Antigen-Specific Monitoring and Therapy in Pancreatic Cancer

胰腺癌的抗原特异性监测和治疗

• 批准号: 8096766
• 负责人: ELIZABETH M. JAFFEE
• 金额: $ 24.65万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8096766
• 关键词: Adjuvant; Affect; Allogenic; Antigens; Autoimmunity; Autologous; Avidity; Bacterial Antigens; Binding; Biological Assay; Biological Markers; Cancer Patient; Cancer Vaccines; Candidate Disease Gene; Cells; Clinical Trials; Collaborations; Colony-Stimulating Factors; Data; Databases; Delayed Hypersensitivity; Differentiation Antigens; Disease; Disease Progression; Disease-Free Survival; Enrollment; Eosinophilia; Epitopes; Exanthema; Flow Cytometry; Gene Targeting; Generations; Genes; Granulocyte-Macrophage Colony-Stimulating Factor; HLA Antigens; Human; Immune; Immune Targeting; Immune response; Immune system; Immunization; Immunologics; Listeria monocytogenes; Lymphocyte; Lytic; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Monitor; Monitoring Clinical Trials; Mutate; Normal tissue morphology; Oncogenes; Pancreas; Pancreatic Adenocarcinoma; Patients; Peptides; Phase; Proteins; Reaction; Relative (related person); Reporting; Reproduction spores; Resected; Serum; Staining method; Stains; System; T cell response; T memory cell; T-Lymphocyte; Testing; Time; Tissues; Translating; Vaccinated; Vaccination; Vaccines; Viral; base; combinatorial; cytokine; design; enzyme linked immunospot assay; feeding; follow-up; functional genomics; immunogenic; immunogenicity; mesothelin; overexpression; pancreatic neoplasm; phase 2 study; programs; prostate stem cell antigen; response; success; therapeutic target; tumor; tumor progression; vaccine safety

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.

该提案的主要目标是鉴定人类胰腺表达的抗原 腺癌并验证这些抗原作为免疫反应的预测因子。这些抗原可以 最终用于靶向癌症疫苗策略。我们一直在开发同种异体粒细胞巨噬细胞 集落刺激因子（GM-CSF）分泌型胰腺肿瘤疫苗方法 胰腺癌患者的治疗。最近完成的第一阶段和第二阶段研究表明 通过接种后血清 GM-CSF 水平升高来衡量该疫苗的生物活性 与全身性疫苗相关皮疹和疫苗召回反应以及疫苗接种后相关的嗜酸性粒细胞增多 对自体肿瘤的迟发型超敏反应（DTH）。这些回应最多 经常在表现出延长无病生存期的患者中观察到。疫苗接种后免疫分析 反应将间皮素和前列腺干细胞抗原 (PSCA) 确定为两个候选新靶标 这两种 T 细胞反应都是针对保持无病状态的患者。随着最近完成的 在切除患者中进行的 II 期研究，以及目前正在招募的一项新的 II 期组合疫苗研究，我们正在 准备扩展我们的免疫靶点发现计划并验证已识别的基因是否与免疫相关 免疫反应的目标。在目标 1 中，我们将筛选一组在早期和晚期开启的基因。 使用来自我们接受治疗的患者的免疫白细胞分离淋巴细胞来观察胰腺癌的进展 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目标的相关性。在目标 3 中，我们将 评估目标 1 和 2 中确定的新抗原靶点特异性 T 细胞的功能。我们将重点关注 三个功能参数：裂解功能的表达、记忆 T 细胞的诱导以及更高的诱导 亲和力T细胞。 我们将利用临床试验和 Core 2 中的组织来翻译在 拟议的项目 3C（以前的 2A）用于临床试验监测和新试验，优先考虑候选抗原 拟议项目 1B 中的基础研究，以及在拟议项目中应用宿主免疫反应的措施 2B。