Host and microbe-dependent mechanisms of enhanced autoimmune susceptibility driven by checkpoint inhibitors
检查点抑制剂驱动的增强自身免疫易感性的宿主和微生物依赖性机制
基本信息
- 批准号:10750805
- 负责人:
- 金额:$ 5.27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-12-01 至 2026-11-30
- 项目状态:未结题
- 来源:
- 关键词:AbdomenAgingAntibodiesAntitumor ResponseApoptosisAutoimmuneAutoimmune DiseasesAutoimmunityAutomobile DrivingB-Cell ActivationB-LymphocytesBacteriaBiological ModelsCD19 geneCD3 AntigensCT26CellsChronicClinicalClinical TrialsColon AdenocarcinomaCombined Modality TherapyCommunitiesControl GroupsCytotoxic T-LymphocytesDataDepositionDevelopmentDiseaseEvaluationExclusionFatty acid glycerol estersFoundationsGenerationsGeneticGenetic Predisposition to DiseaseGenetic ScreeningGerm-FreeGoalsGreater sac of peritoneumHistologicHomeostasisHumanImmuneImmune checkpoint inhibitorImmune systemImmunoglobulin GImmunologicsImpairmentIncidenceIndividualInfiltrationIntestinesLeadLifeLinkLymphocyte antigenMalignant NeoplasmsMediatingMedicalMedical GeneticsMesenteryMicrobeModelingMusPancreasPatient CarePatientsPeritonealPre-Clinical ModelPredispositionPsoriasisRiskRoleSeveritiesSignal TransductionSingle Nucleotide PolymorphismSjogren&aposs SyndromeSystemic Lupus ErythematosusT-LymphocyteTNFRSF5 geneTestingTherapeutic UsesTissuesToxic effectWild Type Mouseagedautoimmune pathogenesisautoimmune toxicitycancer immunotherapycheckpoint inhibitioncheckpoint therapyclinical practiceexperimental studygerm free conditiongut microbesgut microbiotaimmune activationimmune cell infiltrateimmune-related adverse eventsimmunopathologyimprovedmembermicrobiomemicrobiome componentsmicrobiotamouse modelpatient populationpatient prognosispermissivenessresponsesuccesstumor
项目摘要
Project Summary
Immune checkpoint inhibitor therapy has drastically improved the prognosis of patients with several advanced-
stage cancers that were initially considered terminal. However, the increased use of checkpoint inhibitors has
resulted in the common emergence of immune-related adverse events (irAEs). Even though they are typically
excluded from clinical trials, in clinical practice, patients with autoimmune predisposition are offered checkpoint
inhibitors and have the greatest risk for developing irAEs. The mechanism driving this immune toxicity is poorly
understood, and even less is known about how checkpoint inhibitors interact with immune systems prone to
autoimmunity. Since malignancies are life-threatening diseases, there is an unmet medical need to decouple
autoimmune toxicities from checkpoint inhibitor antitumor response. I hypothesize that individuals can be
predisposed to irAEs based on a combination of their genetics and specific gut microbes. In this proposal,
I established a mouse model that reflects the emerging paradigm of autoimmune predisposition and the role of
the microbiome in the development of irAEs. I will use the Act1-/- mice, which develop spontaneous systemic
lupus erythematous and Sjogren-like autoimmune diseases in specific pathogen free conditions with elevated
baseline Th17 and B cell activity after aging. Combined treatment with anti-PD-1 and anti-CTLA-4 antibodies
significantly expedited and exacerbated the onset and severity of autoimmune attack. In Aim 1, I will test the
hypothesis that B cells drive irAEs in Act1-/- mice while still maintaining checkpoint inhibitor efficacy. I also
determined that GF Act1-/- mice are not susceptible to irAE development, which aligns with the growing evidence
of the microbiome’s critical role in defining responsiveness to checkpoint inhibitors as well as the mitigation of
irAEs. In Aim 2, I will test the hypothesis that while ICI efficacy has been linked to certain members of the
intestinal microbiota community, a distinct subset of microbes can allow for the induction of irAEs in a genetically
susceptible host. The mechanisms studied in this proposal may prove useful for the foundation of a clinical
genetic screening approach for the patient population prior to ICI delivery.
项目摘要
免疫检查点抑制剂治疗已经大大改善了几种晚期-
最初被认为是晚期的癌症。然而,检查点抑制剂的使用增加,
导致免疫相关不良事件(irAE)的常见出现。尽管他们通常
从临床试验中排除,在临床实践中,为具有自身免疫易感性的患者提供检查点
抑制剂,发生irAE的风险最大。驱动这种免疫毒性的机制很差,
人们对检查点抑制剂如何与免疫系统相互作用的了解更少,
自身免疫由于恶性肿瘤是危及生命的疾病,因此,
来自检查点抑制剂抗肿瘤反应的自身免疫毒性。我假设个人可以
根据其遗传学和特定肠道微生物的组合,易患irAE。在这项提案中,
我建立了一个小鼠模型,该模型反映了自身免疫易感性的新范式以及
微生物组在irAE发展中的作用。我将使用Act 1-/-小鼠,
狼疮性和干燥样自身免疫性疾病在无特定病原体的条件下,
老化后基线Th 17和B细胞活性。抗PD-1和抗CTLA-4抗体的联合治疗
显著加速和加剧自身免疫性攻击的发作和严重程度。在目标1中,我将测试
假设B细胞在Act 1-/-小鼠中驱动irAE,同时仍维持检查点抑制剂功效。我也
确定GF Act 1-/-小鼠对irAE发展不敏感,这与越来越多的证据一致
微生物组在定义对检查点抑制剂的反应性以及缓解
irAE。在目标2中,我将检验一个假设,即虽然ICI的疗效与某些成员有关,
肠道微生物群,一个独特的微生物亚群可以允许在遗传学上诱导irAE。
易感宿主在这项建议中研究的机制可能被证明是有用的基础上,临床
在ICI递送之前对患者群体的遗传筛查方法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Vanessa Salazar其他文献
Vanessa Salazar的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
相似海外基金
Interplay between Aging and Tubulin Posttranslational Modifications
衰老与微管蛋白翻译后修饰之间的相互作用
- 批准号:
24K18114 - 财政年份:2024
- 资助金额:
$ 5.27万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
The Canadian Brain Health and Cognitive Impairment in Aging Knowledge Mobilization Hub: Sharing Stories of Research
加拿大大脑健康和老龄化认知障碍知识动员中心:分享研究故事
- 批准号:
498288 - 财政年份:2024
- 资助金额:
$ 5.27万 - 项目类别:
Operating Grants
EMNANDI: Advanced Characterisation and Aging of Compostable Bioplastics for Automotive Applications
EMNANDI:汽车应用可堆肥生物塑料的高级表征和老化
- 批准号:
10089306 - 财政年份:2024
- 资助金额:
$ 5.27万 - 项目类别:
Collaborative R&D
関節リウマチ患者のSuccessful Agingに向けたフレイル予防対策の構築
类风湿性关节炎患者成功老龄化的衰弱预防措施的建立
- 批准号:
23K20339 - 财政年份:2024
- 资助金额:
$ 5.27万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Baycrest Academy for Research and Education Summer Program in Aging (SPA): Strengthening research competencies, cultivating empathy, building interprofessional networks and skills, and fostering innovation among the next generation of healthcare workers t
Baycrest Academy for Research and Education Summer Program in Aging (SPA):加强研究能力,培养同理心,建立跨专业网络和技能,并促进下一代医疗保健工作者的创新
- 批准号:
498310 - 财政年份:2024
- 资助金额:
$ 5.27万 - 项目类别:
Operating Grants
Life course pathways in healthy aging and wellbeing
健康老龄化和福祉的生命历程路径
- 批准号:
2740736 - 财政年份:2024
- 资助金额:
$ 5.27万 - 项目类别:
Studentship
I-Corps: Aging in Place with Artificial Intelligence-Powered Augmented Reality
I-Corps:利用人工智能驱动的增强现实实现原地老龄化
- 批准号:
2406592 - 财政年份:2024
- 资助金额:
$ 5.27万 - 项目类别:
Standard Grant
NSF PRFB FY 2023: Connecting physiological and cellular aging to individual quality in a long-lived free-living mammal.
NSF PRFB 2023 财年:将生理和细胞衰老与长寿自由生活哺乳动物的个体质量联系起来。
- 批准号:
2305890 - 财政年份:2024
- 资助金额:
$ 5.27万 - 项目类别:
Fellowship Award
虚弱高齢者のSuccessful Agingを支える地域課題分析指標と手法の確立
建立区域问题分析指标和方法,支持体弱老年人成功老龄化
- 批准号:
23K20355 - 财政年份:2024
- 资助金额:
$ 5.27万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
「ケア期間」に着目したbiological aging指標の開発
开发聚焦“护理期”的生物衰老指数
- 批准号:
23K24782 - 财政年份:2024
- 资助金额:
$ 5.27万 - 项目类别:
Grant-in-Aid for Scientific Research (B)