PANCREAS CANCER MESOTHELIN ANIMAL MODEL

这项建议的主要目标是确定组合疫苗方法，以导致对表达间硫蛋白的胰腺癌进行有效免疫。在一项完整的I期试验中，两个分泌GM-CSF的同种异体胰腺细胞株显示了对切除疾病患者T细胞免疫的剂量依赖诱导。疫苗接种后免疫反应分析确定间甲硫蛋白为新的候选靶点 哪些HotT细胞和抗体反应针对保持无病的患者。然而，最近的研究结果强烈表明，免疫耐受机制为大多数癌症患者的有效免疫提供了强大的障碍。在这个方案中，我们将开发和优化一种间甲硫蛋白导向的疫苗，确定最具治疗效力的疫苗和免疫调节剂的组合，并探索协同作用。 在这些治疗方式之间。了解相互作用的机制应该导致设计合理的组合，以提高对胰腺癌的疗效。提出了五个具体目标。目的1鉴定和鉴定能够诱导免疫反应的肿瘤疫苗，该疫苗能够有效地治疗表达间硫蛋白的Panc02肿瘤。一种分泌GM-CSF、表达间充质蛋白的全肿瘤细胞方法 单核细胞增多性李斯特菌(Lm)含有间硫蛋白疫苗的方法，将进行评估。在项目2中开发的间皮蛋白特异性DNA疫苗也将在这个模型中进行测试。AIM 2将优化T调节细胞(Treg)抑制剂，当与Mesothelin靶向疫苗结合时，可增强抗肿瘤免疫。两种现有的Treg抑制剂和一种新的Treg抑制剂(项目3)将在Panc02模型中进行评估。AIM 3将优化Treg耗尽剂的组合，当与TREG耗尽剂同时给予时，这些药物可以增强间硫蛋白靶向疫苗的效力 抗体通过抗CTLA-4的T细胞调节途径，增强T细胞的活性。在目标4中，免疫调节剂/疫苗组合在不严格的可移植肿瘤模型中有效，将测试它们治疗半脾移植后自然发展的Panc02肝转移的能力。AIM 5将比较最有效的疫苗/抗CTLA-4/和Treg细胞抑制剂组合在以下情况下的增强效果 结合针对其他免疫调节检查点的新制剂(项目3和4)。这些组合方法将首先针对可移植的Panc02进行测试，然后再针对自然转移的Panc02进行测试。最终结果将是确定一种针对间甲硫蛋白的组合疫苗方法，用于在患者身上进行测试。

The broad objective of this proposal is to identify combinatorial vaccine approaches that will result in effective immunization against mesothelin-expressing pancreatic adenocarcinomas. In a completed phase I trial, two allogeneic GM-CSF-secreting pancreatic cell lines demonstrated a dose-dependent induction of T cell immunity in patients with resected disease. Analysis of post-vaccination immune responses identified mesothelin as a candidate new target against which hoth T cell and antibody responses were directed in patients who remain disease-free. However, recent findings strongly suggest that immune tolerance mechanisms provide a formidable barrier to effective immunization in most cancer patients. In this proposal, we will develop and optimize a mesothelin-directed vaccine, identify the most therapeutically potent combinations of vaccine and immune modulating agents, and explore the synergistic interaction between these treatment modalities. Understanding the mechanisms of interaction should lead to the design of rational combinations with improved efficacy against pancreatic adenocarcinoma. Five specific aims are proposed. Aim 1 will identify and characterize mesothelin-specific tumor vaccines that can induce immune responses potent enough to treat mesothelin-expressing Panc02 tumors. A GM-CSF secreting, mesothelin-expressing whole tumor cell approach and a Listeria Monocytogenes (LM) containing mesothelin vaccine approach, will be evaluated. Mesothelin-specific DNA vaccines developed in project 2 will also be tested in this model. Aim 2 will optimize T regulatory cell (Treg) inhibiting agents that enhance anti-tumor immunity when combined with the mesothelin-targeted vaccines. Two existing and one new Treg inhibiting agent (project 3) will be evaluated in the Panc02 model. Aim 3 will optimize combinations of Treg depleting agents that enhance mesothelin-targeted vaccine potency when also given with the antibody to the anti-CTLA-4 T cell regulatory pathway, to enhance T cell activation. In aim 4, the immune modulating agent/vaccine combinations that are effective in the less stringent transplantable tumor model will be tested for their ability to treat naturally developing Panc02 hepatic metastases following hemisplenic transplantation. Aim 5 will compare the most potent vaccine/anti-CTLA-4/and Treg cell-inhibiting agent combinations for enhanced efficacy when combined with new agents targeted at other immune regulatory checkpoints (projects 3 and 4). These combinatorial approaches will first be tested against transplantable Panc02, and then against natural Panc02 metastases. The final outcome will be the identification of a mesothelin-targeted, combinatorial vaccine approach for testing in patients.