Promoting Tumor Immunity by Cross-Linking B7-DC

通过交联 B7-DC 促进肿瘤免疫

• 批准号: 6859413
• 负责人: LARRY R PEASE
• 金额: $ 24.19万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-23 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6859413
• 关键词: breast neoplasms; crosslink; dendritic cells; disease /disorder model; genetic strain; genetically modified animals; immune response; immunomodulators; laboratory mouse; leukocyte activation /transformation; melanoma; myelogenous leukemia; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; surface antigens

DESCRIPTION (provided by applicant): Human sHIgM12 antibody (Ab) activates mouse and human dendritic cells (DCs) by cross-linking the co-stimulatory molecule B7-DC. DCs treated with sHIgM12 Ab do not undergo maturation, distinguishing this activation state from those achieved by engaging the CD40, TNF-, and the toll-like receptors. Antigen-pulsed DCs treated with sHIgM12 induce robust activation of naive T cells. Remarkably, systemic Ab treatment induces an immune-mediated protective response against a lethal challenge of B16 melanoma and promotes resistance against developing tumor nodules in a lung metastasis model. The Ab appears to induce signals directly in DCs, promoting a variety of changes including robust activation of NF-KappaB, increased resistance to apoptosis, and upregulation of cytokines, including IL-12. The current experimental aims are: (1) To determine the mechanism of protection from B16 melanoma induced by treatment of mice with B7-DC cross-linking Ab. We will evaluate the hypothesis that systemic treatment of mice with sHIgM12 Ab leads to the activation of effector T, NK, and B cells, promoting tumor killing mediated by classical effector molecules. (2) To evaluate therapeutic strategies designed to enhance multiple steps in the immune response. Current therapeutic strategies are only partially protective. Experiments are proposed to enhance this novel strategy by recruitment of DCs to the site of tumor growth with GMCSF prior to activation of DCs with B7-DC cross-linking Ab and by promoting the induced effector phase of the immune response by systemic co-stimulation with anti-41BB Ab. (3) To determine the generality of the immune protective effects of sHIgM12 Ab treatment in other tumor models: transplantable myelogenous leukemia WEHI-3B and the spontaneous breast cancer model MMT. As the sHIgM12 Ab activates DCs from multiple mouse strains, as well as human DCs, we seek to determine whether this remarkable therapeutic approach has general applicability to diverse tumor systems in disparate strains of mice.

描述（由申请人提供）：人sHIgM12抗体（Ab）通过交联共刺激分子B7-DC激活小鼠和人树突状细胞（dc）。用sHIgM12 Ab处理的dc不经历成熟，将这种激活状态与CD40、TNF-和toll样受体的激活状态区分开来。用sHIgM12处理抗原脉冲dc可诱导初始T细胞的强激活。值得注意的是，在肺转移模型中，系统性Ab治疗诱导免疫介导的保护反应，抵抗B16黑色素瘤的致命攻击，并促进对肿瘤结节的抵抗。Ab似乎直接在dc中诱导信号，促进多种变化，包括NF-KappaB的强大激活，对凋亡的抗性增强，以及细胞因子（包括IL-12）的上调。目前的实验目的是：(1)确定B7-DC交联抗体对小鼠B16黑色素瘤的保护机制。我们将评估sHIgM12抗体对小鼠的全身治疗导致效应T、NK和B细胞的激活，促进经典效应分子介导的肿瘤杀伤的假设。(2)评估旨在增强免疫反应多个步骤的治疗策略。目前的治疗策略只有部分保护作用。在B7-DC交联抗体激活dc之前，通过GMCSF将dc招募到肿瘤生长部位，并通过与抗41bb抗体的全身共刺激促进免疫反应的诱导效应期，我们提出了实验来增强这种新策略。(3)确定sHIgM12 Ab治疗在其他肿瘤模型中的免疫保护作用的共性：可移植骨髓性白血病WEHI-3B和自发性乳腺癌模型MMT。由于sHIgM12 Ab激活多种小鼠品系和人类dc，我们试图确定这种显著的治疗方法是否普遍适用于不同小鼠品系的不同肿瘤系统。