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

• 批准号: 9899213
• 负责人: Catherine C Hedrick
• 金额: $ 44.82万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 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/9899213
• 关键词: Address; Animals; Antitumor Response; Apoptotic; B-Cell Leukemia; Blood; Blood Circulation; Blood Vessels; Blood specimen; CAR T cell therapy; Cancer Patient; Cell Communication; Cell Therapy; Cells; Childhood; Childhood Hematopoietic Neoplasm; Childhood Solid Neoplasm; 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-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; chimeric antigen receptor T cells; clinical center; clinical efficacy; early phase clinical trial; engineered T cells; 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

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（在人类中鉴定为CD 14 dimCD 16+）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。非经典 单核细胞在循环中起作用以帮助从脉管系统中除去病原体和碎片。我们最近 发现非经典单核细胞在血管系统中发挥作用，通过协调 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证据表明其具有促肿瘤发生和促转移功能相反， 骨髓细胞在许多肿瘤类型中。在目前的提议中，我们假设非经典单核细胞 以抗肿瘤方式发挥作用，以支持CAR T细胞扩增和在实体瘤患者中的功效。 肿瘤的因此，我们建议的一个主要目标是确定使用抗肿瘤药物的单核细胞疗法是否能够抑制肿瘤细胞的增殖。 非经典单核细胞与现有的CAR T免疫疗法组合将提高功效。我们将 使用质谱仪研究癌症患者的单核细胞亚群，以确定新的标志物， 很容易确定一种拟议的免疫疗法对患者的成功程度。目标1将识别唯一 多次复发肉瘤患者与健康受试者的非经典单核细胞标志物， 质谱细胞仪目标1将使用来自现有GD 2 CAR T试验的库存样本进行， NIH临床中心。目的2将检验非经典单核细胞在细胞凋亡中发挥功能性作用的假设。 当与用于实体瘤转移的免疫疗法联合使用时，促进抗肿瘤免疫。 目标2将使用异种移植人源化小鼠和同基因小鼠肿瘤模型。目标3将研究 CAR-T细胞联合非经典单核细胞免疫治疗安全性和初步疗效 针对多发性复发、转移或进展性儿科实体瘤患者的细胞治疗。在目标3中，我们 将启动第二代GD 2 CAR T细胞试验，用于多次复发的骨肉瘤患者， 神经母细胞瘤考虑到巡逻单核细胞的潜在抗肿瘤功效，我们计划启动一项早期的 作为一项临床试验，单独递送非经典单核细胞以及与CAR T细胞疗法组合递送非经典单核细胞， 是审判的一部分该项目有3名研究人员：一名在NCI的校外研究人员，一名在NCI的校内研究人员，一名在 NIH临床中心。从本提案的结果中，我们将对以下方面的作用有重要的了解： 各种骨髓细胞亚群对促进和抑制CAR T细胞的抗肿瘤应答的影响 治疗实体瘤。作为一个研究团队，我们具有独特的优势，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中的CAR T细胞相互作用。我们的调查结果显示， 研究小组将大大推进知识，这将导致有效的CAR T细胞治疗固体 肿瘤的由于单核细胞与T细胞发生类似的相互作用， 试验，我们预计我们的研究结果将揭示单核细胞：T细胞相互作用的背景下， 检查点抑制疗法。