Fairman Jeffery, Liu Katherine H, Menne Stephan
Juvaris BioTherapeutics, Inc., Pleasanton, CA, 94566, USA.
Present address: SutroVax, Inc., South San Francisco, CA, 94080, USA.
BMC Cancer. 2017 Mar 6;17(1):172. doi: 10.1186/s12885-017-3163-2.
Approximately 250 million people worldwide are chronically infected with hepatitis B virus (HBV) and more than half of the hepatocellular carcinoma (HCC) cases are attributed to this infection. As HCC has a high mortality rate, and current treatment options are remarkably limited, the development of new therapeutic treatment strategies is warranted.
In this study, woodchucks infected with woodchuck hepatitis virus (WHV), and with pre-existing liver tumors, were used as a model to investigate if complexes of cationic liposomes and non-coding DNA (JVRS-100) were effective in treatment of HCC.
It was observed that the high serum viral load that is present in a typical chronic WHV infection (i.e., approximately 100-fold higher than human viral loads) results in immune suppression and resistance to treatment with JVRS-100. Treatment of woodchucks with lower serum viral load that more closely matched with the viral load usually seen in human HBV infection appears a better model for immunotherapeutic development based on the responsiveness to JVRS-100 treatment. In the latter case, marked declines in WHV DNA and WHV surface antigen were determined over the 12-week treatment period and WHV markers stayed suppressed during most time points of the 12-week follow-up period. Even more remarkably, the formation of new liver tumors was not observed in woodchucks treated with a well-tolerated dose of JVRS-100, as compared to several new tumors that developed in vehicle-treated control animals.
Although there was little decrease in the volumes of the liver tumors existing at the time of treatment, it is generally accepted that preventing the spread and metastasis of almost always fatal cancers such as HCC and thus, reducing it to a chronic and treatable disease can also be a successful therapeutic approach. The results in woodchucks warrant the investigation of JVRS-100 as an intervention to prevent liver cancer in patients chronically infected with HBV and at high risk for HCC development.
全球约有2.5亿人慢性感染乙肝病毒（HBV），超过半数的肝细胞癌（HCC）病例归因于这种感染。由于HCC死亡率高，且目前的治疗选择极为有限，因此有必要开发新的治疗策略。
在本研究中，感染土拨鼠肝炎病毒（WHV）且已存在肝肿瘤的土拨鼠被用作模型，以研究阳离子脂质体与非编码DNA复合物（JVRS - 100）对HCC的治疗效果。
观察到典型慢性WHV感染中存在的高血清病毒载量（即比人类病毒载量高约100倍）会导致免疫抑制以及对JVRS - 100治疗产生抗性。用血清病毒载量较低且更接近人类HBV感染中常见病毒载量的土拨鼠进行治疗，基于对JVRS - 100治疗的反应性，似乎是免疫治疗开发的更好模型。在后一种情况下，在12周的治疗期内，WHV DNA和WHV表面抗原显著下降，并且在12周随访期的大多数时间点，WHV标志物一直处于被抑制状态。更值得注意的是，与接受载体治疗的对照动物中出现的几个新肿瘤相比，用耐受性良好剂量的JVRS - 100治疗的土拨鼠未观察到新肝肿瘤的形成。
尽管治疗时现有肝肿瘤的体积几乎没有减小，但人们普遍认为，预防像HCC这样几乎总是致命的癌症的扩散和转移，并将其转化为一种慢性且可治疗的疾病，也可以是一种成功的治疗方法。土拨鼠实验的结果证明有必要研究将JVRS - 100作为一种干预措施，用于预防慢性感染HBV且有HCC发生高风险患者的肝癌。
