Antigen-Specific Monitoring and Therapy in Pancreatic Cancer

成为公共信息。因此，不包括专有/机密信息。不要超过所提供的空间。 该建议的广泛目标是鉴定人胰腺癌表达的抗原， 并验证这些抗原作为免疫应答的预测因子。这些抗原可以 最终用于靶向癌症疫苗策略。我们一直在开发一种同种异体粒细胞巨噬细胞 集落刺激因子（GM-CSF）分泌的胰腺肿瘤疫苗方法 胰腺癌的治疗最近完成的I期和II期研究表明， 通过接种后血清GM-CSF水平升高、接种后 与全身性疫苗相关皮疹和疫苗回忆反应相关的嗜酸性粒细胞增多症，以及疫苗接种后 对自体肿瘤的迟发型超敏反应。这些回答大多数 通常在无病生存期延长的患者中观察到。接种后免疫分析 免疫应答将间皮素和前列腺干细胞抗原（PSCA）确定为两个候选新靶点， 这两种T细胞反应都是针对那些保持无病的患者。最近完成的一项 在切除患者中进行的II期研究，以及一项新的目前正在招募的II期组合疫苗研究，我们 准备扩展我们的免疫靶点发现计划，并验证已鉴定的免疫相关基因， 免疫反应的目标。在Aim 1中，我们将筛选一组基因，这些基因在胚胎发育的早期和晚期被打开， 使用免疫白细胞去除淋巴细胞的胰腺癌进展， 辅助II期研究。在目标2中，我们将使用患者验证目标1中评估的基因组。 来自两项疫苗研究的淋巴细胞作为疫苗接种后免疫靶点的相关性。在目标3中，我们 评价对目标1和2中鉴定的新抗原靶标特异性的T细胞的功能。我们将专注于 三个功能参数：溶解功能的表达、记忆T细胞的诱导和高表达T细胞的诱导。 亲合力T细胞。 我们将利用来自临床试验的组织和核心蛋白2来翻译在大肠杆菌中发现的表达的标记抗原。 拟议的项目3C（以前为2A）用于临床试验监测和新试验，以优先考虑候选抗原， 在拟议项目1B中进行基础研究，并在拟议项目2B中应用宿主免疫反应的措施。

become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACE PROVIDED. The broad objective of this proposal is to identify antigens expressed by human pancreatic adenocarcinomas and validate these antigens as predictors of immune response. These antigens can ultimately be used in targeted cancer vaccine strategies. We have been developing an allogeneic granulocytemacrophage colony-stimulating factor (GM-CSF) secreting pancreatic tumor vaccine approach for the treatment of patients with pancreatic cancer. Recently completed phase I and II studies demonstrated the bioactivity of this vaccine as measured by elevated post-vaccination serum levels of GM-CSF, post-vaccination eosinophilia that is associated with systemic vaccine related rashes and vaccine recall reactions, and postvaccination delayed type hypersensitivity (DTH) reactions to autologous tumor. These responses are most often observed in patients demonstrating prolonged disease-free survival. Analysis of post-vaccination immune responses identified mesothelin and prostate stem cell antigen (PSCA) as two candidate new targets against which both T cell responses were directed in patients who remain disease-free. With a recently completed phase II study in resected patients, and a new currently enrolling phase II combinatorial vaccine study, we are poised to extend our immune target discovery program and to validate identified genes as immune relevant targets of the immune response. In Aim 1, we will screen a panel of genes that are turned on early and late in pancreatic cancer progression using immunized leukopheresed lymphocytes from patients treated in our adjuvant phase II study. In aim 2, we will validate the panel of genes evaluated in aim 1 using patient lymphocytes from two vaccine studies for their relevance as post-vaccination immune targets. In aim 3, we will evaluate the function of T cells specific for new antigenic targets identified in aims 1 and 2. We will focus on three functional parameters: expression of lytic function, induction of memory T cells, and induction of higher avidity T cells. We will utilize tissues from clinical trials and Core 2 to translate expressed marker antigens found in proposed Project 3C (formerly 2A) to clinical trial monitoring and new trials, to prioritize candidate antigens for basic studies in proposed Project 1B, and to apply measures of host immune responses in proposed Project 2B.