Breaking tolerance to mEGP self-antigen

大多数肿瘤抗原（Ag）也由正常组织表达，因此诱导免疫反应。 肿瘤宿主的耐受性。然而，这些自身蛋白质是活性特异性免疫的主要靶点。 免疫疗法这些疗法需要在动物模型中开发，以模拟 癌症患者。人胃肠道癌相关的Ag GA 733（EpCAM）是合适的 作为癌症患者中这些肿瘤被动和主动免疫治疗的靶点。小鼠表达 人Ag的同源物，鼠上皮糖蛋白（mEGP），在正常和肿瘤组织上提供了一种 针对GA 733 Ag的主动特异性免疫治疗的相关动物模型。我们的主要目标是定义 在这种情况下，显著且可重复地抑制已建立的小鼠结肠癌细胞生长的疫苗， 肿瘤模型系统我们的主要假设是，mEGP的模拟物，由于相似，但不 与mEGP相同将有效地免疫小鼠并诱导建立的mEGP阳性结肠消退 癌 具体来说，我们将：1）测试mEGP模拟物诱导针对以下的保护性免疫的假设： 皮下肿瘤和内脏转移。这涉及：a）生成和选择 mEGP模拟物（抗独特型抗体[Ab 2]、Ab 2片段、衍生自VH的肽或小基因 和Ab 2的VL区，衍生自合成文库并模拟Ab 2识别的表位的肽， 抗mEGP单克隆抗体，和mEGP CTL表位的肽和小基因）;和B）评估 疫苗抑制CT 26-mEGP结肠皮下和内脏转移性生长的能力 癌细胞在小鼠的治疗环境中。2)确定肿瘤生长抑制的机制， mEGP模拟物。这涉及：a）评价体液免疫应答（细胞毒性抗体）和细胞免疫应答。 免疫应答（小鼠中的增殖性、细胞毒性和迟发型超敏淋巴细胞， 用mEGP模拟物免疫后使肿瘤消退; B）确定在肿瘤生长中的直接作用 抑制抗体、CD 8+或CD 4 + T淋巴细胞、记忆淋巴细胞和表位扩散。 拟议的研究为结直肠癌患者接种GA 733 Ag疫苗提供了基础。

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.