Adrenergic modulation of cellular immune functions in CAR T cell-induced cytokine release syndrome

CAR T 细胞诱导的细胞因子释放综合征中细胞免疫功能的肾上腺素调节

基本信息

批准号：
10532157
负责人：
Renyuan Bai
金额：
$ 61.39万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10532157
关键词：
Adrenergic Agents Adrenergic Receptor Antitumor Response B lymphoid malignancy Biological Assay CD14 gene CD19 gene CRISPR/Cas technology Cancer Patient Catecholamines Cell Therapy Cells Clinical Coculture Techniques Data Dedications Development Epinephrine Functional disorder Genetic Goals Granulocyte-Macrophage Colony-Stimulating Factor Hematologic Neoplasms Human IL6 gene Immune Immune response Immunosuppression Immunotherapy In Vitro Individual Inflammatory Institution Interleukin-6 Knock-out Knockout Mice Laboratories Life Macrophage Macrophage Activation Malignant Neoplasms Measures Mediating Mediator Modeling Molecular Mus Myelogenous Myeloid Cells NOS2A gene Pathogenesis Patient Monitoring Patient-Focused Outcomes Patients Pennsylvania Peripheral Blood Mononuclear Cell Prazosin Production Productivity Receptor Signaling Research Role Safety Sampling Scientist Serum Severities Shapes Solid Neoplasm Supportive care Symptoms T cell response T cell therapy T-Lymphocyte TNFSF5 gene Therapeutic Toxic effect Tyrosine 3-Monooxygenase United States National Institutes of Health alpha-Methyltyrosine anakinra antagonist cancer therapy chimeric antigen receptor chimeric antigen receptor T cells clinical implementation cytokine cytokine release syndrome data sharing effective intervention immune activation immune function immune-related adverse events immunotoxicity improved in vivo in vivo evaluation indexing inhibitor knock-down leukemia mortality mouse model neoplastic cell novel pharmacologic prevent receptor response small hairpin RNA success therapy outcome tool translational potential tumor tumor eradication

项目摘要

Immunotherapy using tumor-directed chimeric antigen receptor (CAR)-expressing T cells (CART) is a rapidly- emerging, promising cancer therapy that can elicit rapid, durable clinical responses, seen in anti-CD19 CART (CART19)-treated CD19+ B-cell malignancies. However, CART-evoked severe or fatal immune-related adverse events (irAE) including cytokine-release syndrome (CRS) are significant clinical barriers and safety concerns that impede CART use in cancer patients, even with strict patient monitoring and supportive care. Current tools for mitigating such immunotoxicities/CRS target individual cytokines/receptors (e.g. IL-6R, IL-1Ra, GM-CSF) or nonspecific immunosuppression, but preventing and treating such toxicity will require better understanding of cellular/molecular mediators of CART-induced CRS. This project aims to overcome these barriers and enable more effective interventions against immunotoxicities, and thus more effective CART treatments, building upon the PIs' novel, potentially translatable findings of a key role of catecholamines (CATs) in shaping CART therapy- associated immune activation. We found that blocking CAT synthesis both reduced CRS during CART therapy in mice and also enhanced its tumor eradication, and also found that CAT levels are elevated in patients with CART-evoked CRS, and correlated with symptoms and IL-6 levels, suggesting CATs contribute to human CRS pathophysiology. The project's goal is to identify the mechanistic CRS-modulating roles of these novel CAT actions and their impacts on macrophages and anti-tumor responses, and assess translational potential for improving CART cancer therapy outcomes using human patient samples. Specific Aims are: 1) Determine the mediating α1-AR subtype and its role in modulating CART-evoked cytokine release and anti-tumor responses in vitro and in vivo, based on our finding that CAT-associated cytokine release is mediated by α1-adrenergic receptors (α1-AR), of as-yet unknown subtype(s). We will identify the α1-AR subtype(s) that mainly mediate(s) CAT-evoked cytokine production in macrophages and CART, using in vitro co-culture assays and a mouse CART therapy model via genetic knockout (KO) and knockdown (KD) of α1-AR subtypes. 2) Determine the impact of myeloid-derived CATs on cytokine release and myeloid function during CART-therapy in vitro and in a mouse model, by inactivating CAT synthesis in myeloid cells via tyrosine hydroxylase (TH) KO, and assess its impact on cytokine release and macrophage function in a co-culture assay and in vivo using a LysM-Cre-mediated TH KO mouse. 3) Assess CAT induction in human patients during CART therapy, and CATs' dual impacts on irAE and tumor responses, and potential utility of CAT measures and blockers in predicting and preventing CRS, by quantifying circulating CAT and cytokine levels in patient serum samples collected during CART therapy, and evaluating correlations of CAT levels with clinical and laboratory CRS indices, anti-tumor responses and survival.

使用肿瘤定向的嵌合抗原受体（CAR）表达T细胞（CART）的免疫疗法是一种快速在抗CD19 CART中看到的新兴，有希望的癌症治疗，可以引起快速，耐用的临床反应（CART19）处理的CD19+ B细胞恶性肿瘤。但是，卡车引起的严重或致命的免疫相关不良包括细胞因子释放综合征（CRS）在内的事件（IRAE）是重大的临床障碍和安全问题即使严格的患者监测和支持性护理，也会阻碍癌症患者的使用。当前工具为了降低这种免疫毒性/CR，靶向单个细胞因子/受体（例如IL-6R，IL-1RA，GM-CSF）或非特异性免疫抑制，但预防和治疗这种毒性将需要更好地理解手推车诱导的CR的细胞/分子介质。该项目旨在克服这些障碍并实现基于 PIS的新颖的，可能翻译的发现是儿茶酚胺（CAT）在塑造购物车治疗中的关键作用的发现 - 相关的免疫激活。我们发现阻断CAT合成既降低了CART治疗期间的CR 在小鼠中，还增强了其肿瘤的放射定位，还发现手推车引起的CR，与符号和IL-6级别相关，表明猫有助于人类CRS 病理生理学。该项目的目标是确定这些新猫的机械性CRS调节作用行动及其对巨噬细胞和抗肿瘤反应的影响，并评估转化潜力使用人类患者样品改善购物车癌症治疗结果。具体目的是：1）确定介导α1-ar亚型及其在调节菜单诱发的细胞因子释放和抗肿瘤反应中的作用基于我们的发现，基于我们的发现，cAT相关的细胞因子释放是由α1-肾上腺素能介导的尚未知道的亚型的受体（α1-ar）。我们将确定主要介导的α1-ar亚型使用体外共培养分析和小鼠推车，巨噬细胞和购物车中的猫诱发的细胞因子产生通过基因敲除（KO）和α1-AR亚型的敲低（KD）的治疗模型。 2）确定髓样衍生的猫在体外和小鼠中进行了骨细胞因子释放和髓样功能模型，通过通过酪氨酸羟化酶（Th）KO灭活CAT合成，并评估其影响在共培养测定中的细胞因子释放和巨噬细胞功能上，使用Lysm-Cre介导的TH ko鼠标。 3）评估手推车治疗期间人类患者的CAT诱导，以及猫对IRAE的双重影响和肿瘤的反应，以及猫测量和阻滞剂在预测和预防CRS中的潜在效用，量化在卡车治疗期间收集的患者血清样品中的循环CAT和细胞因子水平，以及评估CAT水平与临床和实验室CRS指数，抗肿瘤反应和生存的相关性。