Antitumor Mechanisms of anti-CD40/CpG-activated Macrophages

抗CD40/CpG激活巨噬细胞的抗肿瘤机制

• 批准号: 8117797
• 负责人: PAUL M SONDEL
• 金额: $ 26.19万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8117797
• 关键词: Abbreviations; Antitumor Response; CC chemokine LCC-1; CD40 Antigens; Cancer Patient; Cancerous; Cell physiology; Cell surface; Cells; Chimeric Proteins; Clinical Trials; Data; Effector Cell; Future; Generations; Goals; High Dose Chemotherapy; Human; Immune; Immune response; Immune system; Immunocompromised Host; Immunomodulators; Immunosuppression; Immunotherapeutic agent; In Vitro; Infection; Lead; Leukocytes; Ligation; Link; Macrophage Activation; Malignant Neoplasms; Mediating; Modality; Monoclonal Antibodies; Mus; Myelogenous; Natural Killer Cells; Necrosis; Patients; Phenotype; Population; Prior Chemotherapy; Publishing; Regimen; Research; Residual state; Resistance; SCID Beige Mouse; Site; Suppressor-Effector T-Lymphocytes; T-Lymphocyte; TLR9 gene; TNFRSF5 gene; Testing; Therapeutic; Translating; arginase; base; cancer therapy; chemokine; chemotherapy; cytotoxic; in vivo; macrophage; melanoma; monocyte; novel; novel strategies; pre-clinical; preclinical study; prevent; response; tumor; tumor eradication; tumor growth

DESCRIPTION (provided by applicant): Activation of immune system cells via ligation of their cell surface CD40 molecules can induce both T cell- dependent and independent antitumor effects in tumor-bearing mice. We have recently shown that CD40 and Toll-like receptor-9 (TLR9) ligation by the combination of two immunomodulators, anti-CD40 monoclonal antibody (1CD40) and CpG, induces synergistic activation of macrophages and results in potent antitumor responses even in mice lacking T, B and cytolytic NK cells. As macrophages can be relatively resistant to chemotherapy, we hypothesize that in vivo macrophage activation with 1CD40 plus CpG therapy will augment the antitumor effect of prior chemotherapy in tumor-bearing hosts. Recent preliminary data support this hypothesis. We also hypothesize that targeting macrophages to the tumor microenvironment using a fusion protein consisting of a tumor reactive monoclonal antibody linked to the CCL16 chemokine will further enhance their antitumor effects in mice with established tumors. We also hypothesize that strategies known to interfere with tumor induced immune-suppression will enable even greater macrophage mediated antitumor activity following 1CD40 and CpG treatment. The purpose of this project is to characterize the antitumor mechanisms and therapeutic utility of 1CD40+CpG-activated macrophages. Specifically we will accomplish this objective through the following 4 aims, which include in vitro and in vivo analyses of murine macrophages and their effects on murine tumors, particularly the B16 melanoma: 1. Utilize 1CD40+CpG to overcome tumor-induced suppression of MF. 2. Determine how pretreatment with specific chemotherapy agents synergizes with the antitumor effects of MF activated with 1CD40+CpG. 3. Determine if localizing of 1CD40+CpG-MF in the tumor using chTNT-3/LEC FP will result in better antitumor effects. 4. Evaluate preclinical strategies of combinatory 1CD40+CpG therapy. This research will determine how to augment antitumor reactivity by macrophages activated with 1CD40 and CpG by interfering with tumor induced immune suppression in vivo. It will then identify combined regimens that further enhance these antitumor effects in mice with established tumors. As both murine and human macrophages can be activated through CD40 and TLR9, these basic and preclinical studies should provide a framework for future clinical trials utilizing this novel strategy of combining chemotherapy with macrophage- activating and localizing modalities. PUBLIC HEALH RELEVANCE: Macrophages are important derivatives of white blood cells that are critical in our defense against infections and in activating protective immune responses. This proposal is based on the concept that macrophages can also be activated to mediate direct anticancer effects; we hypothesize that proper activation of macrophages in patients with cancer has great therapeutic potential, especially in combination with other anti-cancer therapies, including conventional chemotherapy. The overall goal of this proposal is to characterize and further develop this novel strategy for macrophage activation in cancerous mice, where beneficial anti-cancer effects have already been shown, in order to determine how best to use this as a future strategy for treating human cancers.

描述（由申请人提供）：通过连接免疫系统细胞的细胞表面CD 40分子激活免疫系统细胞，可在荷瘤小鼠中诱导T细胞依赖性和非依赖性抗肿瘤作用。我们最近已经表明，通过两种免疫调节剂，抗CD 40单克隆抗体（1CD 40）和CpG的组合，CD 40和Toll样受体-9（TLR 9）的连接诱导巨噬细胞的协同活化，并导致有效的抗肿瘤反应，即使在缺乏T，B和细胞溶解NK细胞的小鼠中。由于巨噬细胞可能对化疗具有相对抗性，因此我们假设用1CD 40加CpG治疗的体内巨噬细胞活化将增强荷瘤宿主中先前化疗的抗肿瘤作用。最近的初步数据支持这一假设。我们还假设，使用由与CCL 16趋化因子连接的肿瘤反应性单克隆抗体组成的融合蛋白将巨噬细胞靶向肿瘤微环境，将进一步增强其在已建立肿瘤的小鼠中的抗肿瘤作用。我们还假设，已知干扰肿瘤诱导的免疫抑制的策略将使1CD 40和CpG治疗后的巨噬细胞介导的抗肿瘤活性更强。本项目的目的是表征1CD 40 + CpG激活的巨噬细胞的抗肿瘤机制和治疗效用。具体而言，我们将通过以下4个目标来实现这一目标，其中包括鼠巨噬细胞的体外和体内分析及其对鼠肿瘤，特别是B16黑色素瘤的作用：1.利用1CD 40 +CpG克服肿瘤诱导的MF抑制。2.确定特异性化疗药物预处理如何与1CD 40 +CpG激活的MF的抗肿瘤作用协同作用。3.确定使用chTNT-3/LEC FP在肿瘤中定位1CD 40 +CpG-MF是否会产生更好的抗肿瘤效果。4.评价1CD 40 +CpG联合治疗的临床前策略。本研究将探讨如何通过干扰肿瘤诱导的免疫抑制来增强1CD 40和CpG激活的巨噬细胞的抗肿瘤活性。然后，它将确定联合方案，进一步增强这些抗肿瘤作用的小鼠建立肿瘤。由于鼠和人巨噬细胞都可以通过CD 40和TLR 9活化，这些基础和临床前研究应该为利用这种将化疗与巨噬细胞活化和定位方式相结合的新策略的未来临床试验提供框架。公共卫生相关性：巨噬细胞是白色血细胞的重要衍生物，在我们抵御感染和激活保护性免疫反应中至关重要。该提议基于巨噬细胞也可以被激活以介导直接抗癌作用的概念;我们假设，癌症患者中巨噬细胞的适当激活具有巨大的治疗潜力，特别是与其他抗癌疗法（包括常规化疗）组合。该提案的总体目标是表征和进一步开发这种用于癌小鼠中巨噬细胞活化的新策略，其中已经显示出有益的抗癌作用，以确定如何最好地将其用作治疗人类癌症的未来策略。