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

• 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
• 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

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导向的嵌合抗原受体（CAR）-T细胞疗法用于复发或难治性B细胞急性 淋巴细胞白血病（所有）可导致70-90％其他无法治愈的患者完全缓解。大车 细胞与靶抗原的接合可诱导活性CAR-T细胞的扩展，从而产生细胞因子 和其他促炎性介体。不幸的是，大约50％的患者这种炎症 反应还会产生免疫效应子细胞相关的神经毒性综合征（ICAN），这是一个严重的 以ir妄，脑病，不稳定和严重情况为特征的神经毒性，弥漫性大脑 可能致命的水肿。此外，ICAN增加了长期认知障碍的风险；可能的 尚未系统地研究的后果。因此，ICAN仍然是 更广泛地采用CAR-T细胞疗法，迫切需要减轻或防止Icans，以了解其 病理生理学，并预测其不良的长期结局。我们有引人入胜的初步数据 证明几种前输注神经影像学标记物以高精度预测ICAN。建筑 根据这些发现，我们将在本提案中开发一种预测算法，该算法将促进更紧密的监视 高危患者，预防治疗的支持以及CAR-T细胞的风险适应性剂量。我们的 初步数据还表明，神经成像生物标志物是临床和 亚临床偶像。这些标记可能指导靶向抗周期和小分子的未来发展 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 我们假设ICAN引起的大脑注意网络异常引起的假设会导致长期导致 神经认知障碍。在低年级神经毒性中还可以看到不良结果，这表明更大 对CAR-T细胞患者的认知和行为干预措施的需求比以前预期 仅在具有佛罗里德神经毒性的患者中。扩大我们的试点研究，我们建议进行前瞻性， 纵向队列研究对80例接受CAR-T细胞治疗的连续患者进行B-all。我们将收集 最先进的（a）ICAN和CRS的临床评估，（b）多模式MRI以表征大脑 结构，功能和代谢，（c）使用Cytof（质量 通过飞行时间的细胞仪）并介绍了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）预先收集 输注基线；然后在第（2）天的第10天，当Icans风险最大时，（3）第28天， ICANS解决方案，（4）第12个月，用于长期结局。这些数据将识别，无与伦比 推理能力，基于大脑的预测因子和ICAN的炎症介质有助于发展大脑MRI CAR-T细胞疗法的指南，并帮助建议特定的认知训练和神经保护 持续性大脑缺陷患者的策略。