RECOMBINANT ADENOVIRUS VACCINE FOR COLON CANCER

描述：（申请人的描述）我们提出了一种 使用腺病毒载体治疗转移性结肠癌的疫苗 GA 733抗原广泛表达于人胃肠道， 恶性肿瘤。 人类被动免疫研究表明， 抗原是治疗性免疫应答所针对的有效靶标 可以生成。 在动物模型中，我们已经证明， 抗原将引发细胞和体液免疫应答， 作为由腺病毒载体表达的重组蛋白施用。 用该载体（Ad.GA733）接种动物不仅可以预防 新肿瘤的发展，但导致已建立的肿瘤消退 也 此外，可以产生针对免疫原性的免疫应答。 小鼠中GA 733抗原的鼠同源物，表明对该抗原的耐受性 蛋白质可以通过疫苗接种策略来克服。 在本提案中，我们将在一系列动物中测试Ad.GA733的安全性。 建立疫苗的安全性模型。 然后我们将进行一次 I/II期临床试验，以证明安全性和免疫功效 在早期转移性结肠癌患者中的应用。 患者 将接种单剂量的Ad.GA733，经腹膜内给药。 然后监测它们是否出现抗原特异性 免疫反应 将对每种剂量的患者亚组进行以下检测： 使用腹膜灌洗以恢复腹膜的抗原表达的证据 巨噬细胞和间皮细胞。 对GA 733抗原的免疫应答 将通过对纯化药物的迟发型超敏反应进行评估 GA 733抗原，并通过一系列体外试验。 后者将包括 检测GA 733抗原抗体、肿瘤抗体结合的ELISA测定 细胞、淋巴细胞增殖测定和细胞毒性T细胞测定。 患者将入组，每组6名患者，接受5种剂量 程度. 这项研究将确定这种药物的剂量限制性毒性。 并评估在什么剂量下对肿瘤抗原的免疫应答 发生。

DESCRIPTION: (Applicant's Description) We propose the development of a vaccine to treat metastatic colon cancer using an adenovirus vector encoding the GA733 antigen that is widely expressed on human gastrointestinal malignancies. Passive immunization studies in humans has shown that this antigen is an effective target against which a therapeutic immune response can be generated. In animal models we have demonstrated that this same antigen will elicit both cellular and humoral immune responses when it is administered as a recombinant protein expressed by an adenovirus vector. Vaccination of animals with this vector (Ad.GA733) not only prevents the development of new tumors but leads to the regression of established tumors as well. Furthermore, an immune response can be generated against the murine homologue of GA733 antigen in mice, indicating that tolerance to this protein can be overcome by vaccination strategies. In this proposal we will test the safety of Ad.GA733 in a series of animal models to establish the safety of this vaccine. We will then conduct a phase I/II clinical trial to demonstrate the safety and immunologic efficacy of this approach in patients with early metastatic colon cancer. Patients will be vaccinated with a single dose of Ad.GA733 given intraperitoneally. They will then be monitored for the development of an antigen specific immune response. A subset of patients at each dose will be tested for evidence of antigen expression using peritoneal lavage to recover peritoneal macrophages and mesothelial cells. The immune response to GA733 antigen will be assessed by delayed-type hypersensitivity reaction to the purified GA733 antigen and by a series of in vitro tests. The latter will include ELISA assays to detect antibody to GA733 antigen, antibody binding to tumor cells, lymphocyte proliferation assays, and cytotoxic T cell assays. Patients will be enrolled in groups of six patients at each of five dose levels. This study will determine the dose limiting toxicity of this therapy and to assess at what dose an immune response to the tumor antigen occurs.