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: 3752070
• 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/3752070
• 关键词: MHC class I antigen; Macaca mulatta; active immunization; biochemistry; blood cell count; carcinoembryonal antigen; carcinoma; cell mediated cytotoxicity; disease /disorder model; drug screening /evaluation; human genetic material tag; human tissue; humoral immunity; laboratory mouse; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; nonhuman therapy evaluation; prostate neoplasms; recombinant DNA; transfection; tumor antigens; 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）代表了肿瘤治疗的潜在靶标。 主动特异性免疫治疗人癌胚抗原（CEA）是一种 180 Kd糖蛋白在人结肠直肠，胃， 胰腺、乳腺和非小细胞癌。CEA是一种癌胚抗原， 蛋白质，并且被认为在人类中是弱免疫原性的。体液或 细胞介导的对CEA的应答在正常或 癌症患者。CEA与强免疫原如 牛痘病毒将代表诱导抗CEA的合乎逻辑的方法 肿瘤免疫治疗的反应。我们构建并表征了 表达人CEA的重组牛痘病毒，并已将其用作 免疫原，研究其对荷CEA-1小鼠肿瘤生长的影响。 表达肿瘤。啮齿动物肿瘤不表达CEA。为了发展 主动抗CEA治疗的模型系统，我们已经转导了小鼠 结肠腺癌细胞系MC-38与人CEA。这些肿瘤生长 在同基因C57 BL/6小鼠中，并最终杀死动物。我们有 用这个肿瘤模型来评估我们的重组疫苗的有效性 以防止小鼠中的肿瘤生长及其引发细胞介导的 和体液抗CEA免疫应答。免疫的动物 重组疫苗对同源肿瘤的攻击具有抗性 表达CEA的细胞此外，当小鼠具有明显的CEA肿瘤时， 用重组疫苗免疫荷瘤小鼠， 大大减少或消除。重组疫苗免疫动物 开发了抗CEA抗体滴度，并表现出强烈的DTH反应 表达CEA的肿瘤细胞。从免疫小鼠分离的T细胞 对可溶性CEA有特异性反应，也可以介导 CEA表达肿瘤细胞系。在这些动物中未观察到毒性。 对该重组疫苗的免疫原性和安全性进行了非临床试验， 人类灵长类动物用研制的重组疫苗免疫动物 强烈的抗CEA抗体反应和特异性DTH反应。PBL来自 免疫的猴子被发现增殖反应CEA 刺激.血细胞计数和分类以及肝和肾 在整个研究过程中，所有动物的化学成分保持正常， 1、初次免疫后1年内。