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

• 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
• 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

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.

项目总结/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。然而，在这方面， CARTx对体液免疫和感染风险的影响还不完全清楚。发生率很高 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），以预防该患者人群的感染。然而，有限的数据支持 这种实践、不足、副作用和成本使得IGRT的谨慎管理成为必要。新出现的数据 这表明病原体特异性抗体通常在CD 19-CARTx后持续存在，可能会质疑 IGRT。需要良好的对照研究来确定IGRT在CARTx受体中的临床效用。在这 在临床背景下，关于IGRT如何影响CAR-T细胞功能的其他重要和相关问题仍然存在， 除了IGRT对医疗资源利用的影响的可能成本与收益之外。 这一及时而独特的提案将是第一个在CARTx接受者中使用IGRT的随机对照试验， 为IGRT在该患者人群中的潜在风险和获益提供重要见解。的关键目标 本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， 并了解IGRT对先前未探索的结果的影响，如CAR-T细胞扩增，CAR-T细胞增殖， T细胞持久性，CAR-T细胞功能和医疗资源利用。就拟议研究而言，我们 组建了一个由来自大量CARTx中心的医生和科学家组成的跨学科小组， 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。 我们提议在150名血清总IgG ≤400 mg/dL的成年人中进行一项IGRT与安慰剂的随机试验 CD19-CARTx。受试者将在CARTx前14天内以1：1的比例随机接受IGRT或安慰剂治疗 CARTx后每隔28天给药一次，共4个月。目的1将比较研究组之间的 我们还将纵向描述和比较CD 19-CARTx治疗后6个月内的总感染率， 病原体特异性IgG水平及其与感染的相关性。目的2将探讨IGRT与 医疗资源利用、细胞因子释放综合征和CARTx相关神经毒性。目标3将 表征IGRT对CAR-T细胞扩增、持久性和功能的影响。 这将是CARTx后IGRT的第一项随机对照研究，并将提供基础数据， 建立IGRT在CD 19-CARTx受者中的临床疗效和风险-获益的循证评估。 同时，本研究将探索IGRT对CAR-T细胞动力学和医疗资源的其他潜在影响。 利用率该提案生成的数据将为未来研究细化感染提供基础 在不断增长的CARTx接受者中采取预防策略。