PHASE I TRIAL OF ADENOVIRUS GA733-2 VACCINE FOR COLORECTAL CANCER

腺病毒 GA733-2 结直肠癌疫苗的 I 期试验

• 批准号: 6300547
• 负责人: David J. Vaughn
• 金额: $ 15.41万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-01 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6300547
• 关键词: Adenoviridae; cellular immunity; clinical research; clinical trial phase I; colorectal neoplasms; cytotoxicity; dosage; gene expression; human subject; human therapy evaluation; laboratory mouse; metastasis; neoplasm /cancer therapy; neoplasm /cancer vaccine; recombinant proteins; tumor antigens

The major goal of the proposed studies is to test the hypothesis that a recombinant adenovirus expressing the tumor associated antigen GA733 (Ad.GA733-2) can be utilized to elicit a GA733 antigen-specific immune response in patients with metastatic colorectal cancer. The first step will be to produce Ag.GA733-2 for clinical use and to perform preclinical toxicity studies. Administration of Ag.GA733-2 and the mouse homologue Ad.mEGP will be performed in BALB/C mice. The intraperitoneal route will be utilized for the preclinical and clinical studies unless ongoing and future experiments demonstrate that the intradermal/subcutaneous route is efficacious. A range of virus doses will be tested in these animals. We will define the toxicity of this therapy by clinical parameters as well as necropsy. We will then perform a phase I study of intraperitoneal injection of Ad.GA733-2 in humans with metastatic colorectal cancer. We will define the toxicities of this treatment in humans at a range of dose levels as determined in the preclinical toxicity testing. We will define the toxicities of this treatment in humans at a range of dose levels as determined in the preclinical toxicity testing. We will attempt to determine the dose-limiting toxicities of this treatment in humans at a range of dose levels as determined in the preclinical toxicity testing. We will attempt to determine the dose-limiting toxicities and the mechanisms of toxicity of this treatment. As well, all patients treated will undergo extensive immunologic testing to determine the ability of intraperitoneal vaccination with Ad.GA733-2 to induce humoral and/or cellular immune responses (Project 4). We will also assess objective anti-tumor responses in these patients. Subsequent vaccination trials in metastatic colorectal cancer patients will be based upon the results of this phase I trial and Project 2. We anticipate, based on preliminary data obtained in mice, to conduct a subsequent phase I trial that focuses upon the combination of Ad.GA733-2 and interleukin-2. Future phase I trials may incorporate new vaccination strategies derived from Projects 1,2, and 4.

拟议研究的主要目标是检验以下假设： 表达肿瘤相关抗原GA 733的重组腺病毒 GA 733 -2）可用于引发GA 733抗原特异性免疫 转移性结直肠癌患者的缓解。第一步 将生产用于临床的Ag.GA733-2，并进行临床前试验， 毒性研究。Ag.GA733-2和小鼠同源物的施用 将在BALB/C小鼠中进行Ad.mEGP。腹膜内途径将 用于临床前和临床研究，除非正在进行中， 未来的实验表明，皮内/皮下途径是 灵验。将在这些动物中测试一系列病毒剂量。我们 将通过临床参数以及 尸检然后我们将进行一项I期研究， 在患有转移性结直肠癌的人中注射Ad.GA733-2。我们 将定义在一定剂量范围内这种治疗在人体中的毒性 在临床前毒性试验中确定的水平。我们将定义 该治疗在一系列剂量水平下对人体的毒性， 在临床前毒性试验中确定。我们将尝试 确定这种治疗在人类中的剂量限制性毒性， 临床前毒性试验中确定的剂量水平范围。我们 将尝试确定剂量限制性毒性和机制 这种治疗的毒性。同时，所有接受治疗的患者将接受 广泛的免疫学测试，以确定腹腔内的能力， 用Ad.GA733-2接种以诱导体液和/或细胞免疫 项目（4）。我们还将评估客观的抗肿瘤反应 在这些患者中。转移性结直肠癌的后续疫苗接种试验 癌症患者将基于这项I期试验的结果， 项目2.基于在小鼠中获得的初步数据，我们预计， 进行后续的第一阶段试验，重点是结合 Ad.GA733-2和白细胞介素-2。未来的I期试验可能会纳入新的 疫苗接种策略源自项目1、2和4。