Humoral immunity after CAR-T cell therapy for B cell malignancies: The HICAR Study

B 细胞恶性肿瘤 CAR-T 细胞治疗后的体液免疫：HICAR 研究

• 批准号: 9921121
• 负责人: Joshua Aiden Hill
• 金额: $ 67.07万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9921121
• 关键词: Acute; Acute Lymphocytic Leukemia; Address; Adult; Affect; Age; Antibodies; Antigens; Antiviral Agents; B cell differentiation; B lymphoid malignancy; B-Lymphocytes; Blood; Blood Tests; CAR T cell therapy; CD19 gene; Cell Lineage; Cell Maturation; Cells; Characteristics; Childhood; Childhood Leukemia; Clinical; Cohort Studies; Communicable Diseases; Data; Development; Diphtheria; Disease remission; Ensure; Epidemiology; Epitopes; FDA approved; Frequencies; Goals; Guidelines; Haemophilus influenzae; Hepatitis A; Hepatitis B; Humoral Immunities; Immunity; Immunocompetence; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Immunologic Markers; Immunooncology; Immunotherapy; Individual; Infection; Infection prevention; Influenza B Virus; Intervention; Intravenous Immunoglobulins; Kinetics; Knowledge; Laboratories; Long-Term Effects; Medicine; Memory B-Lymphocyte; Methods; Minority; Modeling; Multiple Myeloma; Non-Hodgkin' s Lymphoma; Non-Malignant; Observational Study; Outcome; Patients; Pertussis; Plasma Cells; Population; Recovery; Relapse; Research Personnel; Research Proposals; Risk stratification; Sampling; Scanning; Streptococcus pneumoniae; Subgroup; T-Lymphocyte Subsets; Testing; Tetanus; Time; Vaccinated; Vaccination; Vaccines; Viral; Virus; base; cancer immunotherapy; cancer therapy; cost effective; cytokine release syndrome; evidence base; high risk population; immune-related adverse events; improved; improved outcome; indexing; infection risk; innovation; neurotoxicity; novel; pathogen; pathogenic virus; preservation; programs; prophylactic; prospective; response; selective expression; statistics; success; time use; tumor; vaccination strategy; vaccine response

PROJECT SUMMARY/ABSTRACT The development of chimeric antigen receptor T cell therapies (CARTx) for B cell malignancies is a major milestone in cancer immunotherapy with high rates of durable complete remissions. Although cytokine release syndrome and neurotoxicity are the earliest and most dramatic immune related adverse events (irAEs) after CARTx, severe manifestations are transient and only affect a minority of patients. In contrast, on-target, off- tumor depletion of non-malignant B lineage cells affects the majority of patients and all long-term responders. CD19 expression declines as B cells differentiate into plasma cells, whereas BCMA is selectively expressed by plasma cells. Since plasma cells are responsible for maintaining long-lived antibodies and naïve/memory B cells are important for generating new immunity, CD19 versus BCMA-CARTx may differentially affect preexisting immunity and vaccine responses. Dr. Hill’s goal is to understand the long-term effects of CARTx on humoral immunity. This proposal incorporates the expertise of an outstanding group of researchers in infectious diseases, immuno-oncology, epidemiology, laboratory medicine, and statistics who are dedicated to ensuring the success of this innovative research proposal. They will leverage their expertise and high-volume immunotherapy programs to achieve the following aims. The first Aim involves a prospective observational cohort study of 130 CARTx recipients (50 adult CD19, 50 pediatric CD19, 30 adult BCMA) with relapse-free survival ≥6 months. Dr. Hill will use a novel systematic viral epitope scanning method (VirScan) to longitudinally characterize the antivirome to 206 viral pathogens. These results will describe, and identify correlates of, antivirome diversity metrics at 6- and 12-months post-CARTx. VirScan will allow for a nuanced assessment of the differential impacts of CARTx on humoral immune competence. The second Aim will utilize samples from Aim 1 to determine the effect of CARTx on the durability of preexisting humoral immunity to vaccine-preventable infections and the proportion of patients lacking seroprotection after CARTx. These data will expand on Aim 1 to inform vaccination strategies. In the third Aim, Dr. Hill will perform a prospective observational study of 95 CARTx recipients (50 adult CD19, 25 pediatric CD19, and 20 adult BCMA) to define the frequency and correlates of positive vaccine responses ≥6 months after CARTx. Patients will be vaccinated for S. pneumoniae, tetanus, diphtheria, pertussis, H. influenza b, and hepatitis A and B according to institutional guidelines. This proposal will address critical knowledge gaps by employing innovative methods to elucidate the scope of pathogen-specific deficits in humoral immunity, and whether vaccination can mitigate these irAEs, after CARTx. The findings will guide evidence-based strategies for infection prevention, such as vaccination or immunoglobulin replacement, to improve outcomes in this rapidly growing population of high-risk individuals.

项目摘要/摘要 B细胞恶性肿瘤的嵌合抗原受体T细胞疗法（CARTX）的发展是主要的 癌症免疫疗法中的里程碑，耐用的完全缓解率很高。虽然细胞因子释放 在 CARTX，严重的表现是短暂的，仅影响少数患者。相比之下，靶标，偏离 - 肿瘤对非恶性B谱系细胞的定义会影响大多数患者和所有长期反应者。 CD19表达在B细胞分化为浆细胞中的表达下降，而BCMA选择性地表达 浆细胞。由于血浆细胞负责维持长寿命抗体和幼稚/记忆B细胞 CD19与BCMA-CARTX对新免疫力很重要 免疫力和疫苗反应。希尔博士的目标是了解cartx对体液的长期影响 免疫。该提案结合了一个杰出的传染病研究人员的专业知识， 免疫肿瘤，流行病学，实验室医学和统计，致力于确保成功 这项创新的研究建议。他们将利用他们的专业知识和大量免疫疗法 实现以下目标的计划。 第一个目的涉及130名CARTX接受者的前瞻性观察队列研究（50名成人CD19，50 儿科CD19，30成人BCMA），无救生存活率≥6个月。希尔博士将使用一种新颖的系统病毒 表位扫描方法（VirScan）纵向将抗毒素描述为206种病毒病原体。这些 结果将描述并确定在6个月和12个月后的抗毒素多样性指标的相关性。 VirScan将允许对CARTX对体液免疫的差异影响进行细微的评估 权限。第二个目标将利用AIM 1的样本来确定CARTX对耐用性的影响 对疫苗预防感染的先前免疫力和缺乏疫苗的患者比例 cartx之后的血清保护。这些数据将扩展AIM 1，以告知疫苗接种策略。在第三个目标中 Hill博士将对95个CARTX接受者进行前瞻性观察研究（50名成人CD19，25儿科CD19， 和20个成人BCMA）定义≥6个月后阳性疫苗反应的频率和相关性 cartx。患者将接种肺炎链球菌，破伤风，白喉，百日咳，H。AttractzaB和 根据机构指南，乙型肝炎和B。 该建议将通过采用创新方法来阐明范围的范围来解决关键知识差距 CARTX之后，体液免疫学中的病原体特异性防御​​能力以及疫苗接种是否可以减轻这些IRAE。 这些发现将指导预防感染的循证策略，例如疫苗接种或免疫球蛋白 取代，以改善这种迅速增长的高风险人群的结果。