Accelerated aging after chimeric antigen receptor T-cell therapy (CART): Leveraging a novel population of cancer survivors to elucidate mechanisms of dementia

嵌合抗原受体 T 细胞疗法 (CART) 后加速衰老：利用新型癌症幸存者群体来阐明痴呆机制

• 批准号: 10719874
• 负责人: HEATHER S.L. JIM
• 金额: $ 47.06万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10719874
• 关键词: Acceleration; Affect; Aftercare; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid beta-Protein; Animal Model; Autologous; Autopsy; Behavioral; Biological; Biological Markers; Blood Banks; Blood specimen; Brain; CAR T cell therapy; Cancer Patient; Cancer Survivor; Cell Aging; Cellular Phone; Chronology; Clinical; Cognition; Cognitive; Cognitive aging; DNA Damage; Data; Delirium; Dementia; Disease; Ecological momentary assessment; Effector Cell; Elderly; Encephalitis; Epigenetic Process; Exhibits; Funding; Future; Goals; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematologic Neoplasms; Human; Immune; Impaired cognition; Individual; Inflammation; Inflammatory; Investigation; Knowledge; Lewy Bodies; Malignant Neoplasms; Metabolism; Molecular; Nerve Degeneration; Neurocognition; Neurocognitive; Neurotoxicity Syndromes; Neutropenia; Observational Study; Oxidative Stress; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Persons; Phenotype; Physical activity; Plasma; Play; Population; Process; Psychological Stress; Quality of life; Questionnaires; Recovery; Refractory; Relapse; Research; Resources; Risk; Risk Factors; Role; Sampling; Sleep; Stress; T-Lymphocyte; Telomere Shortening; Time; Toxic effect; Treatment Side Effects; United States; Vascular Dementia; Work; actigraphy; biological sex; cancer type; chimeric antigen receptor T cells; circulating biomarkers; cognitive change; cognitive process; cognitive reserve; comorbidity; cytokine; cytokine release syndrome; dementia risk; depressive symptoms; experience; follow-up; hematopoietic cell transplantation; high risk; improved; in vivo; innovation; insight; mental state; mild cognitive impairment; misfolded protein; modifiable risk; neuroinflammation; neuropathology; novel; parent grant; patient population; phase II trial; physical inactivity; poor sleep; predictive marker; protein aggregation; psychosocial; response; sedentary lifestyle; senescence; socioeconomics; symptomatology; systemic inflammatory response; tau Proteins; theories; ubiquitin C-terminal hydrolase

PROJECT SUMMARY/ABSTRACT Aggregations of misfolded proteins (e.g., tau, amyloid-b) are known to play a causal role in Alzheimer’s disease (AD) and related dementias (i.e., frontotemporal, Lewy body, vascular dementias) (ADRD), but can also be found in the postmortem brains of older adults without ADRD. Thus, a central question in AD is why cognitive pathology manifests in some individuals but not others. Animal models can provide insight into molecular mechanisms of pathogenic protein aggregation and clearance, but generalizability to humans is less clear. This supplement will build on the team’s previous collaborative research demonstrating that observational studies of cancer patients can be used to gain insights into ADRD pathobiology. Specifically, the supplement will focus on the association of accelerated cellular aging (i.e., DNA damage response, telomere shortening, cellular senescence, epigenetic aging, inflammatory senescence-associated secretory phenotype, oxidative stress, cellular metabolism) and plasma markers of neurodegeneration (e.g., amyloid-b, tau, ) with cognitive variability (i.e., an early indicator of ADRD). We will leverage data from a newly-funded study (R01CA244328) of longitudinal change in PROs and neurocognition in a novel cancer patient population, recipients of chimeric antigen receptor T-cell therapy (CAR- T) for relapsed/refractory hematologic malignancies. Over 90% of CAR-T recipients experience excessive release of pro-inflammatory cytokines (i.e., cytokine release syndrome or CRS) and/or neuroinflammation (i.e., immune effector cell neurotoxicity syndrome or ICANS) as side effects of treatment. We know of no other disease paradigm by which such extreme phenotypes of accelerated cellular aging, inflammation, and neuroinflammation can be observed in humans. As such, this supplement will provide a window into how these phenotypes are associated with human cognitive processes in vivo. Parent grant data to be leveraged by supplement includes smartphone-based real-time ecological momentary assessment (EMA) to asses cognitive variability; validated PRO questionnaires; actigraphy data regarding sleep, physical activity, and sedentary behavior; clinical information; and banked blood. New work in the supplement includes analysis of banked blood at the same time points (i.e., pre-CAR-T baseline, 3 and 12 months later), the addition of a blood sample at 7 days post-CAR-T (i.e., when systemic inflammation and neuroinflammation are expected to be greatest), and isolation and storage of T-cells at each time point to use as a resource for future scientific investigation. Goals of the supplement are as follows: 1) to examine accelerated cellular aging, neurodegeneration, and cognitive variability (i.e., an early indicator of ADRD) in the year after CAR-T therapy, 2) to determine psychosocial and behavioral ADRD risk factors associated with accelerated cellular aging, neurodegeneration, and cognitive variability in the year after CAR-T therapy, and 3) to explore the association of accelerated cellular aging with recovery and response to CAR-T. Results will provide new insights into putative mechanisms of ADRD, which will be evaluated further in ADRD patients in future studies.

项目总结/摘要 错误折叠蛋白质的聚集体（例如，tau、淀粉样蛋白-b）在阿尔茨海默病中起着重要作用 (AD)以及相关的痴呆（即，额颞叶，路易体，血管性痴呆）（ADRD），但也可以发现 在没有ADRD的老年人死后的大脑中。因此，AD的一个中心问题是为什么认知病理学 会在某些人身上表现出来但其他人不会动物模型可以提供深入的分子机制， 致病蛋白聚集和清除，但对人类的普遍性不太清楚。该补充将 该团队之前的合作研究表明，对癌症患者的观察性研究 可用于深入了解ADRD病理生物学。具体而言，增刊将重点关注关联 加速的细胞老化（即，DNA损伤反应，端粒缩短，细胞衰老，表观遗传 衰老、炎性衰老相关分泌表型、氧化应激、细胞代谢）和 神经变性的血浆标志物（例如，淀粉样蛋白-B，tau，）具有认知变异性（即，的早期指标 ADRD）。我们将利用一项新资助的PRO纵向变化研究（R01CA244328）的数据， 在新的癌症患者群体中的神经认知，嵌合抗原受体T细胞疗法（CAR-1）的接受者， T）用于复发性/难治性血液恶性肿瘤。超过90%的CAR-T接受者经历过过度 促炎细胞因子的释放（即，细胞因子释放综合征或CRS）和/或神经炎症（即， 免疫效应细胞神经毒性综合征或ICANS）作为治疗副作用。据我们所知 这种极端表型的加速细胞衰老、炎症和 在人类中可以观察到神经炎症。因此，这一补充将提供一个窗口，了解这些 表型与人的体内认知过程有关。要利用的母公司赠款数据 补充包括基于智能手机的实时生态瞬时评估（EMA），以评估认知 变异性;经验证的PRO问卷;关于睡眠、体力活动和久坐的体动记录数据 行为、临床信息和库存血液。补充的新工作包括分析库存血液 在相同的时间点（即，前CAR-T基线，3个月和12个月后），在7个月时添加血液样本， CAR-T后的天数（即，当全身炎症和神经炎症预期最大时），以及 在每个时间点分离和储存T细胞以用作未来科学研究的资源。目标 的补充如下：1）检查加速细胞老化，神经退行性病变，认知 可变性（即，ADRD的早期指标），2）确定心理社会和 与加速细胞衰老、神经退行性变和认知功能相关的行为ADRD风险因素 CAR-T治疗后一年的变异性，以及3）探索加速细胞衰老与 恢复和对CAR-T的反应。结果将为ADRD的假定机制提供新的见解， 将在未来的研究中在ADRD患者中进一步评估。

项目成果

Impact of tumor microenvironment on efficacy of anti-CD19 CAR T cell therapy or chemotherapy and transplant in large B cell lymphoma.

肿瘤微环境对大B细胞淋巴瘤抗CD19 CAR T细胞疗法或化疗和移植疗效的影响。

• DOI: 10.1038/s41591-023-02754-1
• 发表时间: 2024
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: Locke,FrederickL;Filosto,Simone;Chou,Justin;Vardhanabhuti,Saran;Perbost,Regis;Dreger,Peter;Hill,BrianT;Lee,Catherine;Zinzani,PierL;Kröger,Nicolaus;López-Guillermo,Armando;Greinix,Hildegard;Zhang,Wangshu;Tiwari,Gayatri;Budka,
• 通讯作者: Budka,