表时间：
2008-05-01
影响因子：
12.4
通讯作者：
Rubin, Joseph
中科院分区：
文献类型：
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作者：
Galanis, Evanthia;Carlson, Stephanie K.;Rubin, Joseph
Rexin-G是一种具有血管性血友病因子靶向基序并表达显性负性细胞周期蛋白G1基因的嗜病理性逆转录病毒载体。我们在吉西他滨难治性转移性胰腺癌患者中进行了Rexin-G静脉（IV）给药的I期试验。12名患者接受了治疗。从1 x 10（11）个菌落形成单位（CFU）/周期至6 x 10（11）个CFU/周期进行剂量递增。治疗耐受性良好。在剂量水平2（1.5 x 10（11）CFU/周期）观察到1例剂量限制性毒性（DLT），包括3级转氨酶升高。在患者外周血单核细胞（PBMC）中未检测到有复制能力的病毒，也未检测到从PBMC获得的DNA中的病毒整合，也未产生中和抗体。未观察到抗肿瘤活性的证据。12例研究患者中有11例的最佳客观缓解为疾病进展，而1例患者显示放射学稳定的疾病伴临床恶化和CA 19.9肿瘤标志物升高。中位进展时间为32天。研究患者的中位生存期为治疗开始后3.5个月。Rexin-G在复发性胰腺癌患者中的耐受性良好，剂量高达6 × 10（11）CFU，但没有临床抗肿瘤活性的证据。
Rexin-G is a pathotropic retroviral vector displaying a von Willebrand factor-targeting motif and expressing a dominant negative cyclin G1 gene. We undertook a phase I trial of intravenous (IV) administration of Rexin-G in patients with gemcitabine refractory, metastatic pancreatic adenocarcinoma. Twelve patients were treated. Dose escalation was performed from a dose of 1 x 10(11) colony forming units (CFU) per cycle to 6 x 10(11) CFU per cycle. The treatment was well tolerated. One dose-limiting toxicity (DLT) at dose level 2 (1.5 x 10(11) CFU per cycle) was observed, consisting of grade 3 transaminitis. There was no detection of replication-competent virus in patients' peripheral blood mononuclear cells (PBMCs) or viral integration in DNA obtained from PBMCs, and no development of neutralizing antibodies. No evidence of antitumor activity was observed. The best objective response was progressive disease in 11 of the 12 study patients, while 1 patient showed radiographically stable disease with clinical deterioration and increase in the CA19.9 tumor marker. Median time to progression was 32 days. The median duration of survival of the study patients was 3.5 months from treatment initiation. Rexin-G is well tolerated in doses up to 6 x 10(11) CFU in patients with recurrent pancreatic cancer, but there was no evidence of clinical antitumor activity.