RECOMBINANT ADENOVIRUS VACCINE FOR COLON CANCER

描述：(申请人的描述)我们建议开发一种 用腺病毒载体治疗转移性结肠癌的疫苗 在人类胃肠道广泛表达的GA733抗原 恶性肿瘤。对人类的被动免疫研究表明，这一点 抗原是治疗性免疫反应的有效靶点。 可以生成。在动物模型中，我们已经证明了这一点 当抗原被激活时，它会引起细胞和体液免疫反应。 以腺病毒载体表达的重组蛋白的形式注射。 用该载体(Ad.GA733)接种动物不仅可以预防 新肿瘤的发展，但会导致已建立的肿瘤的消退 也是。此外，还可以针对 小鼠体内GA733抗原的同源物，表明对此的耐受性 蛋白质可以通过疫苗接种策略来克服。 在这项提案中，我们将在一系列动物身上测试Ad.GA733的安全性 模型来确定这种疫苗的安全性。然后我们将进行一次 I/II期临床试验证明其安全性和免疫学疗效 这种方法在早期转移性结肠癌患者中的应用。病人 将接种单剂Ad.GA733经腹膜给药。 然后，他们将被监测一种抗原特异性的发展 免疫反应。每种剂量的患者子集将接受测试 利用腹膜灌洗恢复腹膜的抗原表达证据 巨噬细胞和间皮细胞。对GA733抗原的免疫应答 将通过迟发性超敏反应对纯化的 GA733抗原，并进行一系列体外试验。后者将包括 酶联免疫吸附试验检测抗GA733抗原抗体、肿瘤结合抗体 细胞、淋巴细胞增殖试验和细胞毒性T细胞试验。 患者将被分成六组，每组五剂 级别。这项研究将确定该药物的剂量限制毒性。 治疗和评估对肿瘤抗原的免疫反应 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.