B cells in autoimmunity following checkpoint blockade therapy

检查点阻断治疗后的自身免疫中的 B 细胞

• 批准号: 10369680
• 负责人: Kavita Madhav Dhodapkar
• 金额: $ 44.53万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10369680
• 关键词: Address; Affect; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Autoimmune; Autoimmunity; B-Cell Activation; B-Cell Antigen Receptor; B-Lymphocyte Subsets; B-Lymphocytes; Biological Markers; CD8-Positive T-Lymphocytes; CTLA4 gene; Cells; Clinic; Clinical; Combined Modality Therapy; Data; Development; Environment; Epigenetic Process; Evaluation; FDA approved; Frequencies; Genomics; Germ-Line Mutation; Helper-Inducer T-Lymphocyte; Human; Immune; Immunity; In Vitro; Lead; Long-Term Effects; Malignant Neoplasms; Morbidity - disease rate; Myeloid Cells; Natural Killer Cells; Pathogenicity; Pathway interactions; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Plasmablast; Pre-Clinical Model; Prevention; Production; Regulation; Research Personnel; Risk; Role; Severities; T-Cell Activation; T-Lymphocyte; Testing; Toxic effect; Validation; anti-CTLA4; anti-PD-1; anti-PD1 antibodies; autoreactive B cell; autoreactivity; base; biomarker performance; checkpoint therapy; clinical efficacy; cohort; experience; high risk; immune checkpoint blockade; immune-related adverse events; improved; melanoma; monocyte; novel strategies; overexpression; preemptive intervention; prevent; programmed cell death protein 1; response; tumor; tumor immunology

PROJECT SUMMARY Combination checkpoint blockade (CCB) therapy with anti-CTLA4 and anti-PD1 antibodies leads to high rates of tumor regression and has been approved by the FDA for upfront treatment of patients with advanced melanoma and is currently being evaluated in other tumors. Unfortunately, CCB also leads to high rates of immune-related adverse events (IRAEs), with over half of the treated patients experiencing grade 3-4 IRAEs leading to discontinuation of therapy in over a third of patients. Hence, development of IRAEs remain a major obstacle to optimal application of combination checkpoint blockade in human cancer. From a practical perspective, it would be highly desirable if patients at increased risk for the development of autoimmunity could be identified before clinical toxicity and the risk of autoimmunity reduced by preemptive intervention, without affecting clinical efficacy. This application builds on our recent studies to evaluate treatment-induced changes in immune cells that correlate with the risk of development of IRAEs. In these studies, we have observed that CCB therapy leads to a distinct pattern of changes in B cells which preceded and correlated with both the frequency and timing of IRAEs. In contrast, treatment-induced proliferation in circulating CD4 or CD8 T cells or quantitative changes in other immune cells (NK cells, monocytes) did not correlate with or predict the development of IRAEs. We hypothesize that patients with early changes in B cells identify a cohort at high risk for the development of autoimmunity following CCB. Preclinical models have to date not recapitulated the spectrum of CCB-associated autoimmunity observed in the clinic, supporting the need for human studies. The specific aims are: Aim 1. To validate B cell changes as a biomarker for increased risk of IRAEs in melanoma patients receiving CCB therapy and to evaluate the long term effects of CCB therapy on B cell subsets and function compared to those observed in the context of naturally occurring autoimmunity. Aim 2. To identify antigenic targets of B cells expanded following CCB therapy and examine their ability to serve as antigen presenting cells. Aim 3. To examine the role of T helper subsets cells in the activation of CD21lo B cells in patients receiving CCB therapy. We hope these studies will provide a simple marker for identifying increased risk for autoimmunity following combination checkpoint therapy. Understanding B cell changes, defining their antigenic targets and the role of T cells in inducing these B cell changes may also help to identify new pathways and targets for prevention and treatment of IRAEs following combination checkpoint blockade therapy.

项目摘要 使用抗CTLA4和抗PD1抗体的组合检查点阻滞（CCB）疗法导致高率 肿瘤回归的作用，并已获得FDA的批准，用于预先治疗晚期患者 黑色素瘤，目前正在其他肿瘤中进行评估。不幸的是，CCB也导致 免疫相关的不良事件（IRAE），超过一半的治疗患者经历了3-4级IRAES 导致在三分之一的患者中停用治疗。因此，伊拉斯的发展仍然是主要的 最佳组合检查点阻滞在人类癌症中的障碍。来自实用 观点，如果自身免疫发展风险增加的患者可能会非常希望 在临床毒性和自身免疫力的风险降低之前，可以通过先发制人的干预降低，而没有 影响临床功效。该应用基于我们最近的研究，以评估治疗引起的变化 与伊拉斯发育风险相关的免疫细胞。在这些研究中，我们观察到CCB 治疗导致B细胞的不同变化模式，该模式与频率之前并相关 和伊拉斯的时机。相反，处理诱导的循环CD4或CD8 T细胞的增殖或定量 其他免疫细胞（NK细胞，单核细胞）的变化与伊拉斯的发展无关或预测。 我们假设B细胞早期变化早期变化的患者识别出具有高风险发展的队列 CCB之后的自身免疫性。临床前模型迄今为止尚未概括与CCB相关的频谱 在诊所观察到的自身免疫性，支持对人类研究的需求。具体目的是： 目的1。验证B细胞变化作为生物标志物，以增加接受黑色素瘤患者伊拉斯风险的生物标志物 CCB治疗并评估CCB治疗对B细胞子集和功能的长期影响 那些在自然免疫的背景下观察到的。 目标2。确定CCB治疗后B细胞扩展的B细胞的抗原靶标，并检查其能力 用作抗原呈递细胞。 目标3。检查T辅助子集细胞在接受CD21LO B细胞激活中的作用 CCB疗法。 我们希望这些研究将为确定自身免疫风险的增加提供一个简单的标记 组合检查点疗法。了解B细胞的变化，定义其抗原靶标和T的作用 诱导这些B细胞变化的细胞也可能有助于确定预防的新途径和目标 组合检查点阻滞治疗后的伊拉斯的治疗。