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：
Ravi Bansal
金额：
$ 72.58万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
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：
https://reporter.nih.gov/project-details/10657106
关键词：
Abate Acute Lymphocytic Leukemia Adoption Adverse effects Antigen Targeting Attention B-Cell Acute Lymphoblastic Leukemia Behavior Behavior Therapy Behavioral Behavioral Symptoms Biological Markers Biological Response Modifiers Blood - brain barrier anatomy Blood flow Blood specimen Brain Brain Injuries Brain imaging CAR T cell therapy CD19 Antigens CD19 gene Cerebral Edema Characteristics Child Clinical Clinical Trials Clinical assessments Cognition Cognitive Cytometry Data Delirium Development Diffuse Dose Dysphasia Early identification Effector Cell Encephalopathies Endothelial Cells Functional disorder Future Guidelines Immune Immune response Immune system Immunologic Markers Immunologic Monitoring Immunophenotyping Impaired cognition Impairment In complete remission Inflammation Inflammation Mediators Inflammatory Inflammatory Response Infusion procedures Intervention Leukemic Cell Life Long-Term Effects Longitudinal cohort study Machine Learning Magnetic Resonance Imaging Measures Mediating Metabolic Metabolism Monitor Neurobehavioral Manifestations Neurocognitive Deficit Neurologic Neurologic Symptoms Neuronal Injury Neurons Neuropsychological Tests Neurotoxicity Syndromes Outcome Pathway interactions Patients Pilot Projects Preventive treatment Prior Chemotherapy Production Publishing Recommendation Refractory Relapse Resolution Risk Serum Severities Short-Term Memory Structure Surrogate Markers Symptoms T-Cell Activation Thinness Time adverse outcome behavioral outcome brain abnormalities brain based brain magnetic resonance imaging chimeric antigen receptor T cells cognitive change cognitive training cytokine density effective therapy high risk imaging biomarker inflammatory marker leukemia long-term sequelae machine learning algorithm magnetic resonance imaging biomarker multimodality neurocognitive test neuroimaging neuroimaging marker neuroprotection neurotoxicity novel therapeutics peripheral blood prediction algorithm predictive marker prevent preventive intervention processing speed prospective side effect small molecule inhibitor white 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.

项目概要 CD19 定向嵌合抗原受体 (CAR)-T 细胞疗法治疗复发或难治性 B 细胞急性病淋巴细胞白血病 (ALL) 可使 70-90% 无法治愈的患者完全缓解。大车细胞与其靶抗原的结合诱导激活的 CAR-T 细胞的扩增，产生细胞因子和其他促炎介质。不幸的是，大约 50% 的患者患有这种炎症反应还会产生免疫效应细胞相关神经毒性综合征 (ICANS)，这是一种严重的疾病神经毒性，特征为谵妄、脑病、语言障碍，严重时会出现弥漫性脑损伤水肿可能是致命的。此外，ICANS 还会增加长期认知障碍的风险；可能的尚未系统研究的后果。因此，ICANS 仍然是一个重大挑战 CAR-T 细胞疗法的更广泛采用，迫切需要减轻或预防 ICANS，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多种输注前神经影像标记物可以高精度预测 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，以促进更密切的监测高危患者的治疗、预防性治疗的支持以及 CAR-T 细胞的风险适应剂量。我们的初步数据还表明，神经影像生物标志物可以作为临床和临床诊断的客观替代物。亚临床 ICANS。这些标记物可能指导靶向抗细胞因子和小分子的未来开发基于抑制剂的干预措施，以抑制或阻断神经毒性特异性途径。最后，初步数据支持我们的假设是 ICANS 引起的大脑注意力网络异常会导致长期神经认知障碍。不良后果也出现在低度神经毒性中，这表明更大的神经毒性对 CAR-T 细胞患者的认知和行为干预的需求超出了之前的预期，而不是仅适用于严重神经毒性的患者。扩大我们的试点研究，我们建议进行一项前瞻性的、对 80 名连续接受 CAR-T 细胞治疗 B-ALL 的患者进行的纵向队列研究。我们将收集最先进的 (a) ICANS 和 CRS 临床评估，(b) 表征大脑特征的多模态 MRI 结构、功能和代谢，(c) 使用 CyTOF 进行免疫表型分析的外周血样本（质量通过飞行时间进行细胞计数）并分析血脑屏障完整性的细胞因子和生物标志物，以及（d）神经认知测试来表征认知变化。纵向数据将在 (1) 预收集输注基线；然后在输注后 (2) 第 10 天，此时 ICANS 风险最大，(3) 第 28 天，之后 ICANS 决议，以及 (4) 第 12 个月，以获得长期成果。这些数据将具有无与伦比的识别性 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措施持续性脑缺陷患者的治疗策略。