Brain-Imaging Markers of Neurotoxicity and Long-Term Outcomes after CAR-T Cell Therapy
CAR-T 细胞治疗后神经毒性和长期结果的脑成像标志物
基本信息
- 批准号:10657106
- 负责人:
- 金额:$ 72.58万
- 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:2023-04-01 至 2028-03-31
- 项目状态:未结题
- 来源:
- 关键词:AbateAcute Lymphocytic LeukemiaAdoptionAdverse effectsAntigen TargetingAttentionB-Cell Acute Lymphoblastic LeukemiaBehaviorBehavior TherapyBehavioralBehavioral SymptomsBiological MarkersBiological Response ModifiersBlood - brain barrier anatomyBlood flowBlood specimenBrainBrain InjuriesBrain imagingCAR T cell therapyCD19 AntigensCD19 geneCerebral EdemaCharacteristicsChildClinicalClinical TrialsClinical assessmentsCognitionCognitiveCytometryDataDeliriumDevelopmentDiffuseDoseDysphasiaEarly identificationEffector CellEncephalopathiesEndothelial CellsFunctional disorderFutureGuidelinesImmuneImmune responseImmune systemImmunologic MarkersImmunologic MonitoringImmunophenotypingImpaired cognitionImpairmentIn complete remissionInflammationInflammation MediatorsInflammatoryInflammatory ResponseInfusion proceduresInterventionLeukemic CellLifeLong-Term EffectsLongitudinal cohort studyMachine LearningMagnetic Resonance ImagingMeasuresMediatingMetabolicMetabolismMonitorNeurobehavioral ManifestationsNeurocognitive DeficitNeurologicNeurologic SymptomsNeuronal InjuryNeuronsNeuropsychological TestsNeurotoxicity SyndromesOutcomePathway interactionsPatientsPilot ProjectsPreventive treatmentPrior ChemotherapyProductionPublishingRecommendationRefractoryRelapseResolutionRiskSerumSeveritiesShort-Term MemoryStructureSurrogate MarkersSymptomsT-Cell ActivationThinnessTimeadverse outcomebehavioral outcomebrain abnormalitiesbrain basedbrain magnetic resonance imagingchimeric antigen receptor T cellscognitive changecognitive trainingcytokinedensityeffective therapyhigh riskimaging biomarkerinflammatory markerleukemialong-term sequelaemachine learning algorithmmagnetic resonance imaging biomarkermultimodalityneurocognitive testneuroimagingneuroimaging markerneuroprotectionneurotoxicitynovel therapeuticsperipheral bloodprediction algorithmpredictive markerpreventpreventive interventionprocessing speedprospectiveside effectsmall molecule inhibitorwhite matter
项目摘要
Project Summary
CD19-directed chimeric antigen receptor (CAR)-T cell therapy for relapsed or refractory B-cell acute
lymphoblastic leukemia (ALL) induces complete remission in 70-90% of otherwise incurable patients. CAR-T
cell engagement with their target antigens induces expansion of activated CAR-T cells, producing cytokines
and other pro-inflammatory mediators. Unfortunately, in approximately 50% of patients this inflammatory
response also produces an Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS), a serious
neurotoxicity characterized by delirium, encephalopathy, dysphasia, and in severe cases, diffuse cerebral
edema that can be fatal. Additionally, ICANS increases the risk for long-term cognitive impairments; possible
consequences that have not been systematically studied. ICANS therefore remains a major challenge for the
wider adoption of CAR-T cell therapy, creating an urgent need to mitigate or prevent ICANS, to understand its
pathophysiology, and to predict its adverse long-term outcomes. We have compelling preliminary data
demonstrating that several pre-infusion neuroimaging markers predict ICANS with high accuracy. Building
upon these findings, we will develop a predictive algorithm in this proposal that will facilitate closer monitoring
of high-risk patients, support with preventive treatments, and risk-adapted dosing of CAR-T cells. Our
preliminary data also suggest that neuroimaging biomarkers serve as objective surrogates for clinical and
subclinical ICANS. These markers may guide future development of targeted anti-cytokine and small molecule
inhibitor-based interventions to inhibit or block neurotoxicity-specific pathways. Finally, preliminary data support
our hypothesis that ICANS-induced abnormalities in attentional networks of the brain cause long-term
neurocognitive impairments. Adverse outcomes are also seen in low grade neurotoxicity, suggesting a greater
need than previously anticipated for cognitive and behavioral interventions in CAR-T cell patients, rather than
only in patients with florid neurotoxicity. Expanding on our pilot study, we propose to conduct a prospective,
longitudinal cohort study of 80 consecutive patients who receive CAR-T cell therapy for B-ALL. We will collect
state-of-the-art (a) clinical assessments for ICANS and CRS, (b) multi-modal MRI to characterize brain
structure, function, and metabolism, (c) peripheral blood samples for immunophenotyping using CyTOF (mass
Cytometry by Time-Of-Flight) and to profile cytokines and biomarkers of blood brain barrier integrity, and (d)
neurocognitive testing to characterize cognitive changes. Longitudinal data will be collected at (1) a pre-
infusion baseline; and then post-infusion on (2) Day 10, when the ICANS risk is greatest, (3) Day 28, upon
ICANS resolution, and (4) month 12, for long-term outcomes. These data will identify, with unparalleled
inferential capacity, brain-based predictors and inflammatory mediators of ICANS, help develop brain MRI
guidelines for CAR-T cell therapy, and help recommend specific cognitive training and neuroprotective
strategies in patients with persistent brain deficits.
项目摘要
CD 19导向的嵌合抗原受体(CAR)-T细胞治疗复发性或难治性B细胞急性
淋巴母细胞白血病(ALL)在70-90%的其他不可治愈的患者中诱导完全缓解。CAR-T
细胞与其靶抗原的接合诱导活化的CAR-T细胞扩增,产生细胞因子
和其他促炎介质。不幸的是,在大约50%的患者中,
免疫反应还产生免疫效应细胞相关神经毒性综合征(ICANS),
以谵妄、脑病、言语障碍为特征的神经毒性,在严重病例中,
可能致命的水肿此外,ICANS增加了长期认知障碍的风险;可能
这些后果尚未得到系统研究。因此,ICANS仍然是一个重大挑战,
更广泛地采用CAR-T细胞疗法,迫切需要减轻或预防ICANS,了解其
病理生理学,并预测其不良的长期结果。我们有令人信服的初步数据
证明了几种输注前神经影像学标记物以高准确度预测ICANS。建筑
根据这些发现,我们将在本提案中开发一种预测算法,以便于更密切地监测
高风险患者,预防性治疗的支持,以及CAR-T细胞的风险适应性剂量。我们
初步数据还表明,神经影像学生物标志物可作为临床和
亚临床ICANS。这些标记物可能指导未来靶向抗细胞因子和小分子药物的开发。
基于通道的干预措施,以抑制或阻断神经毒性特异性通路。最后,初步数据支持
我们的假设是,ICANS诱导的大脑注意力网络异常会导致长期的
神经认知障碍不良后果也见于低级别神经毒性,表明更大的
对CAR-T细胞患者的认知和行为干预的需求比以前预期的要大,
仅在有明显神经毒性的患者中。在试点研究的基础上,我们建议进行一项前瞻性的,
80例接受CAR-T细胞治疗B-ALL的连续患者的纵向队列研究。我们将收集
最新技术水平(a)ICANS和CRS的临床评估,(B)表征大脑的多模式MRI
结构、功能和代谢,(c)使用CyTOF(质谱)进行免疫表型分析的外周血样品
通过飞行时间的细胞计数法)并描绘细胞因子和血脑屏障完整性的生物标志物,和(d)
神经认知测试来表征认知变化。纵向数据将在(1)预-
输注基线;然后在输注后(2)第10天,ICANS风险最大时,(3)第28天,
ICANS解决方案,以及(4)第12个月的长期结局。这些数据将以无与伦比的
ICANS的推理能力、基于大脑的预测因子和炎症介质有助于开发大脑MRI
CAR-T细胞治疗指南,并帮助推荐特定的认知训练和神经保护
持续性脑损伤患者的治疗策略。
项目成果
期刊论文数量(0)
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Ravi Bansal其他文献
Ravi Bansal的其他文献
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