EVALUATION OF CANCER VACCINES BASED ON GLYCOPEPTIDES /DC

描述（由申请方提供）：我们计划在美国设计和测试几种MUC 1疫苗。 动物临床前研究和癌症患者临床试验。MUC 1是一种上皮性肿瘤 抗原的疫苗设计将基于通过旧项目4的目的获得的对MUC 1免疫原性的新理解以及通过PO 1中的其他项目获得的关于抗原摄取、呈递和DC活化的新知识。我们了解到，MUC 1特异性T细胞的潜在库可能比在癌症患者中观察到的要大得多。我们发现树突状细胞处理MUC 1糖蛋白的困难，严重限制了体内免疫库，并可能限制了抗MUC 1免疫应答的抗肿瘤功效。在动物临床前研究（目的1）和临床试验（目的2）中检验的假设如下：如果MUC 1糖蛋白以促进树突细胞有效加工和呈递的形式施用，产生大量肽和糖肽表位，抗MUC 1 T细胞库将扩大（包括辅助T细胞的产生），这将增加抗MUC 1免疫应答的肿瘤排斥潜力。具体的施舍是：具体的目标1。子目标a）在MUC 1转基因小鼠中测试由可由DC加工和呈递的MUC 1肽和/或糖肽组成的癌症疫苗的肿瘤排斥潜力;子目标B）为了更好地理解MUC 1 +肿瘤的免疫监视（及其失败）的机制，通过 检查各种形式的MUC 1的摄取和加工对各种DC群体的生物学的影响。具体目标2.在I/II期临床试验中测试由DC加工和提呈的MUC 1肽和/或糖肽组成的癌症疫苗的毒性和免疫原性，并评估产生的免疫效应机制。将评价可溶性与颗粒性抗原以及肽特异性与糖肽特异性免疫应答对肿瘤排斥和肿瘤特异性的重要性。这两个目标的目标都是表明MUC 1在动物和患者中具有免疫原性，并且它引发的免疫反应可能是肿瘤排斥反应。

DESCRIPTION (provided by applicant): We propose to design and test several MUC1 vaccines in preclinical studies in animals and in clinical trials in cancer patients. MUC1 is an epithelial tumor antigen. The vaccine design will be based on the new understanding of MUC1 immunogenicity derived through the aims of old Project 4 as well as the new knowledge about antigen uptake, presentation, and DC activation derived through the other projects in the PO1. We learned that the potential repertoire of MUC1 specific T cells could be much larger than had been observed in cancer patients. Difficulty we discovered in processing of the MUC1 glycoprotein by dendritic cells, severely limits the immune repertoire in vivo and, presumably the anti-tumor efficacy of anti-MUC1 immune responses. The hypothesis to be tested in pre-clinical studies in animals (Aim 1) and in clinical trials (Aim 2) is the following: if MUC1 glycoprotein is administered in forms that promote efficient processing and presentation by dendritic cells, resulting in a large number of peptide and glycopeptide epitopes, the anti-MUC1 T cell repertoire will broaden (including generation of helper T cells) and this will increase the tumor rejection potential of anti-MUC1 immune responses. The specific alms are: SPECIFIC AIM 1. Sub-aim a) To test in MUC1 transgenic mice the tumor rejection potential of cancer vaccines composed of a MUC1 peptide and/or glycopeptide that can be processed and presented by DC; Sub-aim b) To better understand the mechanisms of immune surveillance (and failure thereof) of MUC 1 + tumors, by examining the effect of uptake and processing of various forms of MUC1 on the biology of various DC populations. SPECIFIC AIM 2. To test in phase I/II clinical trials toxicity and immunogenicity of cancer vaccine, composed of a MUC1 peptide and/or glycopeptide processed and presented by DC and to evaluate immune effector mechanisms generated. The importance for tumor rejection and tumor specificity of soluble vs. particulate antigen and of peptide-specific versus glycopeptide-specific immune responses will be evaluated. The goal of both aims is to show that MUC1 is immunogenic in animals and patients and that the immune response it elicits could be a tumor rejection response.