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

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 CD19导向嵌合抗原受体(CAR)-T细胞治疗复发或难治性B细胞急性白血病 淋巴母细胞性白血病(ALL)可导致70%-90%的其他无法治愈的患者完全缓解。CAR-T 细胞与其靶抗原结合诱导激活的CAR-T细胞扩张,产生细胞因子 和其他促炎调停者。不幸的是,在大约50%的患者中,这种炎症性 反应还会产生免疫效应细胞相关神经毒性综合征(ICANS),这是一种严重的 神经毒性表现为神志不清、脑病、言语障碍,严重者表现为弥漫性脑损伤。 可能致命的浮肿。此外,ICAN增加了长期认知障碍的风险;有可能 尚未系统研究的后果。因此,ICAN仍然是一项重大挑战 更广泛地采用CAR-T细胞疗法,创造了缓解或预防ICAN的迫切需要,以了解其 病理生理学,并预测其不利的长期结果。我们有令人信服的初步数据 证明了几种输液前神经成像标志物预测ICAN的准确性很高。建房 根据这些发现,我们将在这项提案中开发一种预测性算法,以促进更密切的监控 对于高危患者,支持预防性治疗,并对CAR-T细胞进行风险适应剂量的治疗。我们的 初步数据还表明,神经影像生物标志物可作为临床和临床的客观替代指标。 亚临床的圣像。这些标记物可能会指导未来靶向抗细胞因子和小分子的发展 以抑制剂为基础的干预措施,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引起的大脑注意网络异常会导致长期的 神经认知障碍。不良后果也出现在低级别的神经毒性上,这表明 对CAR-T细胞患者的认知和行为干预的需求高于之前的预期,而不是 仅限于有花样神经毒性的患者。在我们的初步研究的基础上,我们建议进行一项前瞻性的、 连续80例接受CAR-T细胞治疗的B-ALL患者的纵向队列研究。我们会收集 最先进的(A)ICAN和CRS的临床评估,(B)多模式磁共振成像以确定大脑的特征 结构、功能和代谢,(C)外周血样本,用于细胞免疫表型(质量法) 通过飞行时间进行细胞术),并描述血脑屏障完整性的细胞因子和生物标志物,以及(D) 神经认知测试,以表征认知变化。纵向数据将在(1)前收集 输液基线;然后在输液后(2)第10天,ICAN风险最大,(3)第28天, ICANS解决,和(4)12个月,用于长期结果。这些数据将与无与伦比的 ICAN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,并帮助建议具体的认知训练和神经保护 持续性脑缺陷患者的治疗策略。

项目成果

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Ravi Bansal其他文献

Ravi Bansal的其他文献

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{{ truncateString('Ravi Bansal', 18)}}的其他基金

Core 3: Neuro-Imaging Core
核心 3:神经影像核心
  • 批准号:
    8478203
  • 财政年份:
    2013
  • 资助金额:
    $ 72.58万
  • 项目类别:
Core 3: Neuro-Imaging Core
核心 3:神经影像核心
  • 批准号:
    8059832
  • 财政年份:
    2010
  • 资助金额:
    $ 72.58万
  • 项目类别:
MORPHOMETRIC ANALYSIS
形态分析
  • 批准号:
    7955664
  • 财政年份:
    2009
  • 资助金额:
    $ 72.58万
  • 项目类别:
MORPHOMETRIC ANALYSIS
形态分析
  • 批准号:
    7724345
  • 财政年份:
    2008
  • 资助金额:
    $ 72.58万
  • 项目类别:
MORPHOMETRIC ANALYSIS
形态分析
  • 批准号:
    7627702
  • 财政年份:
    2007
  • 资助金额:
    $ 72.58万
  • 项目类别:
'MORPHOMETRIC ANALYSIS
形态分析
  • 批准号:
    7369440
  • 财政年份:
    2006
  • 资助金额:
    $ 72.58万
  • 项目类别:
Core 3: Neuro-Imaging Core
核心 3:神经影像核心
  • 批准号:
    8378310
  • 财政年份:
  • 资助金额:
    $ 72.58万
  • 项目类别:
Core 3: Neuro-Imaging Core
核心 3:神经影像核心
  • 批准号:
    8269757
  • 财政年份:
  • 资助金额:
    $ 72.58万
  • 项目类别:

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