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:
- 金额:$ 27.02万
- 依托单位:
- 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:
- 关键词:Acute Lymphocytic LeukemiaAddressAdoptive TransferAdrenal Cortex HormonesAdverse reactionsAffectAntibodiesAntigensAntitumor ResponseAreaAutoimmuneB lymphoid malignancyB-Cell Acute Lymphoblastic LeukemiaB-LymphocytesBloodBrain NeoplasmsCD19 geneCancer ModelCareer ChoiceCatecholaminesCell physiologyCellsCerebral EdemaCerebrospinal FluidCerebrumClinicalClinical TrialsDose-LimitingEncephalopathiesEngineeringEnzymesEpidermal Growth Factor ReceptorEpinephrineFundingGene ChipsGene-ModifiedGenetic EngineeringGlioblastomaGoalsHematologic NeoplasmsHumanImmuneImmunocompetentImmunotherapyImpairmentInterleukin-12Interleukin-6InterventionKnock-outLymphocyteLymphomaMalignant NeoplasmsMediatingMethodsModelingMusMutationMyeloid CellsNeurologicOncologistPathway interactionsPatientsPharmacologyPopulationPrimary Brain NeoplasmsProductionReceptor GeneReporterResearchRoleSafetySeizuresSignal PathwaySiteSolidSyndromeT cell therapyT-LymphocyteTestingTherapeuticToxic effectTranslational ResearchTreatment EfficacyTyrosine 3-MonooxygenaseUnited States National Institutes of HealthVariantXenograft procedurecancer cellcancer therapycell killingchimeric antigen receptorcytokinecytokine release syndromecytotoxicityeffective interventionengineered T cellsgenetically modified cellsimmune-related adverse eventsimmunotoxicityimprovedimproved outcomeinhibitor/antagonistinnovationinsightinterestmouse modelneoplastic cellneuroinflammationnovelresponseresponse biomarkersuccesstherapy outcometocilizumabtooltreatment responsetreatment strategytumortumor 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。不
治愈方法是存在的,但仅取得了有限的治疗进展。一个极具前景的领域
免疫疗法是基因工程、转染的患者来源的血液淋巴细胞的过继转移
使用嵌合抗原受体基因 (CAR) 来靶向和破坏癌细胞,目前正在探索
治疗 GBM。使用 CAR 修饰 T (CART) 细胞的关键挑战涉及剂量限制性免疫毒性
包括细胞因子释放综合征(CRS)和神经毒性。大多数研究旨在改善
CART 疗效,同时毒性/不良反应的机制、其创新策略
管理及其对抗肿瘤功效的影响仍有待探索。我最近发现
内源性儿茶酚胺通过免疫中的自我放大前馈循环驱动 CART 诱导的 CRS
细胞,并且抑制它们的产生可以保护 CART 治疗的携带 Raji 淋巴瘤的异种移植小鼠免受
致命的 CRS 和增强的肿瘤根除,表明免疫毒性和抗肿瘤途径不同
回复。该提案的目的是阐明儿茶酚胺介导的机制
CART 疗法在脑肿瘤和其他癌症中的免疫毒性,并评估其对抗肿瘤的影响
免疫活性癌症模型中的反应。我的中心假设是儿茶酚胺促进 CART-
诱导 CRS 及其药理学抑制提高了 CART 治疗的安全性和肿瘤特异性杀伤。我
将在 3 个具体目标中测试这一想法:1) 评估儿茶酚胺和 CRS 在
免疫活性 CD19+ B 细胞 ALL CART19 模型,并确定抑制的双重影响
通过分析儿茶酚胺和儿茶酚胺的产生对细胞因子释放和抗肿瘤反应的影响
CD19+ B 细胞 ALL CART19 模型中细胞因子的释放,概括了人类 CART19 中观察到的 CRS
治疗; 2) 确定儿茶酚胺上调儿茶酚胺产生的信号通路
小鼠 CART19 (mCART19) 治疗中的细胞因子释放以及这如何影响 CART 功能,通过使用
基因表达微阵列和通路报告阵列,以发现肾上腺素的作用机制
诱导儿茶酚胺和细胞因子的合成,并通过确定细胞因子的影响最显着
mCART19 细胞活化、扩增和细胞毒性发生改变; 3)判断是否阻断内源性
儿茶酚胺合成可降低 CART 诱导的全身和中枢神经系统免疫毒性并提高抗肿瘤能力
免疫活性小鼠 GBM 模型中的反应。结果将促进对以下内容的基本理解:
内源性途径导致免疫毒性,并可能改善 CART 治疗的结果
通过对其机制的新见解和新的治疗方法来管理不良免疫毒性
儿茶酚胺阻断策略,比抗 IL6R 抗体更广泛地抑制多种细胞因子
(托珠单抗)。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Verena Staedtke其他文献
Verena Staedtke的其他文献
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{{ truncateString('Verena Staedtke', 18)}}的其他基金
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
- 批准号:
10434895 - 财政年份:2018
- 资助金额:
$ 27.02万 - 项目类别:
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