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

项目总结/摘要 开发用于B细胞恶性肿瘤的嵌合抗原受体T细胞疗法（CARTx）是一个主要的挑战。 癌症免疫治疗的里程碑，具有高的持久完全缓解率。虽然细胞因子释放 综合征和神经毒性是最早和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，偏离- 非恶性B谱系细胞的肿瘤耗竭影响大多数患者和所有长期应答者。 随着B细胞分化为浆细胞，CD 19表达下降，而BCMA则选择性表达 浆细胞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是重要的，CD 19与BCMA-CARTx可能会不同地影响先前存在的免疫力。 免疫力和疫苗反应。Hill博士的目标是了解CARTx对体液免疫的长期影响。 免疫力这一建议结合了一组杰出的传染病研究人员的专门知识， 免疫肿瘤学、流行病学、实验室医学和统计学，他们致力于确保 这个创新的研究项目。他们将利用他们的专业知识和高容量免疫疗法 计划实现以下目标。 第一个目标涉及130名CARTx接受者的前瞻性观察性队列研究（50名成人CD 19，50名 儿童CD 19，30例成人BCMA），无复发生存期≥6个月。希尔博士会用一种新型的系统性病毒 表位扫描方法（VirScan）纵向表征抗病毒206种病毒病原体。这些 结果将描述和鉴定CARTx后6个月和12个月的抗病毒多样性指标的相关性。 VirScan将允许对CARTx对体液免疫的不同影响进行细致入微的评估， 能力。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 对疫苗可预防感染的既存体液免疫和缺乏体液免疫的患者比例 CARTx后的血清保护。这些数据将扩展目标1，为疫苗接种战略提供信息。在第三个目标中， 博士Hill将对95名CARTx接受者（50名成人CD 19，25名儿童CD 19， 和20例成人BCMA），以确定接种后≥6个月阳性疫苗应答的频率和相关性 CARTx。患者将接种S。肺炎、破伤风、白喉、百日咳、H.流感B，和 甲型和B型肝炎。 本提案将通过采用创新方法阐明 病原体特异性体液免疫缺陷，以及接种疫苗是否可以减轻这些irAE，CARTx后。 这些发现将指导基于证据的感染预防策略，如疫苗接种或免疫球蛋白 替代，以改善这一快速增长的高风险人群的结果。

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.