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

CD19 靶向 CAR-T 细胞治疗后的免疫球蛋白替代疗法和感染并发症

基本信息

批准号：
10732195
负责人：
Joshua Aiden Hill
金额：
$ 93.04万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10732195
关键词：
Accounting Adoptive Immunotherapy Adult Adverse event Affect Antibiotics Antibodies B lymphoid malignancy Bacterial Infections Benefits and Risks Blood CAR T cell therapy CD19 gene Caring Cell Cycle Kinetics Cell Surface Proteins Cell physiology Cells Cessation of life Clinical Communicable Diseases Controlled Study Cox Models Cytometry Data Disease remission Double-Blind Method Dropout Emergency department visit Ensure Equity Future Health Resources Healthcare High Prevalence Hospitalization Humoral Immunities Image Immune Immunoglobulin G Immunoglobulins Immunooncology Incidence Infection Infection prevention Infusion procedures Intention Kinetics Life Lymphoma Malignant Neoplasms Measures Medical Medical Records Outcome Outcomes Research Outpatients Participant Patients Persons Pharmaceutical Preparations Physicians Placebos Population Prevention strategy Progression-Free Survivals Randomized Randomized, Controlled Trials Recovery Replacement Therapy Resolution Resources Risk Scientist Serum Severities Signal Transduction Site Streptococcus pneumoniae Subgroup Toxic effect Visit arm cancer therapy chimeric antigen receptor T cells clinical efficacy clinical risk cost cytokine release syndrome design dimensional analysis evidence base follow-up hypogammaglobulinemia immune reconstitution infection rate infection risk insight neurotoxicity pathogen patient population placebo controlled study prophylactic radiological imaging randomized placebo controlled trial randomized trial randomized, controlled study side effect tumor

项目摘要

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.

项目概要/摘要嵌合抗原受体 T 细胞疗法 (CARTx) 已经改变了 B 细胞恶性肿瘤的治疗方法。 CARTx 对体液免疫和感染风险的影响尚不完全清楚。 CARTx 接受者的低丙种球蛋白血症导致频繁使用预防性免疫球蛋白 G (IgG) 替代疗法（IGRT）可预防该患者群体的感染，但是支持的数据有限。这种做法以及短缺、副作用和成本需要对新兴数据进行仔细管理。表明病原体特异性抗体在 CD19-CARTx 后通常会持续存在，这可能会质疑对 CD19-CARTx 的需求 IGRT 需要良好的对照研究来确定 IGRT 在 CARTx 接受者中的临床效用。临床背景下，关于 IGRT 如何影响 CAR-T 细胞功能的其他重要且相关的问题仍然存在，除了 IGRT 对医疗资源利用的影响可能产生的成本与收益之外。这项及时而独特的提案将是第一个在 CARTx 接受者和患者中使用 IGRT 的随机对照试验。提供有关 IGRT 在该患者群体中的潜在风险和益处的重要见解。这项研究的目的是评估与安慰剂相比，CARTx 接受者的 IGRT 是否可以降低感染率，并了解 IGRT 对先前未探索的结果的影响，例如 CAR-T 细胞扩增、CAR- 对于拟议的研究，我们有 T 细胞持久性、CAR-T 细胞功能和医疗资源利用。组建了一个由来自大容量 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 IgG ≤ 400 mg/dL 的成人进行 IGRT 与安慰剂的随机试验。 CD19-CARTx 参与者将在 CARTx 前 14 天内以 1:1 的比例随机接受 IGRT 或安慰剂。 CARTx 持续 4 个月后，每隔 28 天将比较研究组之间的发生率。 CD19-CARTx 后 6 个月内的感染；我们还将纵向描述和比较总感染和病原体特异性 IgG 水平及其与感染的关联。目标 2 将探讨 IGRT 与感染的关联。医疗资源利用、细胞因子释放综合征和 CARTx 相关神经毒性将成为目标 3。描述 IGRT 对 CAR-T 细胞扩增、持久性和功能的影响。这将是继 CARTx 之后第一个 IGRT 随机对照研究，将为以下研究提供基础数据：对 CD19-CARTx 接受者中 IGRT 的临床疗效和风险效益建立基于证据的估计。与此同时，本研究将探讨 IGRT 对 CAR-T 细胞动力学和医疗资源的其他潜在影响该提案生成的数据将为未来改进感染的研究奠定基础。针对不断增长的 CARTx 接受者群体的预防策略。