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

项目摘要 CD19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）表征大脑的多模态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。

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.