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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症之一。否