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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

基本信息

批准号：
9893845
负责人：
Kavita Madhav Dhodapkar
金额：
$ 46.57万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
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/9893845
关键词：
Address Affect Antibodies Antigen Presentation Antigen-Presenting Cells Autoimmune Process Autoimmunity B-Cell Activation 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 Receptors, Antigen, B-Cell 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 genomic profiles 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

项目摘要

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.

项目总结