The role of catecholamines in immunotoxicity and tumor response of adoptive T cell therapy in cancer

儿茶酚胺在癌症过继性 T 细胞疗法的免疫毒性和肿瘤反应中的作用

基本信息

批准号：
10206054
负责人：
Verena Staedtke
金额：
$ 27.02万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10206054
关键词：
Acute Lymphocytic Leukemia Address Adoptive Transfer Adrenal Cortex Hormones Adverse reactions Affect Antibodies Antigens Antitumor Response Area Autoimmune B lymphoid malignancy B-Cell Acute Lymphoblastic Leukemia B-Lymphocytes Blood Brain Neoplasms CD19 gene Cancer Model Career Choice Catecholamines Cell physiology Cells Cerebral Edema Cerebrospinal Fluid Cerebrum Clinical Clinical Trials Dose-Limiting Encephalopathies Engineering Enzymes Epidermal Growth Factor Receptor Epinephrine Funding Gene Chips Gene-Modified Genetic Engineering Glioblastoma Goals Hematologic Neoplasms Human Immune Immunocompetent Immunotherapy Impairment Interleukin-12 Interleukin-6 Intervention Knock-out Lymphocyte Lymphoma Malignant Neoplasms Mediating Methods Modeling Mus Mutation Myeloid Cells Neurologic Oncologist Pathway interactions Patients Pharmacology Population Primary Brain Neoplasms Production Receptor Gene Reporter Research Role Safety Seizures Signal Pathway Site Solid Syndrome T cell therapy T-Lymphocyte Testing Therapeutic Toxic effect Translational Research Treatment Efficacy Tyrosine 3-Monooxygenase United States National Institutes of Health Variant Xenograft procedure cancer cell cancer therapy cell killing chimeric antigen receptor cytokine cytokine release syndrome cytotoxicity effective intervention engineered T cells genetically modified cells immune-related adverse events immunotoxicity improved improved outcome inhibitor/antagonist innovation insight interest mouse model neoplastic cell neuroinflammation novel response response biomarker success therapy outcome tocilizumab tool treatment response treatment strategy tumor tumor eradication

项目摘要

Glioblastoma (GBM) is the most common primary brain tumor, and among the most lethal human cancers. No cure exists, and only limited treatment advances have been achieved. A highly promising area of immunotherapy is adoptive transfer of genetically engineered, patient-derived blood lymphocytes transfected with chimeric antigen receptor genes (CARs) to target and destroy cancer cells, currently being explored for treating GBM. Critical challenges to using CAR-modified T (CART) cells involve dose-limiting immunotoxicities including cytokine-release-syndrome (CRS) and neurological toxicities. Most research has aimed at improving CART efficacy, while the mechanisms of toxicities/adverse reactions, innovative strategies for their management, and their implications for anti-tumor efficacy remain under-explored. I recently discovered that endogenous catecholamines drive CART-induced CRS, via a self-amplifying feed-forward loop in immune cells, and that inhibiting their production protected CART-treated Raji lymphoma-bearing xenograft mice from lethal CRS and enhanced tumor eradication, suggesting separate pathways of immunotoxicity and anti-tumor response. The goal of this proposal is to elucidate the mechanism by which catecholamines mediate immunotoxicity in CART therapy in brain tumors and other cancers and assess their impact on the anti-tumor response in immunocompetent cancer models. My central hypothesis is that catecholamines promote CART- induced CRS and that its pharmacologic inhibition improves CART therapy safety and tumor-specific killing. I will test this idea in 3 Specific Aims: 1) Evaluate the induction of catecholamines and CRS in an immunocompetent CD19+ B cell ALL CART19 model, and determine the dual impact of suppressing catecholamine production on cytokine release and anti-tumor responses, by analyzing catecholamine and cytokine release in a CD19+ B cell ALL CART19 model, which recapitulates the CRS seen in human CART19 therapy; 2) Determine the signaling pathway by which catecholamines upregulate catecholamine production and cytokine release in mouse CART19 (mCART19) therapy and how this affects CART functionality, by using gene expression microarray and pathway reporter arrays to discover contributing mechanisms of epinephrine- induced catecholamine and cytokine synthesis and by determining the effects of cytokines most significantly altered on mCART19 cell activation, expansion and cytotoxicity; 3) Determine whether blocking endogenous catecholamine synthesis reduces CART-induced systemic and CNS immunotoxicity and improves anti-tumor responses in an immunocompetent mouse GBM model. The results will advance basic understanding of endogenous pathways contributing to immunotoxicity, and may enable improved outcomes of CART therapy and management of adverse immunotoxicities, via new insights into their mechanisms and a novel treatment strategy of catecholamine blockade, which inhibits multiple cytokines more broadly than anti-IL6R antibody (tocilizumab).

胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤，也是最致命的人类癌。不存在治疗，并且仅实现了有限的治疗进展。一个非常有前途的领域免疫疗法是转基因，患者衍生的血液淋巴细胞转染的收养转移用嵌合抗原受体基因（CAR）靶向和破坏癌细胞，目前正在探索治疗GBM。使用CAR修饰的T（CART）细胞的关键挑战涉及限制剂量的免疫毒性包括细胞因子释放合成剂（CRS）和神经毒性。大多数研究旨在改善推车功效，而毒性/不利反应的机制，其创新策略管理及其对抗肿瘤功效的影响仍然不足。我最近发现内源性儿茶酚胺驱动购物车引起的CR，通过免疫中的自我扩增前馈环细胞，并抑制其生产受保护的手推车处理的拉吉淋巴瘤的异种移植小鼠致命的CR和增强的消除肿瘤，表明了免疫毒性和抗肿瘤的单独途径回复。该提案的目的是阐明儿茶酚胺介导的机制脑肿瘤和其他癌症的购物车治疗中的免疫毒性，并评估其对抗肿瘤的影响免疫能力癌症模型的反应。我的中心假设是，儿茶酚胺促进了货车诱导CRS，其药理抑制作用可改善购物车治疗安全性和肿瘤特异性杀戮。我将在3个特定目的中测试这个想法：1）评估儿茶酚胺和CRS的诱导免疫功能CD19+ B细胞所有CART19模型，并确定抑制的双重影响儿茶酚胺在细胞因子释放和抗肿瘤反应上产生，通过分析儿茶酚胺和 CD19+ B细胞中的细胞因子释放所有CART19模型，该模型概括了人类CART19中的CR19 治疗; 2）确定儿茶酚胺上调儿茶酚胺产生的信号通路在小鼠Cart19（MCART19）疗法中释放的细胞因子释放，以及通过使用如何影响CART功能基因表达微阵列和途径记者阵列，以发现肾上腺素的促进机制诱导的儿茶酚胺和细胞因子合成，并通过确定细胞因子的作用最为明显 MCART19细胞激活，膨胀和细胞毒性改变了； 3）确定是否阻塞内源性儿茶酚胺合成可降低手推车诱导的全身性和中枢神经系统免疫毒性，并改善抗肿瘤免疫能力的小鼠GBM模型中的响应。结果将提高对内源性途径有助于免疫毒性，并可以改善CART治疗的预后通过对其机制的新见解和一种新颖的治疗方法来管理不良免疫毒性儿茶酚胺阻断的策略，该策略比抗IL6R抗体更广泛地抑制多种细胞因子（Tocilizumab）。