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试剂 腺癌，尤其是胰腺癌。该项目中正在开发的试剂包括 高度特异的小鼠抗循环肿瘤相关抗原(TAA)的单抗，形成 由树突状细胞(DC)和其他抗原提呈细胞(APC)摄取的免疫复合体 被高效地呈现给免疫系统。因此，体液和细胞免疫反应针对 TAA被激活。正在研究的基本假设是，鼠抗病毒抗体 循环中的人类肿瘤抗原在给患者使用时会与这些抗原结合，形成免疫 将直接或在人类抗鼠抗体开发后与APC结合的复合体 捕获这些复合体的抗体(HAMA)反应，APC对抗原的处理将 产生针对目标抗原的免疫反应。我们特别假设抗MUC1抗体 抗体BrevaRex？MAb-AR20.5与患者中可溶性和/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，对胰腺癌具有保护作用 胰腺和其他肿瘤中表达MUC1的患者。该战略具有独特的能力，可以提供 一种通过活体捕获和呈现给每个患者接种自己的肿瘤抗原的方法 循环和细胞相关的肿瘤抗原。我们将靶向与细胞表面相关的粘蛋白MUC1 与BrevaRex？mab-AR20.5一起，针对MUC1串联重复区域的小鼠IgGlK，这应该是 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点 抗原。生产有效的肿瘤疫苗的一个重要挑战是开发能够打破 对肿瘤相关抗原的免疫耐受。在临床前研究中，将利用近亲繁殖的小鼠 在C57BL/6背景上以正确的时间和空间模式表达人MUC1的菌株 (MUC1Tg)，形成耐受性，对MUC1Tg免疫无效。这个实验模型有 使我们能够研究MUC1基因的内源性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 在现有耐受性的背景下，体内抗MUC1制剂的有效性。我们已经开发出了 建立小鼠胰腺癌(Panc02)与C57BL/6同基因肿瘤模型 人MUC1(Panc02.MUC1)可以进行皮下移植和原位移植。在研究中 因此，我们将在小鼠模型中评价BrevaRex？mab-AR20.5的作用机制。 进行临床前研究以确定其作用机制，并调查将其与 胰腺癌患者的临床试验中的其他干预治疗。

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.