P-1: Immunotherapy of Pancreatic Adenocarcinoma

P-1：胰腺腺癌的免疫治疗

• 批准号: 8328169
• 负责人: Michael A. Hollingsworth
• 金额: $ 12.44万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8328169
• 关键词: Adenocarcinoma; Antibodies; Antibody Formation; Antigen Targeting; Antigen-Antibody Complex; Antigen-Presenting Cells; Antigens; Binding; Biological Models; Cancer Vaccines; Cell surface; Cells; Clinical Trials; Complex; Dendritic Cells; Development; Drug Formulations; Experimental Models; Goals; Human; Human Anti-Mouse Antibody; Immune response; Immune system; Immunization; Immunotherapy; Inbred Strains Mice; Individual; Intervention; Investigation; MUC1 gene; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of pancreas; Mediating; Methods; Modeling; Monoclonal Antibodies; Mucin-1 Staining Method; Mucins; Mus; Pancreas; Pancreatic Adenocarcinoma; Patients; Pattern; Reagent; Refractory; Tandem Repeat Sequences; Testing; Transplantation; Tumor Antigens; Vaccinated; antigen processing; improved; in vivo; neoplastic cell; novel; pancreatic neoplasm; preclinical study; response; tumor

We propose to further develop and test novel reagents that can be used for immunotherapy of human adenocarcinomas, particularly those of the pancreas. The reagents under development in this project include highly specific murine monoclonal antibodies to circulating tumor-associated antigens (TAA), which form immune complexes that are taken up by dendritic cells (DCs) and other antigen-presenting cells (APCs) and are efficiently presented to the immune system. As a result, humoral and cellular immune responses against TAA are activated. The fundamental hypothesis under investigation is that murine antibodies against circulating human tumor antigens will bind to those antigens when administered to patients, form immune complexes that will be bound to APCs either directly or subsequent to the development of human anti-mouse antibody (HAMA) responses that capture these complexes, and that antigen processing by the APCs will produce immune responses against the targeted antigen. We specifically hypothesize that the anti-MUC1 antibody BrevaRex¿ MAb-AR20.5, when combined with soluble and/or cell-bound MUC1 in patients, will induce humoral and cellular immune responses to MUC1 that will be protective against pancreatic cancer in patients with MUC1 -expressing pancreatic and other tumors. The strategy has the unique capacity to provide a method of vaccinating each patient with their own tumor antigens through in vivo capture and presentation of circulating and cell associated tumor antigens. We will target the cell surface associated mucin MUC1 with BrevaRex¿ MAb-AR20.5, a murine IgGlK specific for the tandem repeat region of MUC1, which should provide effective targets for cell mediated responses against the tumor cells that produced the circulating antigen. One important challenge of producing effective tumor vaccines is developing reagents that break immunological tolerance to tumor-associated antigens. For preclinical studies, will utilize an inbred mouse strain on the C57BL/6 background that expresses human MUC1 in the correct temporal and spatial pattern (MUC1 Tg), develops tolerance and is refractory to immunization with MUC1. This experimental model has enabled us to study the effect of endogenous expression of the MUC1 gene on the ability of mice to produce protective immune responses to tumors, and represents an improved model system for evaluating the efficacy of anti-MUC1 formulations in vivo within the context of existing tolerance. We have developed and investigated a model in which a murine pancreatic tumor (Panc02) syngeneic to C57BL/6 transfected with human MUC1 (Panc02.MUC1), can be transplanted subcutaneously and orthotopically. In the studies proposed here, we will evaluate the mechanism of action of BrevaRex¿ MAb-AR20.5 in the murine model, conduct preclinical studies to determine its mechanism of action, and investigate the utility of combining this therapy with other interventions in a clinical trial in humans with pancreatic cancer.

我们建议进一步开发和测试可用于人类免疫治疗的新型试剂， 腺癌，特别是胰腺的腺癌。本项目正在开发的试剂包括 针对循环肿瘤相关抗原（TAA）的高度特异性鼠单克隆抗体， 由树突状细胞（DC）和其他抗原呈递细胞（APC）摄取的免疫复合物， 被有效地呈递给免疫系统。因此，体液和细胞免疫反应， TAA已激活。正在研究的基本假设是， 当给予患者时，循环的人肿瘤抗原将与那些抗原结合，形成免疫 将直接或在人抗小鼠抗体的开发之后与APC结合的复合物 抗体（HAMA）反应，捕获这些复合物，抗原处理的APC将 产生针对靶抗原的免疫应答。我们特别假设抗MUC 1 抗体BrevaRex MAb-AR 20.5，当与患者的可溶性和/或细胞结合的MUC 1结合时， 诱导对MUC 1体液和细胞免疫应答，其将保护胰腺癌， 表达MUC 1的胰腺肿瘤和其他肿瘤患者。该战略具有独特的能力， 通过体内捕获和呈递用患者自身的肿瘤抗原接种每个患者的方法 循环和细胞相关的肿瘤抗原。我们将靶向细胞表面相关粘蛋白MUC 1 用BrevaRex MAb-AR 20.5，一种特异于MUC 1串联重复区的鼠IgGlK， 为细胞介导的针对肿瘤细胞的反应提供有效靶点， 抗原的生产有效的肿瘤疫苗的一个重要挑战是开发能够破坏 对肿瘤相关抗原的免疫耐受性。对于临床前研究，将使用近交系小鼠 以正确的时间和空间模式表达人MUC 1的C57 BL/6背景上的菌株 (MUC1 Tg）产生耐受性，并且对MUC 1免疫是难治的。该实验模型具有 使我们能够研究MUC 1基因的内源性表达对小鼠产生 对肿瘤的保护性免疫反应，并代表了一种改进的模型系统，用于评估 抗MUC 1制剂在现有耐受性背景下的体内功效。我们已经开发并 研究了小鼠胰腺肿瘤（Panc 02）的模型，该模型与转染有 人MUC 1（Panc02.MUC1）可以皮下和原位移植。研究中 本文提出，我们将评估BrevaRex？MAb-AR 20.5在鼠模型中的作用机制， 进行临床前研究，以确定其作用机制，并调查与此相结合的效用 在胰腺癌患者的临床试验中使用其他干预措施进行治疗。