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

基本信息

批准号：
10650136
负责人：
Joshua Aiden Hill
金额：
$ 64.46万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
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/10650136
关键词：
Acute Acute Lymphocytic Leukemia Adult Affect Age Antibodies Antigens B cell differentiation B cell therapy B lymphoid malignancy B-Lymphocytes Blood Blood Tests CAR T cell therapy CD19 gene Cell Lineage Cell Maturation Cells Characteristics Childhood Childhood Leukemia Clinical Communicable Diseases Data Dedications 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 Institution Intravenous Immunoglobulins Kinetics Knowledge Laboratories Long-Term Effects Medicine Memory B-Lymphocyte Methods Minority Modeling Multiple Myeloma Non-Hodgkin&apos s Lymphoma Non-Malignant Observational Study Outcome Patients Pertussis Plasma Cells Population Recovery Relapse Research Personnel Research Proposals Sampling Scanning Streptococcus pneumoniae Subgroup T cell therapy T-Lymphocyte Subsets Testing Tetanus Time Vaccinated Vaccination Vaccines Viral Virus 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 observational cohort study pathogen pathogenic virus pragmatic intervention preservation programs prophylactic prospective response risk stratification selective expression statistics success targeted treatment time use tumor vaccination strategy vaccine response

项目摘要

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.

项目概要/摘要针对 B 细胞恶性肿瘤的嵌合抗原受体 T 细胞疗法 (CARTx) 的开发是一个重大进展尽管细胞因子释放，但持久完全缓解率很高，是癌症免疫治疗的里程碑。综合征和神经毒性是术后最早、最严重的免疫相关不良事件 (irAE) CARTx，严重的表现是短暂的，只影响少数患者，相反，在目标上，脱靶。非恶性 B 谱系细胞的肿瘤耗竭影响着大多数患者和所有长期反应者。随着 B 细胞分化为浆细胞，CD19 表达下降，而 BCMA 则选择性表达由于浆细胞负责维持长寿命抗体和幼稚/记忆 B 细胞。对于产生新的免疫力很重要，CD19 与 BCMA-CARTx 可能会对先前存在的免疫力产生不同的影响 Hill 博士的目标是了解 CARTx 对体液的长期影响。该提案融合了传染病领域杰出研究人员的专业知识，免疫肿瘤学、流行病学、检验医学和统计学致力于确保成功他们将利用他们的专业知识和大容量免疫疗法。计划以实现以下目标。第一个目标涉及对 130 名 CARTx 接受者（50 名成人 CD19、50 名成人 CD19）进行的前瞻性观察队列研究。 Hill 博士将使用一种新型系统病毒治疗，儿童 CD19，30 成人 BCMA，无复发生存期≥6 个月。表位扫描方法 (VirScan) 纵向表征 206 种病毒病原体的抗病毒组。结果将描述 CARTx 后 6 个月和 12 个月的抗病毒组多样性指标，并确定其相关性。 VirScan 将允许对 CARTx 对体液免疫的不同影响进行细致的评估第二个目标将利用目标 1 中的样本来确定 CARTx 对耐久性的影响。预先存在的对疫苗可预防感染的体液免疫以及缺乏体液免疫的患者比例 CARTx 后的血清保护作用将在目标 1 上进行扩展，为第三个目标中的疫苗接种策略提供信息。 Hill 博士将对 95 名 CARTx 接受者（50 名成人 CD19、25 名儿童 CD19、和 20 名成人 BCMA），以确定接种后 ≥6 个月后阳性疫苗反应的频率和相关性 CARTx 患者将患有肺炎链球菌、破伤风、白喉、百日咳、乙型流感嗜血杆菌和根据机构指南，甲型和乙型肝炎。该提案将通过采用创新方法来阐明关键知识差距 CARTx 后体液免疫中病原体特异性缺陷，以及疫苗接种是否可以减轻这些 irAE。研究结果将指导基于证据的感染预防策略，例如疫苗接种或免疫球蛋白替代，以改善这个快速增长的高风险人群的结果。