Immunoglobulin Replacement Therapy and Infectious Complications After CD19-Targeted CAR-T-Cell Therapy

项目摘要/摘要 嵌合抗原受体T细胞疗法(CARTx)改变了B细胞恶性肿瘤的治疗方法。然而， CARTx对体液免疫和感染风险的影响尚不完全清楚。高流行率 CARTx受者低丙种球蛋白血症的发生促使预防性免疫球蛋白G(IgG)的频繁使用 替代疗法(IGRT)，以预防该患者群体中的感染。然而，支持这一观点的数据有限 这种做法，以及短缺、副作用和成本，要求对IGRT进行仔细的管理。新兴数据 这表明病原体特异性抗体在CD19-CARTx之后通常会持续存在，这可能会竞争 IGRT。需要良好的对照研究来确定IGRT在CARTx接受者中的临床有效性。在这个范围内 临床背景下，关于IGRT如何影响CAR-T细胞功能的其他重要和相关的问题仍然存在， 除了IGRT对医疗资源利用的影响可能带来的成本和收益。 这项及时而独特的建议将是首次在CARTx接受者和 对IGRT在这一患者群体中的潜在风险和好处提供关键的见解。主要目标 这项研究的目的是评估与安慰剂相比，CARTx接受者的IGRT是否降低了感染率， 为了了解IGRT对以前未被探索的结果的影响，如CAR-T细胞扩增，CAR-T细胞- T细胞持久性、CAR-T细胞功能、医疗资源利用。就拟议的研究而言，我们有 召集了一个由来自高容量CARTx中心的医生和科学家组成的跨学科小组，他们将 利用我们在免疫肿瘤学、传染病和癌症结果研究方面的专业知识。 我们建议对150名血清总免疫球蛋白≤为400 mg/dL的成年人进行IGRT和安慰剂的随机试验。 CD19-CARTx。参与者将在CARTx前14天内以1：1随机方式接受IGRT或安慰剂治疗 CARTx后间隔28天，连续4个月。目标1将比较研究组之间的发病率 CD19-CARTx后6个月的感染；我们还将纵向描述和比较总和 病原体特异性免疫球蛋白水平及其与感染的关系。目标2将探索IGRT与 医疗资源利用、细胞因子释放综合征和CARTx相关的神经毒性。目标3将 描述IGRT对CAR-T细胞扩增、持久性和功能的影响。 这将是CARTx后IGRT的第一次随机对照研究，并将为 建立CD19-CARTx受者IGRT临床疗效和风险收益的循证评估。 同时，这项研究将探索IGRT对CAR-T细胞动力学和医疗资源的其他潜在影响 利用率。这项提议产生的数据将为未来研究改进感染提供基础 CARTx接受者日益增长的人口中的预防策略。

PROJECT SUMMARY/ABSTRACT Chimeric antigen receptor T cell therapy (CARTx) has transformed treatment for B cell malignancies. However, the effects of CARTx on humoral immunity and infection risk are incompletely understood. The high prevalence of hypogammaglobulinemia in CARTx recipients has driven frequent use of prophylactic immunoglobulin G (IgG) replacement therapy (IGRT) to prevent infections in this patient population. However, limited data exist to support this practice, and shortages, side effects, and cost necessitate careful stewardship of IGRT. Emerging data indicate that pathogen-specific antibodies often persist after CD19-CARTx, potentially contesting the need for IGRT. Well controlled studies are needed to ascertain the clinical utility of IGRT in CARTx recipients. Within this clinical context, other important and connected questions remain about how IGRT affects CAR-T cell function, in addition to the possible costs versus benefits of the effect of IGRT on healthcare resource utilization. This timely and unique proposal will be the first randomized, controlled trial of IGRT use in CARTx recipients and provide critical insights into the potential risks and benefits of IGRT in this patient population. The key objectives of this study are to evaluate whether IGRT in CARTx recipients reduces infection rates compared to placebo, and to understand the impact of IGRT on previously unexplored outcomes such as CAR-T cell expansion, CAR- T cell persistence, CAR-T cell function, and healthcare resource utilization. For the proposed study, we have assembled an interdisciplinary group of physicians and scientists from high-volume CARTx centers who will leverage our expertise in immuno-oncology, infectious diseases, and cancer outcomes research. We propose a randomized trial of IGRT versus placebo in 150 adults with serum total IgG ≤400 mg/dL prior to CD19-CARTx. Participants will be randomized 1:1 to receive IGRT or placebo within 14 days prior to CARTx and at 28-day intervals after CARTx for 4 months. Aim 1 will compare between study arms the incidence rate of infections through 6 months after CD19-CARTx; we will also longitudinally characterize and compare total and pathogen-specific IgG levels and their association with infections. Aim 2 will explore the association of IGRT with healthcare resource utilization, cytokine release syndrome, and CARTx-associated neurotoxicity. Aim 3 will characterize the impact of IGRT on CAR-T cell expansion, persistence, and function. This will be the first randomized controlled study of IGRT after CARTx and will provide foundational data to establish evidence-based estimates of the clinical efficacy and risk-benefit of IGRT in CD19-CARTx recipients. In parallel, this study will explore other potential effects of IGRT on CAR-T cell dynamics and healthcare resource utilization. The data generated by this proposal will provide the groundwork for future studies to refine infection prevention strategies in the growing population of CARTx recipients.