ACTIVE IMMUNOTHERAPY TO HUMAN CARCINOMA ASSOCIATED ANTIGENS

针对人类癌相关抗原的主动免疫治疗

• 批准号: 3796509
• 负责人: J KANTOR
• 金额: --
• 依托单位: DIVISION OF CANCER BIOLOGY AND DIAGNOSIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3796509
• 关键词: active immunization; carcinoembryonal antigen; carcinoma; genetic manipulation; human genetic material tag; immunoconjugates; laboratory mouse; molecular cloning; monoclonal antibody; neoplasm /cancer immunotherapy; nucleic acid hybridization; polymerase chain reaction; recombinant DNA; southern blotting; tissue /cell culture; transfection; vaccinia virus

Active specific immunotherapy is a new and potentially non toxic approach for cancer therapy. Tumor associated antigens could serve as targets for this type of therapy. Carcinoembryonic antigen (CEA) is a 180,000 dalton oncofetal glycoprotein expressed on most gastrointestinal carcinomas and many other human carcinoma types. CEA is generally considered to be weakly immunogenic in humans; that is, little evidence exists for humoral or cell mediated immunity to CEA in normal or cancer patients. The copresentation of CEA with a strong immunogen would represent a logical approach to inducing anti-CEA responses for tumor immunotherapy. Recent advances in recombinant vaccinia virus technology has provided a powerful method for antigenic copresentation. To this end, a 2.4 bb cDNA clone, containing the complete coding sequence, was isolated from a human colon tumor cell library and was inserted into a vaccinia virus genome. This recombinant construct was characterized by Southern blotting, restriction endonuclease digestion, polymerase chain re action analysis, and subsequent DNA hybridization. The CEA gene was stably integrated in the vaccinia virus thymidine kinase gene. This recombinant was efficiently replicated upon serial passages in cell culture and in animals. The recombinant virus expressed on the surface of infected cells, a protein product recognized by the MAb COL-1 directed against CEA. Immunization of mice with the recombinant vaccinia virus resulted in a humoral immune response against CEA.Pilot studies demonstrated that the administration of the recombinant vaccinia virus was able to greatly reduce the growth of tumors in mice. This murine colon adenocarcinoma had been transduced with the human CEA gene, expressed human CEA, and grew in syngeneic animals. The use of this new recombinant CEA vaccinia virus may provide a new approach in the specific active immunotherapy of human gastrointestinal cancer and other CEA expressing carcinoma types.

主动特异性免疫治疗是一种新的、潜在无毒的治疗方法 用于癌症治疗。 肿瘤相关抗原可以作为靶点， 这种类型的治疗。癌胚抗原（CEA）是一种180，000道尔顿 癌胚糖蛋白在大多数胃肠道癌中表达， 许多其他人类癌症类型。 一般认为， 在人类中免疫原性弱;也就是说，几乎没有证据表明存在体液免疫。 或细胞介导的对CEA的免疫。 的 CEA与强免疫原的共表达将代表一种逻辑的 诱导抗CEA应答用于肿瘤免疫治疗的方法。 最近 重组牛痘病毒技术的进步提供了一种强有力的 抗原共表达的方法。 为此，2.4 bb cDNA克隆， 从人类结肠中分离出含有完整编码序列的 肿瘤细胞文库中，并插入到牛痘病毒基因组中。 这 用Southern印迹、限制性内切酶切和酶切鉴定 核酸内切酶消化，聚合酶链反应分析，和 随后DNA杂交。 CEA基因稳定整合在大肠杆菌中， 牛痘病毒胸苷激酶基因。 该重组体有效地 在细胞培养物和动物中连续传代后复制。 的 在感染细胞表面表达的重组病毒， 由针对CEA的MAb COL-1识别的产物。 免疫 重组牛痘病毒感染小鼠， 对CEA的反应。初步研究表明， 重组牛痘病毒能够极大地减少 小鼠的肿瘤 这种小鼠结肠腺癌已经用 人CEA基因，表达人CEA，并在同基因动物中生长。 使用这种新的重组CEA牛痘病毒可能会提供一种新的 特异性主动免疫治疗人胃肠道肿瘤的研究进展 癌和其它表达CEA的癌类型。