RECOMBINANT VACCINES FOR ACTIVE SPECIFIC IMMUNOTHERAPY OF HUMAN CARCINOMA

用于人类癌症主动特异性免疫治疗的重组疫苗

• 批准号: 3774358
• 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/3774358
• 关键词: Primates; active immunization; carcinoembryonal antigen; carcinoma; delayed hypersensitivity; disease /disorder model; drug screening /evaluation; human genetic material tag; laboratory mouse; lymphocyte proliferation; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; neoplastic growth; nonhuman therapy evaluation; recombinant DNA; transfection; vaccinia virus

Certain tumor associated antigens (TAAs) represent potential targets for active specific immunotherapy. Human carcinoembryonic antigen (CEA) is a 180 Kd glycoprotein which is overexpressed in human colorectal, gastric, pancreatic, breast and non-small cell carcinomas. CEA is an oncofetal protein and is considered to be weakly immunogenic in humans. Humoral or cell mediated responses to CEA have not been well documented in normal or cancer patients. The copresentation of CEA with a strong immunogen such as vaccinia virus would represent a logical approach to inducing anti-CEA responses for tumor immunotherapy. We have constructed and characterized a recombinant vaccinia virus expressing human CEA and have used it as an immunogen to study its effect on tumor growth in mice bearing CEA- expressing tumors. Rodent tumors do not express CEA. In order to develop a model system for active anti-CEA therapies, we have transduced a mouse colon adenocarcinoma cell line, MC-38, with human CEA. These tumors grow in syngeneic C57BL/6 mice and will eventually kill the animal. We have used this tumor model to evaluate the efficacy of our recombinant vaccine to prevent tumor growth in mice and its ability to elicit cell mediated and humoral anti-CEA immune responses. Animals immunized with the recombinant vaccine were resistant to challenge with the syngeneic tumor cells expressing CEA. Moreover, when mice having a palpable CEA tumor burden were immunized with the recombinant vaccine tumor growth was greatly reduced or eliminated. The recombinant vaccine immunized animals developed anti-CEA antibody titers and demonstrated a strong DTH response to CEA-expressing tumor cells. T cells isolated from immunized mice responded specifically to soluble CEA and could also mediate lysis of the CEA-expressing tumor cell line. No toxicity was observed in these animals. Immunogenicity and safety of this recombinant vaccine was tested in non human primates. Animals immunized with the recombinant vaccine developed strong anti-CEA antibody responses and specific DTH responses. PBLs from immunized monkeys were found to proliferate in response to CEA stimulation. Blood counts and differentials and hepatic and renal chemistries remained normal in all animals throughout the study and for up to 1 year following the primary immunization.

某些肿瘤相关抗原(TAA)是潜在的靶点 主动特异性免疫治疗。人癌胚抗原是一种 180kD糖蛋白在人结肠、胃、 胰腺癌、乳腺癌和非小细胞癌。CEA是一种肿瘤胎儿 蛋白质，被认为对人类具有弱的免疫原性。幽默或 细胞介导的对CEA的反应在正常或 癌症患者。CEA与一种强免疫原如 痘苗病毒将是一种诱导抗CEA的合理方法 对肿瘤免疫治疗的反应。我们已经构建并刻画了 一种表达人CEA的重组痘苗病毒并用于 免疫基因研究其对CEA-小鼠肿瘤生长的影响 表现为肿瘤。啮齿动物肿瘤不表达CEA。为了发展 一个主动抗CEA治疗的模型系统，我们已经转导了一只小鼠 人CEA结肠腺癌细胞系MC-38。这些肿瘤生长 在同基因C57BL/6小鼠中，并最终将杀死该动物。我们有 使用该肿瘤模型评估我们的重组疫苗的效果 预防小鼠肿瘤生长及其诱导细胞介导性的研究 体液抗CEA免疫反应。用疫苗免疫的动物 重组疫苗对同基因肿瘤的耐受性 表达CEA的细胞。此外，当有明显CEA肿瘤的小鼠 Burden用重组疫苗免疫，肿瘤生长情况为 大大减少或消除的。重组疫苗免疫动物 发展了抗CEA抗体效价，并表现出很强的DTH反应 至表达CEA的肿瘤细胞。从免疫小鼠体内分离T细胞 特异性地对可溶性CEA作出反应，也可以介导裂解 表达CEA的肿瘤细胞系。在这些动物身上没有观察到毒性。 该重组疫苗的免疫原性和安全性在非 人类灵长类动物。研制出的重组疫苗免疫动物 抗CEA抗体反应强，特异性DTH反应强。PBL来自 免疫的猴子被发现对CEA有反应而增殖 刺激。血细胞计数和辨别与肝、肾 在整个研究过程中，所有动物的化学成分都保持正常 至初次免疫后1年。