P-1: Immunotherapy of Pancreatic Adenocarcinoma

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，形成 被树突状细胞 (DC) 和其他抗原呈递细胞 (APC) 摄取的免疫复合物， 有效地呈现给免疫系统。结果，体液和细胞免疫反应 TAA 已激活。正在研究的基本假设是小鼠抗体 当给患者施用时，循环人类肿瘤抗原将与这些抗原结合，形成免疫 将直接或在人类抗小鼠开发后与 APC 结合的复合物 捕获这些复合物的抗体（HAMA）反应，以及 APC 的抗原处理将 产生针对目标抗原的免疫反应。我们特别假设抗 MUC1 抗体 BrevaRex¿ MAb-AR20.5 当与患者体内可溶性和/或细胞结合的 MUC1 结合时，将 诱导针对 MUC1 的体液和细胞免疫反应，从而预防胰腺癌 患有表达MUC1的胰腺肿瘤和其他肿瘤的患者。该战略具有独特的能力，可以提供 通过体内捕获和呈递为每位患者接种自己的肿瘤抗原的方法 循环和细胞相关肿瘤抗原。我们将靶向细胞表面相关的粘蛋白 MUC1 与 BrevaRex¿ MAb-AR20.5 一起使用，这是一种对 MUC1 串联重复区域具有特异性的鼠 IgGlK，它应该 为细胞介导的针对产生循环的肿瘤细胞的反应提供有效的靶标 抗原。生产有效肿瘤疫苗的一项重要挑战是开发能够破坏肿瘤细胞的试剂 对肿瘤相关抗原的免疫耐受。对于临床前研究，将利用近交系小鼠 C57BL/6 背景上的菌株以正确的时间和空间模式表达人类 MUC1 (MUC1 Tg)，产生耐受性并对 MUC1 免疫产生耐药性。该实验模型有 使我们能够研究 MUC1 基因的内源表达对小鼠生产能力的影响 对肿瘤的保护性免疫反应，代表了一种改进的模型系统，用于评估 在现有耐受性的情况下，抗MUC1制剂的体内功效。我们已经开发并 研究了一个模型，其中与 C57BL/6 同基因的小鼠胰腺肿瘤 (Panc02) 转染 人MUC1（Panc02.MUC1）可以皮下移植和原位移植。在研究中 在此提出，我们将在小鼠模型中评估 BrevaRex¿ MAb-AR20.5 的作用机制， 进行临床前研究以确定其作用机制，并研究将其结合起来的效用 在人类胰腺癌临床试验中结合其他干预措施进行治疗。

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.