Identification of circulating and tissue-specific autoimmune responses in checkpoint inhibitor-induced immune-related adverse events
检查点抑制剂诱导的免疫相关不良事件中循环和组织特异性自身免疫反应的识别
基本信息
- 批准号:10578771
- 负责人:
- 金额:$ 19.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-03-01 至 2024-02-29
- 项目状态:已结题
- 来源:
- 关键词:AddressAdvisory CommitteesAffectAntigenic SpecificityAntigensAreaAutoantibodiesAutoantigensAutoimmuneAutoimmune ResponsesAutoimmunityAwardB-LymphocytesBasic ScienceBindingBiologyBiometryBloodCaliforniaCancer PatientCellsCirculationClinical TrialsClinical Trials DesignClonal ExpansionColitisCollectionComplementDataDermatitisDoctor of PhilosophyEffectivenessEnvironmentFoundationsFundingGoalsHomeHumanImmune checkpoint inhibitorImmune responseImmune systemImmunologic MarkersImmunologic StimulationImmunologic TestsImmunologistImmunotherapyIncidenceInterventionLaboratoriesLibrariesMalignant NeoplasmsMedical OncologistMentorshipMethodsMorbidity - disease rateNormal tissue morphologyPathogenesisPathway interactionsPatientsPeptidesPhage DisplayPhysiciansPopulationProteinsProteomePublishingQuality of lifeResearchResearch PersonnelResolutionRiskSamplingSan FranciscoScienceScientistSignal PathwaySortingSourceSpecificitySpottingsStructureT cell infiltrationT cell receptor repertoire sequencingT cell responseT-Cell Immunologic SpecificityT-LymphocyteT-Lymphocyte SubsetsT-cell diversityTestingTissue BanksTissuesToxic effectTrainingTranslational ResearchTumor ImmunityUniversitiesValidationWorkanti-tumor immune responseautoreactive T cellcancer immunotherapyclinical biomarkersenzyme linked immunospot assayexperiencefunctional statushands on researchhigh riskimmune activationimmune-related adverse eventsimprovednext generation sequencingnovelnovel strategiespatient screeningpredictive markerpreventrecruitresponsescreeningside effectsingle-cell RNA sequencingskillstranscriptometranslational scientisttumor
项目摘要
PROJECT SUMMARY/ABSTRACT
The goal of this resubmission application is to train David Y. Oh, MD PhD, a medical oncologist and
immunologist, providing him with the skills to become an independently funded laboratory investigator studying
immune-related adverse events (IRAEs) after checkpoint inhibitors (CPIs). CPIs are cancer immunotherapies
that activate anti-tumor immune responses leading to improved survival in several cancers, but also trigger
IRAEs which are autoimmune responses against normal tissues that represent an increasing source of morbidity
for cancer patients. The proposed training plan incorporates didactic and practical experience to provide a
foundation in the following areas which complement his existing expertise and are critical to accomplishing his
research goals: (1) fundamental B cell biology including B cell-driven autoimmunity and methods for autoantibody
discovery and validation, (2) next-generation sequencing methods and analysis including single-cell approaches
appropriate for human patient samples, (3) methods in clinical trial design including biostatistics and correlative
science. The research plan addresses key limitations in our understanding of IRAE mechanisms by studying
both cellular (T cell) as well as humoral (B cell) responses to autoantigens during IRAEs. By studying IRAE
tissues, the proposed research will identify and validate the specific immune responses that may be directed
towards tissue-specific autoantigens. Dr. Oh’s hypothesis is that autoimmune responses in IRAE-affected tissues
are newly induced by CPIs and not present before treatment, and the tissue autoantigens responsible for IRAEs
are targeted by a distinct subset of tissue-resident T cells and by specific autoantibodies. The Aims of the
proposed research are: (1) to dissect the antigenic and functional profile of autoreactive T cells that are enriched
in IRAE-affected tissues, and (2) to discover and validate autoantibody responses to tissue-specific autoantigens
that are associated with IRAEs. The training and research plan encompass a structured combination of formal
coursework, tutorials, mentorship, and hands-on research experience within the dynamic environment of the
University of California, San Francisco, a renowned center for basic and translational research. Dr. Oh’s training
will be conducted under the mentorship of Dr. Lawrence Fong, a leading translational researcher in cancer
immunotherapies who co-directs the Parker Institute for Cancer Immunotherapy at UCSF, and a distinguished
advisory committee of physician-scientists with extensive mentorship experience and expertise in each area
corresponding to Dr. Oh’s training and research aims. The intermediate goal of this proposal is to identify IRAE-
specific immune responses that will be the basis for an R01. The long-term goal of this award is to provide the
skills to enable Dr. Oh to become a leader in mechanistic studies of IRAE samples from immunotherapy-treated
patients using novel approaches, yielding clinically useful biomarkers and targets for intervention to be validated
in larger clinical trials.
项目总结/摘要
这个重新提交申请的目的是训练大卫Y。哦,医学博士,肿瘤学家,
免疫学家,为他提供技能,成为一个独立资助的实验室研究员,
检查点抑制剂(CPI)后的免疫相关不良事件(IRAE)。CPI是癌症免疫疗法
激活抗肿瘤免疫反应,从而提高几种癌症的生存率,但也引发
IRAE是针对正常组织的自身免疫反应,代表发病率增加的来源
for cancer癌症patients病人.拟议的培训计划包括教学和实践经验,
在以下领域奠定了基础,这些领域补充了他现有的专业知识,对实现他的目标至关重要。
研究目标:(1)基础B细胞生物学,包括B细胞驱动的自身免疫和自身抗体的方法
发现和验证,(2)下一代测序方法和分析,包括单细胞方法
适用于人类患者样本,(3)临床试验设计方法,包括生物统计学和相关
科学该研究计划通过研究解决了我们对IRAE机制理解的关键限制。
在IRAE期间细胞(T细胞)以及体液(B细胞)对自身抗原的应答。通过研究IRAE
组织,拟议的研究将确定和验证可能被引导的特异性免疫反应。
针对组织特异性自身抗原。Oh博士的假设是,IRAE影响组织中的自身免疫反应
是由CPI新诱导的,在治疗前不存在,而负责IRAE的组织自身抗原
由组织驻留T细胞的不同子集和特异性自身抗体靶向。的目标
建议的研究是:(1)解剖富集的自身反应性T细胞的抗原和功能谱,
在IRAE影响的组织中,和(2)发现和验证对组织特异性自身抗原的自身抗体应答
与IRAE相关的。培训和研究计划包括一个结构化的组合,
课程,教程,导师,和动手研究的动态环境中的经验,
加州大学旧金山分校弗朗西斯科,著名的基础和转化研究中心。吴医生的训练
将在劳伦斯·方博士的指导下进行,劳伦斯·方博士是一位领先的癌症转化研究人员
他是加州大学旧金山分校帕克癌症免疫治疗研究所的共同负责人,
由在各领域具有丰富指导经验和专门知识的医生-科学家组成的咨询委员会
符合吴博士的培训和研究目标。该提案的中期目标是确定伊拉克难民事务高级专员办事处-
特异性免疫反应将成为R 01的基础。该奖项的长期目标是提供
技能,使吴博士成为免疫治疗的IRAE样品的机制研究的领导者
患者使用新的方法,产生临床上有用的生物标志物和干预目标,以进行验证
在更大的临床试验中。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
CD38 as a Novel Immunosuppressive Target in Prostate Cancer.
CD38 作为前列腺癌的新型免疫抑制靶点。
- DOI:10.1016/j.eururo.2021.02.022
- 发表时间:2021
- 期刊:
- 影响因子:23.4
- 作者:Oh,DavidY
- 通讯作者:Oh,DavidY
Balancing the Checkpoint: Managing Colitis Associated with Dual Checkpoint Inhibitors and High-Dose Aspirin.
平衡检查点:治疗与双检查点抑制剂和大剂量阿司匹林相关的结肠炎。
- DOI:10.1007/s10620-019-05534-5
- 发表时间:2019
- 期刊:
- 影响因子:3.1
- 作者:Hammami,MuhammadB;Gill,Ryan;Thiruvengadam,Nikhil;Oh,DavidY;Beck,Kendall;Mahadevan,Uma;Kattah,MichaelG
- 通讯作者:Kattah,MichaelG
Mesothelin-targeting T cell receptor fusion construct cell therapy in refractory solid tumors: phase 1/2 trial interim results.
- DOI:10.1038/s41591-023-02452-y
- 发表时间:2023-08
- 期刊:
- 影响因子:82.9
- 作者:Hassan, Raffit;Butler, Marcus;O'Cearbhaill, Roisin E. E.;Oh, David Y. Y.;Johnson, Melissa;Zikaras, Kevin;Smalley, Munisha;Ross, Michael;Tanyi, Janos L. L.;Ghafoor, Azam;Shah, Nirali N. N.;Saboury, Babak;Cao, Liang;Quintas-Cardama, Alfonso;Hong, David
- 通讯作者:Hong, David
Molecular and Radiological Features of Microsatellite Stable Colorectal Cancer Cases With Dramatic Responses to Immunotherapy.
- DOI:10.21873/anticanres.15080
- 发表时间:2021-06
- 期刊:
- 影响因子:2
- 作者:Keenan BP;VAN Loon K;Khilnani AD;Fidelman N;Behr SC;Atreya CE;Oh DY
- 通讯作者:Oh DY
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{{ truncateString('David Yoonsuk Oh', 18)}}的其他基金
Identification of circulating and tissue-specific autoimmune responses in checkpoint inhibitor-induced immune-related adverse events
检查点抑制剂诱导的免疫相关不良事件中循环和组织特异性自身免疫反应的识别
- 批准号:
10348146 - 财政年份:2019
- 资助金额:
$ 19.91万 - 项目类别:
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$ 19.91万 - 项目类别:
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