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

项目摘要/摘要 嵌合抗原受体T细胞疗法(CARTx)的发展是治疗B细胞恶性肿瘤的主要手段 癌症免疫治疗的里程碑，持久的完全缓解率很高。尽管细胞因子的释放 综合征和神经毒性是免疫相关不良事件(IrAEs)发生的最早和最显著的原因 CARTx，严重的症状是短暂的，只影响少数患者。相比之下，对准目标，偏离目标- 肿瘤耗尽的非恶性B细胞系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，CD19的表达下降，而BCMA通过以下方式选择性表达 浆细胞。由于浆细胞负责维持长寿抗体和幼稚/记忆B细胞 对产生新的免疫很重要，CD19和BCMA-CARTx可能会对先前存在的免疫产生不同的影响 免疫和疫苗反应。希尔博士的目标是了解CARTx对体液的长期影响 豁免权。这项建议融合了一批杰出的传染病研究人员的专业知识， 致力于确保成功的免疫肿瘤学、流行病学、实验室医学和统计学 这项创新的研究提案。他们将利用他们的专业知识和大量的免疫疗法 这些方案旨在实现以下目标。 第一个目标是对130名CARTx接受者(50名成人CD19，50名)进行前瞻性观察队列研究 儿童CD19例，成人BCMA 30例)，无复发生存≥6个月。希尔博士将使用一种新的系统性病毒 用表位扫描法(VirScan)对206种病毒病原体进行纵向鉴定。这些 结果将描述和确定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微差别的评估 能力。第二个目标将利用目标1的样本来确定CARTx对耐久性的影响 对疫苗可预防感染的先前存在的体液免疫以及缺乏的患者比例 CARTx后的血清保护。这些数据将扩大到目标1，以便为疫苗接种战略提供信息。在第三个目标中， 希尔博士将对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6个月后≥阳性疫苗应答的频率和相关性 CARTX。病人将接种肺炎链球菌、破伤风、白喉、百日咳、乙型流感和 根据机构指南，甲型和乙型肝炎。 这项提案将通过采用创新的方法来阐明 CARTx后，体液免疫中的病原体特异性缺陷，以及接种疫苗是否可以减轻这些irAEs。 这些发现将指导基于证据的感染预防策略，如接种疫苗或免疫球蛋白。 替代，以改善这一快速增长的高危人群的结果。

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.