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首页> 外文期刊>Gene Therapy and Molecular Biology >Vaccine therapy for ovarian cancer using Herpes Simplex virus thymidine kinase (HSV- TK) suicide gene transfer technique: a phase I trial
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Vaccine therapy for ovarian cancer using Herpes Simplex virus thymidine kinase (HSV- TK) suicide gene transfer technique: a phase I trial

机译：使用单纯疱疹病毒胸苷激酶（HSV-TK）自杀基因转移技术的卵巢癌疫苗治疗：I期试验

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Genetically altered tumor cells expressing the HSV-TK gene have been used as vaccine therapy formultiple cancers, based on their ability to kill adjacent native cancer cells and activate an antitumor immune response. Our in vitro studies demonstrate that transduction with the HSV-TK system confers ganciclovir (GCV) susceptibility to cultured ovarian cancer cells. A murine tumor model was developed using HSV-TK modified ovarian cancer cells to test efficacy in a preclinical setting. Mice bearing intraperitoneal tumors were injected with gene modified cells and ganciclovir (GCV). The mice were evaluated for survival and immune response by analysis of tumor samples collected post treatment. Murine HSV-TK tumors undergo hemorrhagic tumor necrosis and express a cytokine cascade including TNF-, IL-1, IL-6, IL-2, IFN- and GM-CSF following GCV treatment. Tumor regression occurs much less frequently in immune deficient mice than immune competent mice. These studies led to a Phase I trial of intraperitoneal administration of the vaccine in which 18 patients with recurrent chemotherapy resistant ovarian cancer were enrolled. The mean survival of patients in the Phase I trial was 11.9 months. 4/18 patients had responses based on physical findings or CA-125. One patient died of breast cancer with no evidence of ovarian cancer at 24 months. Toxicities include all patients developing grade I or II temperature elevations without other evidence of infection, seven patients who developed grade I abdominal discomfort or nausea, and one patient with a grade III elevation of kidney function tests. We conclude that the use of an HSV- TK modified vaccine is associated with tumor regression in mice, and results in the alteration of the tumor microenvironment, which becomes less immunosuppressive. The use of the vaccine in humans is technically feasible and associated with minimal toxicity. Survival in these heavilypretreated patients is similar to that seen using standard cytotoxic chemotherapy.
机译：表达HSV-TK基因的基因改变的肿瘤细胞已被用于多种癌症的疫苗治疗，因为它们具有杀死相邻天然癌细胞并激活抗肿瘤免疫反应的能力。我们的体外研究表明，HSV-TK系统的转导使更昔洛韦（GCV）对培养的卵巢癌细胞具有敏感性。使用HSV-TK修饰的卵巢癌细胞建立了小鼠肿瘤模型，以在临床前环境中测试功效。向携带腹膜内肿瘤的小鼠注射基因修饰的细胞和更昔洛韦（GCV）。通过分析治疗后收集的肿瘤样品评估小鼠的存活和免疫应答。鼠HSV-TK肿瘤经历出血性肿瘤坏死并在GCV治疗后表达包括TNF-，IL-1，IL-6，IL-2，IFN-和GM-CSF的细胞因子级联反应。免疫缺陷小鼠的肿瘤消退频率要比免疫活性小鼠低得多。这些研究导致了疫苗腹膜内给药的I期试验，其中招募了18例复发性化疗耐药性卵巢癌患者。 I期试验中患者的平均生存期为11.9个月。 4/18例患者根据身体检查结果或CA-125做出了反应。一名患者死于乳腺癌，在24个月时没有卵巢癌的迹象。毒性反应包括所有I级或II级温度升高而无其他感染迹象的患者，7名I级腹部不适或恶心的患者以及1名肾功能测试升高III级的患者。我们得出的结论是，使用HSV-TK修饰的疫苗与小鼠体内的肿瘤消退有关，并导致肿瘤微环境的改变，其免疫抑制性降低。在人类中使用疫苗在技术上是可行的，并且毒性最小。这些经过严格治疗的患者的生存率与使用标准细胞毒性化学疗法的生存率相似。

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