NATURAL KILLER CELL BASED IMMUNOTHERAPY

基于自然杀伤细胞的免疫疗法

基本信息

批准号：
7897361
负责人：
ROBERT Charles SEEGER
金额：
$ 19.69万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7897361
关键词：
Antibodies Autologous Biology Blood Bolus Infusion Bone Marrow Cell Line Cells Child Clinical Investigator Clinical Trials Collaborations Cyclophosphamide Data Databases Development Disease Drug Combinations Drug usage Drug-sensitive Femur Gene Expression Gene Expression Profiling Goals Grant Growth Human Ifni Image Immune Immunosuppressive Agents Immunotherapy In Vitro In complete remission Inflammation Injection of therapeutic agent Interleukin-12 Interleukin-15 Interleukin-2 Interleukin-6 Intravenous Laboratory Research Maps Mediating Methods Microarray Analysis Modeling Monoclonal Antibodies Mononuclear Mus NK Cell Activation NOD/SCID mouse Natural Killer Cells Neuroblastoma New Agents Pathway interactions Patients Phagocytes Pharmaceutical Preparations Protein Array Analysis Recurrence Research Design Residual Neoplasm Resistance Role STAT3 gene Site Survival Rate TGFB1 gene Testing Therapeutic Zoledronic Acid antibody-dependent cell cytotoxicity base bevacizumab cell growth cell killing chemokine chemotherapy combinatorial cytokine cytotoxicity high risk immunoregulation improved in vitro Model in vivo in vivo Model inhibitor/antagonist insight killings lenalidomide monocyte mouse model neoplastic cell novel strategies receptor research study response sialogangliosides small hairpin RNA small molecule subcutaneous therapeutic target tumor tumor growth

项目摘要

Our long-term goal is to develop immunotherapy for high-risk neuroblastoma that realizes the full potential of natural killer (NK) cells combined with antitumor monoclonal antibodies (e.g., anfi-GD2) to eradicate primary and metastatic disease. We hypothesize the following: 1) Anti-tumor efficacy of NK antibody dependent cellular cytotoxicity (ADCC) depends upon the quantity, persistence, and anti-tumor function of NK cells in tumor microenvironments. 2) Neuroblastoma cells and mononuclear phagocytes reciprocally cooperate to create a microenvironment milieu, which includes IL-6 and TGFB1, that is pro-tumor and immunosuppressive. Thus, therapeutic strategies must both maximize NK activation for ADCC and cytokine secretion (e.g., Ifni) and minimize microenvironment suppression (e.g., IL-6 and TGFB1). Our Specific Aims are as follows: 1) Identify interactions between tumor cells and mononuclear phagocytes that promote tumor growth and/or suppress anti-tumor NK functions. 2) Develop combinatorial therapy for established and minimal disease by maximizing anti-tumor activities of NK cells while abrogating pro-tumor activities of mononuclear phagocytes. Research Design and Methods. In Aim 1. we shall use our existing microarray database to gain further insight into inflammation-related gene expression of tumors from patients (e.g., IL- 6/STAT3 and TGFB pathways) and then validate findings with protein array analyses. Next, we shall use in vitro models to understand interactions between tumor cells and monocytes that increase growth of tumor cells and suppress activation of NK cells for ADCC and Ifni secretion. Finally we shall use In vivo models of local and disseminated disease in NOD/SCID mice that include bioluminescent imaging of tumor cells monocytes, and NK cells to further understand how monocytes promote tumor growth and to determine if they cause resistance to NK ADCC. In Aim 2, we shall develop combinatorial therapy that maximizes antitumor NK ADCC while negating pro-tumor and immunosuppressive contributions from tumor cells and mononuclear phagocytes. Here, we shall use In vitro models to develop strategies with drugs such as the immune modulator lenalidomide for maximizing induction of NK ADCC and cytokine secretion while modulating the pro-tumor functions of monocytes. This aim will include generating microarray data for use in connectivity mapping aimed at identifying new agents for immune modulation. The most promising strategies then will be tested with our in vivo NOD/SCID models, which include imaging, of minimal and established disseminated and local disease. These experiments will provide the basis for clinical trial development.

我们的长期目标是开发针对高风险神经母细胞瘤的免疫疗法，以充分发挥其潜力自然杀伤 (NK) 细胞与抗肿瘤单克隆抗体（例如 anfi-GD2）结合来根除原发性疾病和转移性疾病。我们假设如下：1）NK抗体的抗肿瘤功效依赖性细胞毒性（ADCC）取决于细胞的数量、持久性和抗肿瘤功能肿瘤微环境中的 NK 细胞。 2）神经母细胞瘤细胞和单核吞噬细胞相互作用合作创造一个微环境环境，其中包括IL-6和TGFB1，这是促肿瘤和免疫抑制。因此，治疗策略必须最大化 ADCC 的 NK 激活和细胞因子分泌（例如，Ifni）并最大限度地减少微环境抑制（例如，IL-6 和 TGFB1）。我们的具体目的如下： 1) 确定肿瘤细胞和单核吞噬细胞之间的相互作用，从而促进肿瘤生长和/或抑制抗肿瘤 NK 功能。 2）针对已建立的治疗方案开发组合疗法通过最大限度地提高 NK 细胞的抗肿瘤活性，同时消除促肿瘤活性，将疾病最小化单核吞噬细胞。研究设计和方法。在目标 1 中，我们将使用现有的微阵列数据库，以进一步了解患者肿瘤的炎症相关基因表达（例如，IL- 6/STAT3 和 TGFB 途径），然后通过蛋白质阵列分析验证结果。接下来，我们将使用在体外模型来了解肿瘤细胞和单核细胞之间促进肿瘤生长的相互作用细胞并抑制 NK 细胞的 ADCC 和 Ifni 分泌激活。最后我们将使用体内模型 NOD/SCID 小鼠的局部和播散性疾病，包括肿瘤细胞的生物发光成像单核细胞和 NK 细胞，以进一步了解单核细胞如何促进肿瘤生长并确定是否它们会对 NK ADCC 产生耐药性。在目标 2 中，我们将开发最大化抗肿瘤效果的组合疗法 NK ADCC 同时消除肿瘤细胞的促肿瘤和免疫抑制作用单核吞噬细胞。在这里，我们将使用体外模型来制定药物策略，例如免疫调节剂来那度胺可最大限度地诱导 NK ADCC 和细胞因子分泌，同时调节单核细胞的促肿瘤功能。该目标将包括生成微阵列数据以用于连接图谱旨在识别免疫调节的新药物。最有前途的策略然后将使用我们的体内 NOD/SCID 模型进行测试，其中包括最小和已建立的成像传播性和局部疾病。这些实验将为临床试验的开展提供基础。