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.

项目概要/摘要 已知错误折叠蛋白（例如 tau 蛋白、淀粉样蛋白 -b）的聚集与阿尔茨海默病有关 (AD) 和相关痴呆（即额颞叶痴呆、路易体痴呆、血管性痴呆）(ADRD)，但也可以发现 因此，ADRD 的一个核心问题是为什么会产生认知病理学。 动物模型可以深入了解某些个体的分子机制。 致病蛋白聚集和清除，但这种补充剂对人类的普遍性尚不清楚。 建立在该团队之前的合作研究的基础上，该研究表明对癌症患者的观察性研究 具体来说，该增刊将重点关注这种关联。 加速细胞衰老（即 DNA 损伤反应、端粒缩短、细胞衰老、表观遗传 衰老、炎症衰老相关的分泌表型、氧化应激、细胞代谢）和 神经退行性变的血浆标志物（例如，淀粉样蛋白-b、tau 蛋白）与认知变异性（即，神经退行性变的早期指标） ADRD）。我们将利用一项新资助的关于 PRO 和纵向变化的研究 (R01CA244328) 的数据。 嵌合抗原受体 T 细胞疗法（CAR- T) 对于复发/难治性血液恶性肿瘤，超过 90% 的 CAR-T 接受者经历了过度治疗。 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 我们不知道还有其他治疗副作用。 加速细胞衰老、炎症等极端表型的疾病范式 因此，这种补充剂将为了解这些神经炎症的发生机制提供一个窗口。 表型与人类体内认知过程相关。 补充包括基于智能手机的实时生态瞬时评估（EMA）来评估认知能力 变异性；经过验证的 PRO 问卷调查有关睡眠、体力活动和久坐的数据； 补充品中的新工作包括对储存的血液进行分析。 在同一时间点（即 CAR-T 前基线、3 个月和 12 个月后），在 7 点添加血液样本 CAR-T 后几天（即预计全身炎症和神经炎症最严重的时候），以及 在每个时间点分离和储存 T 细胞，作为未来科学研究目标的资源。 该补充剂的作用如下： 1) 检查加速的细胞衰老、神经退行性变和认知能力 CAR-T 治疗后一年的变异性（即 ADRD 的早期指标），2) 以确定心理社会和 与加速细胞衰老、神经退行性变和认知相关的行为 ADRD 危险因素 CAR-T 治疗后一年的变异性，以及 3) 探索加速细胞衰老与 CAR-T 的恢复和反应结果将为 ADRD 的假定机制提供新的见解。 将在未来的研究中对 ADRD 患者进行进一步评估。

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。

• 发表时间: 2024-02
• 影响因子: 82.9
• 作者: Locke, Frederick L;Filosto, Simone;Chou, Justin;Vardhanabhuti, Saran;Perbost, Regis;Dreger, Peter;Hill, Brian T;Lee, Catherine;Zinzani, Pier L;Kröger, Nicolaus;López;Greinix, Hildegard;Zhang, Wangshu;Tiwari, Gayatri;Budka
• 通讯作者: Budka