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Protective Role of Nonclassical Monocytes in Immunotherapies for Solid Cancers

非经典单核细胞在实体癌免疫治疗中的保护作用

基本信息

批准号：
9471276
负责人：
Catherine C Hedrick
金额：
$ 41.83万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9471276
关键词：
Address Animals Antitumor Response Apoptotic B-Cell Leukemia Blood Blood Circulation Blood Vessels Blood specimen Cancer Patient Cell Communication Cell Therapy Cells Childhood Childhood Hematopoietic Neoplasm Childhood Solid Neoplasm Clinical Clinical Trials Cytometry Disease remission Dose Exhibits Extramural Activities Generations Genetic Engineering Goals Hematopoietic stem cells Homeostasis Human ITGAM gene Immune Immune Targeting Immune checkpoint inhibitor Immune system Immunotherapy Inflammation Knowledge Leukocytes Lymphoma Malignant Neoplasms Modeling Mus Myelogenous Myeloid Cells Myeloid-derived suppressor cells Myeloproliferative disease Neoplasm Metastasis Neuroblastoma Patients Peripheral Blood Mononuclear Cell Phase Phenotype Play Population Primary Neoplasm Proteins Relapse Research Research Personnel Role Safety Sampling Sentinel Side Site Solid Solid Neoplasm Surveys T cell therapy T-Lymphocyte Testing Therapy trial Tumor Immunity United States National Institutes of Health Vascular Endothelium Work Xenograft procedure arm cancer cell cancer immunotherapy cancer therapy cancer type checkpoint inhibition chimeric antigen receptor clinical efficacy humanized mouse improved insight interest intravital imaging leukemia macrophage monocyte mouse model neoplastic cell new therapeutic target novel marker osteosarcoma particle pathogen pediatric patients phase I trial prevent recruit relapse patients response safety study sarcoma success tumor tumor growth tumor microenvironment tumor progression tumorigenic

项目摘要

Nonclassical monocytes (identified as CD14dimCD16+ in humans) exhibit a unique ability to `patrol' or survey the luminal side of the vascular endothelium both at steady state and during inflammation. Nonclassical monocytes function in circulation to aid in removing pathogens and debris from the vasculature. We recently found that nonclassical monocytes function in the vasculature to prevent tumor metastasis by orchestrating the killing and clearance of metastasizing tumor cells. The anti-tumor immune potential of nonclassical patrolling monocytes is in contrast to the growing evidence for pro-tumorigenic and pro-metastatic functions of myeloid cells in many tumor types. In the current proposal, we hypothesize that nonclassical monocytes function in an anti-tumoral manner to support CAR T cell expansion and efficacy in patients with solid tumors. Thus, one major goal of our proposal is to determine whether monocyte therapy using anti-tumoral nonclassical monocytes in combination with existing CAR T immunotherapy would improve efficacy. We will use mass cytometry to study monocyte subsets in cancer patients to identify new markers that will help readily determine how successful a proposed immunotherapy may be for patients. Aim 1 will identify unique markers of nonclassical monocytes in multiply relapsed sarcoma patients versus healthy subjects using mass cytometry. Aim 1 will be performed using banked samples from the existing GD2 CAR T trial at the NIH Clinical Center. Aim 2 will test the hypothesis that nonclassical monocytes play a functional role in promoting anti-tumor immunity when used in combination with immunotherapy for solid tumor metastasis. Aim 2 will use both xenografted humanized mouse and syngeneic mouse tumor models. Aim 3 will study the safety and preliminary efficacy of CAR T cell immunotherapy in combination with nonclassical monocyte cell therapy for patients with multiple relapsed, metastatic or progressive pediatric solid tumors. In Aim 3, we will initiate a second generation GD2 CAR T cell trial for multiply relapsed patients with osteosarcoma and neuroblastoma. Given the potential anti-tumor efficacy of patrolling monocytes we plan to initiate an early phase clinical trial delivering nonclassical monocytes alone and in combination with CAR T cell therapy as part of this trial. There are 3 investigators in this project: one extramural, one intramural at NCI, and one at the NIH Clinical Center. From the results of this proposal, we will achieve significant insight into the roles of various myeloid cell subpopulations on promoting and inhibiting the anti-tumoral responses of CAR T cell therapies for solid tumors. We are uniquely poised as a research team to directly address the role of monocytes and other myeloid cells in interacting with CAR T cells in human patients. The findings of our research team will significantly advance the knowledge that will lead to effective CAR T cell therapy for solid tumors. As similar interactions of monocytes occur with T cells that are modulated by checkpoint inhibitor trials, we anticipate that our findings will shed insight into monocyte:T cell interactions in the context of checkpoint inhibition therapy.

非经典单核细胞（在人类中被识别为 CD14dimCD16+）表现出独特的“巡逻”或调查能力在稳态和炎症期间血管内皮的管腔侧。非古典的单核细胞在循环中发挥作用，帮助清除脉管系统中的病原体和碎片。我们最近发现非经典单核细胞在脉管系统中发挥作用，通过协调来预防肿瘤转移杀死和清除转移的肿瘤细胞。非经典的抗肿瘤免疫潜力巡逻单核细胞与越来越多的促肿瘤发生和促转移功能的证据形成鲜明对比许多肿瘤类型中的骨髓细胞。在当前的提案中，我们假设非经典单核细胞以抗肿瘤方式发挥作用，支持实体瘤患者的 CAR T 细胞扩增和疗效肿瘤。因此，我们建议的一个主要目标是确定单核细胞治疗是否使用抗肿瘤药物非经典单核细胞与现有的 CAR T 免疫疗法相结合将提高疗效。我们将使用质谱流式细胞仪研究癌症患者的单核细胞亚群，以确定新的标记物，这将有助于轻松确定所提出的免疫疗法对患者的成功程度。目标 1 将识别独特的多发性复发肉瘤患者与健康受试者的非经典单核细胞标记质谱流式细胞术。目标 1 将使用来自现有 GD2 CAR T 试验的银行样本来执行美国国立卫生研究院临床中心。目标 2 将检验以下假设：非经典单核细胞在与实体瘤转移的免疫疗法联合使用时可促进抗肿瘤免疫。目标 2 将使用异种移植的人源化小鼠和同基因小鼠肿瘤模型。目标3将学习 CAR T细胞免疫疗法联合非经典单核细胞的安全性和初步疗效针对多发性复发、转移性或进展性儿童实体瘤患者的细胞疗法。在目标 3 中，我们将针对骨肉瘤多次复发患者启动第二代 GD2 CAR T 细胞试验成神经细胞瘤。鉴于巡逻单核细胞的潜在抗肿瘤功效，我们计划启动早期研究单独提供非经典单核细胞以及与 CAR T 细胞疗法相结合的二期临床试验本次试验的一部分。该项目有 3 名研究者：一名校外、一名 NCI 校内、一名美国国立卫生研究院临床中心。从该提案的结果中，我们将深入了解以下角色：不同骨髓细胞亚群对CAR T细胞抗肿瘤反应的促进和抑制作用实体瘤的治疗。作为一个研究团队，我们拥有独特的优势，可以直接解决以下问题：单核细胞和其他骨髓细胞与人类患者的 CAR T 细胞相互作用。我们的调查结果研究团队将显着推进知识的进步，从而为实体瘤提供有效的 CAR T 细胞疗法肿瘤。由于单核细胞与受检查点抑制剂调节的 T 细胞发生类似的相互作用试验中，我们预计我们的发现将有助于深入了解单核细胞：T 细胞在以下情况下的相互作用：检查点抑制疗法。