Brain-Imaging Markers of Neurotoxicity and Long-Term Outcomes after CAR-T Cell Therapy

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。

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.