The IL-18-IFNγ axis predicts response to immunotherapy
IL-18-IFNγ轴预测对免疫治疗的反应
基本信息
- 批准号:10584972
- 负责人:
- 金额:$ 84.58万
- 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:2023-02-01 至 2028-01-31
- 项目状态:未结题
- 来源:
- 关键词:AdoptedAntigensAntitumor ResponseAutomobile DrivingBiological MarkersBiologyBloodBody Weight decreasedCD14 geneCD19 geneCD22 geneCell physiologyCell-Mediated CytolysisCellsCellular immunotherapyCessation of lifeCharacteristicsChildChildhoodChildhood Hematopoietic NeoplasmChildhood LeukemiaClinicalClinical TrialsCollaborationsCoupledCytokine SignalingDangerousnessDataDevelopmentDiseaseDoseEngineeringEngraftmentEtiologyExcisionFunctional disorderGenetic Predisposition to DiseaseGenetic TranscriptionGrantHIF1A geneHematopoietic NeoplasmsHemophagocytic LymphohistiocytosesHistologyHumanIL18 geneImmuneImmune systemImmunityImmunotherapyIn VitroIndividualInflammatoryInterferon Type IIInterferonsInterleukin-10Interleukin-12InvestmentsKLRB1 geneKineticsLifeMachine LearningMeasuresMediatingMedicalMyelogenousMyeloproliferative diseaseNervous System TraumaNeuroblastomaOutcomePatientsPediatric NeoplasmPeripheral Blood Mononuclear CellPhenotypePlayPopulationProductionRecording of previous eventsRecurrenceRelapseResearchResourcesRiskRoleSafetySamplingSeriesSerumSignal TransductionSolid NeoplasmT-LymphocyteThe Jackson LaboratoryTherapeuticTimeToxic effectTreatment-related toxicityTumor BiologyWorkbiomarker validationblood treatmentblood-brain barrier crossingchimeric antigen receptorchimeric antigen receptor T cellsclinical biomarkersclinical predictorscohortcytokinecytokine release syndromeexperienceexperimental studyfamilial hemophagocytic lymphohistiocytosishumanized mouseimprovedimproved outcomeinsightinterleukin-18 receptorleukemiamachine learning algorithmmonocytemouse modelneurotoxicitynovelpatient populationpatient responsepatient subsetspediatric patientspredicting responsepredictive markerprogramsresponseside effectsuccesssurvival predictiontraffickingtrendtrial designtumor
项目摘要
ABSTRACT
CAR T-cells have revolutionized the treatment of pediatric leukemia. However, ~50% of responsive patients
eventually relapse and in ~50-70% of patients, this therapy induces devastating side effects (i.e. neurotoxicity
(NTX) and cytokine release syndrome (CRS)), potentially leading to long term neurological damage and death.
There are no clinical biomarkers to predict survival or toxicity despite a crucial need. SCRI has made a substantial
investment in CAR T therapy and is a world leader in pediatric CAR T cell clinical trials. This proposed project
will build upon this program by helping to predict and mitigate the devastating, life-threatening side effects caused
by this revolutionary therapy and may aide in the prediction of non-response cases. Data from our pilot
experiments utilizing samples from patients on CAR-T trials at SCRI suggests that pre-monocyte activation
status and cytokine profiles from the monocyte fraction of a patient can predict CAR T toxicity across both blood
and solid tumors, in particular we see trends in the IL-18- IFN𝛾𝛾 axis. We plan to act on this encouraging pilot
data in this proposal to develop a series of validated monocytic biomarkers (cytokine, flow and transcriptional)
and machine learning algorithms which can be utilized prior to patients going on trial in order to save time and
resources for patients who are set to fail treatment and allow medical teams to be more prepared to mitigate
toxicity in those who are more prone to it. The proposal further expands to the development a humanized mouse
model that can adopt the healthy donor and pediatric patient immune systems recapturing natural variability in
human immunity to investigate causality of the IL-18- IFN𝛾𝛾 axis in driving both therapeutic toxicity. The project
combines existing but unused large bank of SCRI CAR T patient samples/data with monocytic omics profiling to
develop predictive biomarkers for therapeutic toxicity (AIM 1). We aim to further extend the impact of this work
to mechanistically understand why certain patients’ cells are working against them through the use of novel
humanized mouse models (AIM2). This is built upon to develop therapeutics or strategies to improve safety and
efficacy of CAR-T treatments. Importantly, our team of experts in clinical CAR T (Dr. Rebecca Gardner, Dr. Navin
Pinto), machine learning (Dr. Bobbie-Jo Webb-Robertson), humanized mice (Dr. James Keck), and myeloid
tumor biology (Dr. Heather Gustafson) pose this grant for optimal success.
摘要
CAR T细胞彻底改变了儿童白血病的治疗方法。然而,约50%的有反应的患者
最终复发,在约50%-70%的患者中,这种疗法会导致毁灭性的副作用(即神经毒性
(NTX)和细胞因子释放综合征(CRS)),可能导致长期的神经损伤和死亡。
尽管有迫切的需求,但没有临床生物标记物来预测生存或毒性。SCRI已经取得了实质性的进展
投资于CAR T疗法,是儿科CAR T细胞临床试验的世界领先者。这项拟议的项目
将通过帮助预测和减轻破坏性的、危及生命的副作用来加强这一计划
通过这种革命性的疗法,可能有助于预测无应答病例。来自我们飞行员的数据
使用SCRI CAR-T试验患者样本的实验表明,前单核细胞激活
患者单核细胞组分的状态和细胞因子谱可以预测两种血液中的CAR T毒性
和实体肿瘤,特别是我们看到了IL-18-干扰素𝛾𝛾轴的趋势。我们计划对这一令人鼓舞的试点项目采取行动
本提案中的数据以开发一系列有效的单核细胞生物标记物(细胞因子、流动和转录)
和机器学习算法,可以在患者进行试验之前使用,以节省时间和
为治疗失败的患者提供资源,并允许医疗团队做好更多准备,以缓解
对那些更容易患上这种病的人有毒性。该建议进一步扩展到开发人性化的老鼠
可以采用健康供体和儿科患者免疫系统恢复自然变异性的模型
人类免疫力调查IL-18-干扰素𝛾𝛾轴在驱动这两种治疗毒性方面的因果关系。该项目
将现有但未使用的SCRI CAR患者样本/数据大库与单核细胞组学分析相结合,以
开发治疗毒性的预测生物标记物(AIM 1)。我们打算进一步扩大这项工作的影响
为了机械地理解为什么某些患者的细胞通过使用新奇的
人源化小鼠模型(AIM2)。这是建立在开发治疗或战略,以提高安全性和
CAR-T治疗的疗效。重要的是,我们的临床T车专家团队(丽贝卡·加德纳博士、纳文博士
机器学习(Bobbie-Jo Webb-Robertson博士)、人性化小鼠(James Keck博士)和髓系小鼠
肿瘤生物学(希瑟·古斯塔夫森博士)为最佳成功提供了这笔赠款。
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 }}
HEATHER LEIGH HERD GUSTAFSON其他文献
HEATHER LEIGH HERD GUSTAFSON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 }}
相似国自然基金
Neo-antigens暴露对肾移植术后体液性排斥反应的影响及其机制研究
- 批准号:2022J011295
- 批准年份:2022
- 资助金额:10.0 万元
- 项目类别:省市级项目
结核分枝杆菌持续感染期抗原(latency antigens)的重组BCG疫苗研究
- 批准号:30801055
- 批准年份:2008
- 资助金额:19.0 万元
- 项目类别:青年科学基金项目
相似海外基金
Bovine herpesvirus 4 as a vaccine platform for African swine fever virus antigens in pigs
牛疱疹病毒 4 作为猪非洲猪瘟病毒抗原的疫苗平台
- 批准号:
BB/Y006224/1 - 财政年份:2024
- 资助金额:
$ 84.58万 - 项目类别:
Research Grant
Uncovering tumor specific antigens and vulnerabilities in ETP-acute lymphoblastic leukemia
揭示 ETP-急性淋巴细胞白血病的肿瘤特异性抗原和脆弱性
- 批准号:
480030 - 财政年份:2023
- 资助金额:
$ 84.58万 - 项目类别:
Operating Grants
A novel vaccine approach combining mosquito salivary antigens and viral antigens to protect against Zika, chikungunya and other arboviral infections.
一种结合蚊子唾液抗原和病毒抗原的新型疫苗方法,可预防寨卡病毒、基孔肯雅热和其他虫媒病毒感染。
- 批准号:
10083718 - 财政年份:2023
- 资助金额:
$ 84.58万 - 项目类别:
Small Business Research Initiative
Regulation of B cell responses to vaccines by long-term retention of antigens in germinal centres
通过在生发中心长期保留抗原来调节 B 细胞对疫苗的反应
- 批准号:
MR/X009254/1 - 财政年份:2023
- 资助金额:
$ 84.58万 - 项目类别:
Research Grant
Adaptive Discrimination of Risk of Antigens in Immune Memory Dynamics
免疫记忆动态中抗原风险的适应性辨别
- 批准号:
22KJ1758 - 财政年份:2023
- 资助金额:
$ 84.58万 - 项目类别:
Grant-in-Aid for JSPS Fellows
22-ICRAD Call 2 - Improving the diagnosis of tuberculosis in domestic ruminants through the use of new antigens and test platforms
22-ICRAD 呼吁 2 - 通过使用新抗原和测试平台改善家养反刍动物结核病的诊断
- 批准号:
BB/Y000927/1 - 财政年份:2023
- 资助金额:
$ 84.58万 - 项目类别:
Research Grant
Protective immunity elicited by distinct polysaccharide antigens of classical and hypervirulent Klebsiella
经典和高毒力克雷伯氏菌的不同多糖抗原引发的保护性免疫
- 批准号:
10795212 - 财政年份:2023
- 资助金额:
$ 84.58万 - 项目类别:
Integrative proteome analysis to harness humoral immune response against tumor antigens
综合蛋白质组分析利用针对肿瘤抗原的体液免疫反应
- 批准号:
23K18249 - 财政年份:2023
- 资助金额:
$ 84.58万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)
Functionally distinct human CD4 T cell responses to novel evolutionarily selected M. tuberculosis antigens
功能独特的人类 CD4 T 细胞对新型进化选择的结核分枝杆菌抗原的反应
- 批准号:
10735075 - 财政年份:2023
- 资助金额:
$ 84.58万 - 项目类别:
Targeting T3SA proteins as protective antigens against Yersinia
将 T3SA 蛋白作为针对耶尔森氏菌的保护性抗原
- 批准号:
10645989 - 财政年份:2023
- 资助金额:
$ 84.58万 - 项目类别: