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: 5200983
• 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/5200983
• 关键词: Macaca mulatta; active immunization; breast neoplasms; carcinoembryonal antigen; carcinoma; cell mediated cytotoxicity; colorectal neoplasms; disease /disorder model; drug screening /evaluation; human tissue; humoral immunity; laboratory mouse; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; nonhuman therapy evaluation; nonsmall cell lung cancer; pancreas neoplasms; prostate neoplasms; prostate specific antigen; southern blotting; stomach neoplasms; transfection; tumor antigens; vaccinia virus

Certain tumor associated antigens (TAAs) represent potential targets for active specific immunotherapy. Studies are ongoing to evaluate the immunogenicity, safety, and toxicity of recombinant vaccinia viruses expressing human tumor associated antigens, as immunogens for the treatment of human carcinomas. We have constructed, characterized and determined the safety and immunogenicity of two recombinant vaccinia viruses in both a murine tumor model as well as rhesus monkeys. The first recombinant vaccinia virus contained the gene for the human carcinoembryonic antigen and was designated rV-CEA; and the second vaccinia virus, designated rV-PSA, expressed human prostate specific antigen. CEA is a 18OKd glycoprotein which is overexpressed in human colorectal, gastric, pancreatic, breast and non small cell carcinoma, while PSA is a 30-33 Kd glycoprotein overexpressed in prostatic carcinoma. It is unclear whether these TAAs are immunogenic in humans; cell mediated responses to these tumor antigens have not been documented in normal or cancer patients. Anti-tumor activity was demonstrated in an animal tumor model by immunization of mice with rV- CEA. This recombinant immunogen was also shown to induce both cell- mediated and humoral CEA specific immune responses in both mice and non-human primates. Other immunogens such as a polynucliotide vaccine expressing human CEA were also shown to elicit antitumor and CEA specific cell mediated immune responses in mice. The rV-CEA immunogen has been evaluated in Phase I clinical trials, where several patients were shown to elicit specific T-cell responses to CEA following immunization. rV-PSA has also been evaluated for its safety and immunogenicity in both mice and rhesus monkeys. Southern blot analyses have demonstrated that the rhesus monkey contains genes highly related to human PSA and thus represents a relevant model for the ability of rV-PSA to elicit a cellular immune response. rV-PSA was shown to have no toxicity in these animal models. Rhesus monkeys were able to elicit PSA specific humoral as well a T-cell lymphoproliferative responses after immunization with rV-PSA. Recombinant vaccinia virus expressing the costimulatory molecules B7-1 and B7-2 were constructed, characterized, and analyzed for their ability to enhance CEA specific cellular immune responses in a murine tumor model. rV-B7-1 was shown to enhance CEA specific immune responses when co-administered with rV-CEA. Infection of tumor cells with rV-B7-1 enhanced the immunogenicity of tumors in mice and this immunogenicity had long term memory. Direct infection of tumor cells with rV-B7-1 and immunization of patients with these tumor cells may open a new route of immunotherapy. Infection of tumor cells with rV- B7 can be accomplished faster and more efficiently than gene therapy protocols using retroviral vectors and appears to elicit the correct antitumor responses. Other approaches to enhance rV-CEA and rV-PSA specific immunogenicity following primarily immunization are being developed using purified recombinant proteins, peptides, and polynucleotide vaccines. Recombinant vaccinia viruses containing the c-erb/B2 and breast mucin muc-1 genes, respectively, have also been designed and constructed.

某些肿瘤相关抗原(Taa)是潜在的靶点。 用于主动特异性免疫治疗。正在进行研究，以评估 重组痘苗病毒的免疫原性、安全性和毒性 表达人类肿瘤相关抗原作为免疫原 人类癌症的治疗。我们已经构建了、表征和 测定两种重组牛痘疫苗的安全性和免疫原性 病毒在小鼠肿瘤模型和恒河猴中都存在。这个 首个含有人类基因的重组痘苗病毒 癌胚抗原，命名为RV-CEA； 痘苗病毒，命名为RV-PSA，表达人前列腺特异性 抗原。CEA是一种180kd的糖蛋白，在人体内过表达 结直肠癌、胃癌、胰腺癌、乳腺癌和非小细胞癌， 而PSA是一种在前列腺中过度表达的30-33kD的糖蛋白 癌症。目前尚不清楚这些TAA对人类是否具有免疫原性； 细胞对这些肿瘤抗原的反应尚未得到证实。 在正常或癌症患者中有记录。抗肿瘤活性为 用RV-1免疫小鼠建立动物肿瘤模型 CEA。这种重组免疫原还被证明可以诱导两种细胞- 小鼠和小鼠体液中CEA特异性免疫应答 非人灵长类动物。其他免疫原，如多核苷酸疫苗 表达人CEA也被证明能诱导抗肿瘤和CEA 小鼠体内特异性细胞免疫反应。轮状病毒CEA免疫原 已经在I期临床试验中进行了评估，其中几个 研究表明，患者对CEA有特异性的T细胞反应 在免疫后。RV-PSA也进行了安全性评估 对小鼠和恒河猴都有免疫原性。Southern印迹 分析表明，恒河猴体内含有基因 与人类PSA高度相关，因此代表了 RV-PSA诱导细胞免疫反应的能力。RV-PSA是 在这些动物模型中显示没有毒性。恒河猴是 能够诱导PSA特异性体液以及T细胞 RV-PSA免疫后的淋巴细胞增殖反应。 表达共刺激分子B7-1的重组痘苗病毒 和B7-2的构建、表征和分析 增强小鼠CEA特异性细胞免疫反应的能力 肿瘤模型。RV-B7-1可增强CEA特异性免疫 与RV-CEA联合给药时的反应。肿瘤细胞感染 RV-B7-1增强小鼠肿瘤免疫原性 免疫原性具有长期记忆性。肿瘤细胞直接感染 用RV-B7-1和免疫这些肿瘤细胞的患者可能 开辟了免疫治疗的新途径。轮状病毒感染肿瘤细胞的实验研究 B7可以比基因治疗更快、更有效地完成 使用逆转录病毒载体的方案，似乎引出了正确的 抗肿瘤反应。增强RV-CEA和RV-PSA的其他途径 一次免疫后的特异性免疫原性 使用纯化的重组蛋白、多肽和 多核苷酸疫苗。含有重组痘苗病毒的 C-erb/B2和乳腺粘蛋白muc-1基因也分别被 设计和建造。