COMBINATION GENE THERAPY IN COLORECTAL CANCER

描述：（改编自研究者摘要）其临床前 研究表明，肿瘤内基因的抗肿瘤免疫刺激作用 该疗法可能对治疗晚期结肠直肠癌有效。 白细胞介素-2（IL-2）是一种强效的细胞因子，能够诱导强的细胞凋亡， 针对多种抗原的免疫应答。单纯疱疹病毒 胸苷激酶（HSV-tk）是一种非哺乳动物固有的酶 可以磷酸化抗生素更昔洛韦， 被整合到延长的DNA链中并导致细胞死亡。使用 原位小鼠模型中预先建立的转移性结肠癌 我们已经证明，肿瘤内注射两种药物的组合， 腺病毒载体（表达IL 2和HSV-tk基因的ADV-mIL 2和ADV-tk 分别）一起诱导抗肿瘤免疫，产生肿瘤消退 并显著延长了生存期。诱导的抗肿瘤免疫是 全身性，主要由溶细胞性T淋巴细胞（CTL）介导， 随后在远处植入的亲本肿瘤细胞的攻击。到 测试是否可以在患有以下疾病的患者中诱导类似的抗肿瘤免疫应答： 转移性结直肠癌，我们提出了一个I期试验，其中两个载体 （表达人IL 2基因的ADV-hIL 2和ADV-tk）将混合在一起， 通过经皮放置一种 在超声引导下进行细针穿刺4小时后，更昔洛韦将 每天两次静脉内施用，持续七天。ADV-hIL 2的剂量 ADV-tk的剂量将固定在1011- pfu。的 ADV-tk剂量基于我们已完成的ADV-tk I期试验 在转移性结直肠癌患者中以相同的方式给药 然后静脉注射更昔洛韦无严重毒性 在109 - 1011- pfu的剂量下遇到。拟议的审判 载体组合将评价毒性、抗肿瘤免疫、肿瘤应答 和疾病进展。免疫学终点基于 国家的最先进的方法，并将有助于确定之间的关系， 抗肿瘤CTL免疫应答和肿瘤消退。成功完成 拟议的试验将提供证据支持进一步的II期疗效 肿瘤内基因治疗作为一种新的主动基因免疫试验 转移性结直肠癌患者的治疗模式。

DESCRIPTION: (adapted from the investigator's abstract) Their preclinical research indicates that antitumoral immune stimulation by intratumoral gene therapy may be effective for the treatment of advanced colorectal cancer. Interleukin-2 (IL2) is a potent cytokine capable of inducing strong cellular immune responses against a variety of antigens. The Herpes Simplex Virus thymidine kinase (HSV-tk) is an enzyme which is not indigenous to mammalian cells and can phosphorylate the antibiotic ganciclovir which becomes incorporated into elongating DNA strands and produces cell death. Using an orthotopic murine model for pre-established metastatic colon cancer in the liver, we have shown that intratumoral injection of a combination of two adenoviral vectors (ADV-mIL2 and ADV-tk expressing the IL2 and HSV-tk genes respectively) together induced antitumor immunity, produced tumor regression and significantly prolonged survival. The induced antitumor immunity was systemic, mediated primarily by cytolytic T-lymphocytes (CTL) and rejected subsequent challenge of parental tumor cells implanted at distant sites. To test if similar antitumor immune responses can be induced in patients with metastatic colorectal cancer, we propose a Phase I trial where two vectors (ADV-hIL2 expressing the human IL2 gene and ADV-tk) will be mixed together and injected into metastatic tumors in the liver by percutaneous placement of a skinny needle under sonographic guidance. 4 hours later, ganciclovir will be administered intravenously twice daily for seven days. The dose of ADV-hIL2 will be escalated while the dose of ADV-tk will be fixed at 1011- pfu. The ADV-tk dose was based on a Phase I trial which we have completed of ADV-tk administered in the same manner in patients with metastatic colorectal cancer to the liver and followed by intravenous ganciclovir. No serious toxicities were encountered at doses from 109 to 1011- pfu. The proposed trial of the vector combination will evaluate toxicity, antitumor immunity, tumor response and disease progression. The immunologic endpoints are based on state-of-the-art methodologies and will help to define the relationship between antitumor CTL immune responses and tumor regression. Successful completion of the proposed trial will provide evidence to support further Phase II efficacy trials on active genetic immunization by intratumoral gene therapy as a new treatment modality for patients with metastatic colorectal cancer.