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 抗CTLA 4和抗PD 1抗体联合检查点阻断（CCB）治疗导致高发生率 肿瘤消退，并已被FDA批准用于晚期乳腺癌患者的前期治疗。 黑色素瘤，目前正在其他肿瘤中进行评估。不幸的是，建行也导致高利率的 免疫相关不良事件（IRAE），超过一半的治疗患者发生3-4级IRAE 导致超过三分之一的患者停止治疗。因此，IRAE的发展仍然是一个主要的 这是在人类癌症中最佳应用组合检查点阻断的障碍。从实际 从这个角度来看，如果自身免疫性发展风险增加的患者能够 在临床毒性和通过预先干预降低自身免疫风险之前确定， 影响临床疗效。这项应用建立在我们最近的研究，以评估治疗引起的变化， 与IRAE发展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细胞发生明显的变化，这种变化先于并与两种频率相关， 和IRAE的时间。与此相反，治疗诱导的循环CD 4或CD 8 T细胞增殖或定量的 其他免疫细胞（NK细胞、单核细胞）的变化与IRAE的发生无关，也不能预测IRAE的发生。 我们假设，B细胞早期变化的患者确定了发生以下疾病的高风险队列 CCB后的自身免疫。迄今为止，临床前模型尚未概括CCB相关的 在临床中观察到自身免疫，支持人体研究的需要。具体目标是： 目标1.验证B细胞变化作为黑色素瘤患者IRAE风险增加的生物标志物， CCB治疗，并评价CCB治疗对B细胞亚群和功能的长期影响， 这些是在自然发生的自身免疫背景下观察到的。 目标二。为了鉴定CCB治疗后扩增的B细胞的抗原靶点，并检查它们对抗原的抑制能力， 作为抗原呈递细胞。 目标3.为了检测辅助性T细胞亚群在接受免疫调节剂治疗的患者中CD 21 lo B细胞活化中的作用， CCB治疗。 我们希望这些研究将提供一个简单的标记，用于识别以下疾病的自身免疫性风险增加： 联合检查点疗法。了解B细胞的变化，确定其抗原靶点和T细胞的作用 细胞诱导这些B细胞变化也可能有助于确定新的途径和预防目标， 联合检查点阻断治疗后的IRAE治疗。