Breaking tolerance to mEGP self-antigen

打破对 mEGP 自身抗原的耐受性

• 批准号: 7164454
• 负责人: DOROTHEE M HERLYN
• 金额: $ 22.25万
• 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/7164454
• 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

DESCRIPTION (provided by applicant): 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-associated Ag 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.

描述（由申请方提供）：大多数肿瘤抗原（Ag）也由正常组织表达，因此在荷瘤宿主中诱导免疫耐受。然而，这些自身蛋白是主动特异性免疫疗法的主要靶标。这些疗法需要在模拟癌症患者状况的动物模型中开发。人胃肠道癌相关抗原GA 733（EpCAM）已成为癌症患者中这些肿瘤的被动和主动免疫治疗的合适靶点。在正常和肿瘤组织上表达人Ag同源物，鼠上皮糖蛋白（mEGP）的小鼠提供了针对GA 733 Ag的主动特异性免疫治疗的相关动物模型。我们的主要目标是确定疫苗，显着和可重复地抑制建立小鼠结肠癌细胞在这个肿瘤模型系统的生长。我们的主要假设是mEGP的模拟物，由于与mEGP相似但不相同，将有效地免疫小鼠并诱导已建立的mEGP阳性结肠癌消退。具体而言，我们将：1）检验mEGP模拟物诱导针对已建立的皮下肿瘤和内脏转移的保护性免疫的假设。这包括：a）mEGP模拟物的产生和选择（抗独特型抗体[Ab 2]、Ab 2片段、衍生自Ab 2的VH和VL区的肽或小基因、衍生自合成文库并模拟由抗mEGP单克隆抗体识别的表位的肽、以及mEGP CTL表位的肽和小基因）;和B）评价疫苗在小鼠治疗环境中抑制CT 26-mEGP结肠癌细胞皮下和内脏转移性生长的能力。2)确定mEGP模拟物抑制肿瘤生长的机制。这包括：a）评价体液免疫应答（细胞毒性抗体）和细胞免疫应答（在用mEGP模拟物免疫后具有消退肿瘤的小鼠中的增殖性、细胞毒性和迟发型超敏淋巴细胞; B）确定抗体、CD 8+或CD 4 + T淋巴细胞、记忆淋巴细胞和表位扩散在肿瘤生长抑制中的直接作用。拟议的研究为结直肠癌患者接种GA 733 Ag疫苗提供了基础。