Breaking tolerance to mEGP self-antigen

打破对 mEGP 自身抗原的耐受性

• 批准号: 7323314
• 负责人: DOROTHEE M HERLYN
• 金额: $ 19.75万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7323314
• 关键词: Active Immunotherapy; Animal Model; Animals; Anti-Idiotypic Antibodies; Antibodies; Autoantigens; Binding; Biological Models; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Patient; Carcinoma; Cells; Class; Clinical; Colon Carcinoma; Colorectal Cancer; Condition; Disease regression; Epithelial; Epitopes; Evaluation; Generations; Glycoproteins; Goals; Growth; Homologous Gene; Human; Immune; Immune response; Immunity; Immunization; Immunoglobulin Variable Region; Immunotherapy; Libraries; Light; Lymphocyte; Major Histocompatibility Complex; Malignant Epithelial Cell; Modeling; Monoclonal Antibodies; Mus; Neoplasm Metastasis; Normal tissue morphology; Passive Transfer of Immunity; Patients; Peptide Fragments; Peptides; Phase I Clinical Trials; Phase I/II Trial; Proteins; Recombinant KSA Glycoprotein; Role; Serum; T memory cell; T-Lymphocyte; T-Lymphocyte Epitopes; TACSTD2 gene; Testing; Therapeutic; Tumor Antigens; Tumor Tissue; Tumor-Associated Carbohydrate Antigens; Vaccination; Vaccines; Visceral; base; cancer cell; cytotoxic; gastrointestinal; memory CD4 T lymphocyte; neoplastic cell; response; subcutaneous; tumor; tumor growth; vaccine evaluation

Most tumor antigens (Ag) are also expressed by normal tissues and therefore induce immunological tolerance in the tumor-bearing host. Yet, these self proteins are major targets available for active specific immunotherapies. These therapies need to be developed in animal models that mimic the conditions in cancer patients. The human gastrointestinal carcinoma-associatedAg GA733 (EpCAM) has been a suitable target for passive and active immunotherapy of these tumors in cancer patients. Mice expressing the homologue of the human Ag, murine epithelial glycoprotein (mEGP), on normal and tumor tissues provide a relevant animal model of active specific immunotherapy against the GA733 Ag. Our major goal is to define vaccines that significantly and reproducibly inhibit growth of established mouse colon carcinoma cells in this tumor model system. Our major hypothesis is that mimics of mEGP, by virtue of being similar, but not identical to mEGP will effectively immunize mice and induce regression of established, mEGP-positive colon carcinomas. Specifically we will: 1) Test the hypothesis that mEGP mimics induce protective immunity against established, subcutaneous tumors and visceral metastasis. This involves: a) Generation and selection of mEGP mimics (anti-idiotypic antibodies [Ab2], Ab2 fragments, peptides or minigenes derived from the VH and VL regions of Ab2, peptides derived from synthetic libraries and mimicking the epitope recognized by anti-mEGP monoclonal antibody, and peptides and minigenes of mEGP CTL epitopes); and b) Evaluation of vaccines for their capacity to inhibit subcutaneous and visceral, metastatic growth of CT26-mEGP colon carcinoma cells in the therapeutic setting in mice. 2) Determine the mechanism of tumor growth inhibition by mEGP mimics. This involves: a) Evaluation of humoral immune responses (cytotoxic antibodies) and cellular immune responses (proliferative, cytotoxic and delayed-type hypersensitive lymphocytes in mice with regressing tumors after immunization with mEGP mimics; b) Determination of the direct role in tumor growth inhibition of antibodies, CD8+ or CD4+ T lymphocytes, memory lymphocytes, and epitope spreading. The proposed studies provide the basis for vaccinations of colorectal cancer patients against the GA733 Ag.

大多数肿瘤抗原(Ag)也在正常组织中表达，因此诱导免疫性 荷瘤宿主的耐受性。然而，这些自身蛋白是活性特异性的主要靶点。 免疫疗法。这些疗法需要在动物模型中进行开发，以模拟 癌症患者。人胃肠道肿瘤相关抗原GA733(EpCAM)是一种合适的 癌症患者这些肿瘤被动和主动免疫治疗的靶点。表达该基因的小鼠 人类抗原的同源物，小鼠上皮糖蛋白(MEGP)，在正常和肿瘤组织上提供了一种 抗GA733抗原主动特异性免疫治疗的相关动物模型。我们的主要目标是定义 疫苗显著且可重复性地抑制已建立的小鼠结肠癌细胞的生长 肿瘤模型系统。我们的主要假设是，由于相似而模仿了mEGP，但不是 与mEGP相同将有效地免疫小鼠，并诱导已建立的mEGP阳性结肠的消退 癌症。 具体地说，我们将：1)测试mEGP模拟诱导保护性免疫的假设 已确诊的皮下肿瘤和内脏转移。这涉及：a)产生和选择 MEGP模拟物(来自VH的抗独特型抗体[AB2]、AB2片段、多肽或微基因 和AB2的VL区，是从合成文库中衍生出来的模拟 抗mEGP单抗和mEGP CTL表位的多肽和小基因)；以及b)评价 疫苗抑制CT26-mEGP结肠皮下和内脏转移生长的能力 小鼠体内处于治疗环境中的癌细胞。2)确定抑制肿瘤生长的机制： MEGP模拟。这涉及：a)体液免疫反应(细胞毒性抗体)和细胞免疫反应的评估 免疫反应(增殖、细胞毒性和迟发型超敏淋巴细胞) 用mEGP模拟物免疫后肿瘤的消退；b)确定对肿瘤生长的直接作用 抑制抗体、CD8+或CD4+T淋巴细胞、记忆淋巴细胞和表位扩散。 本研究为结直肠癌患者接种GA733抗原疫苗奠定了基础。