Targeted activation of autoimmune checkpoints in B cell malignancies

B 细胞恶性肿瘤中自身免疫检查点的靶向激活

基本信息

批准号：
10339747
负责人：
Markus Müschen
金额：
$ 39.78万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10339747
关键词：
Acute Adjuvant Agonist Autoimmunity B cell repertoire B lymphoid malignancy B-Cell Activation B-Cell Antigen Receptor B-Cell Leukemia B-Cell Lymphomas B-Cell Neoplasm B-Cell NonHodgkins Lymphoma B-Lymphocytes BACH2 gene BCL6 gene Biological Cell Death Cell Lineage Chronic Chronic Lymphocytic Leukemia Classification Clonal Deletion Clonal Evolution Data Development Disease Drug Targeting Drug resistance Excision Foundations Goals Hodgkin Disease Human Hyperactivity Immunotherapy Individual Late Effects Malignant - descriptor Malignant Neoplasms Mantle Cell Lymphoma Medicine Multiple Myeloma Mus Nature Newly Diagnosed Oncogenic Pathway interactions Patients Pharmacology Phosphotransferases Receptor Signaling SYK gene Signal Pathway Signal Transduction Stratification Stress Survival Rate Testing Therapeutic Toxic effect Tumor Subtype Validation Vincristine Work addiction autoimmunity checkpoint autoreactive B cell autoreactivity base cancer cell cancer type cell type disorder subtype improved outcome inhibitor/antagonist leukemia/lymphoma novel novel strategies pre-clinical response survivorship targeted cancer therapy treatment response validation studies

项目摘要

Targeted therapy of cancer typically focuses on agents that suppress oncogenic signaling below a minimum threshold needed for survival and proliferation. Here, we propose a novel strategy to overcome drug-resistance in B cell malignancies based on targeted activation of an autoimmunity checkpoint (AIC) for removal of autoreactive B cells. Owing to the necessity of the B cell repertoire to censor autoreactive clones, B cells fundamentally differ in their signaling requirements from other cell types. Unlike other types of cancer, B cell malignancies are uniquely susceptible to clonal deletion induced by hyperactive signaling from an autoreactive B cell receptor (BCR). Three recent studies from our group showed that targeted AIC-activation is achievable by pharmacological hyperactivation of BCR-signaling above a maximum threshold (Chen et al., Nature 2015; Shojaee et al., Cancer Cell 2015; Shojaee et al., Nature Med 2016). Hence, targeted AIC-activation can be leveraged for eradication of drug-resistant B cell leukemia and lymphoma clones. Based on these and other findings, we propose three Aims to validate targeted autoimmunity checkpoint (AIC)- activation as new concept for the treatment of human B cell malignancies: 1. This proposal includes a mechanistic Aim based on the novel observation that checkpoints to safeguard from autoimmunity disease are still functional in B cell malignancies. This Aim explores how AIC-activation can be reliably achieved in B cell malignancies and how AIC-activation leads to cell death. 2. The stratification Aim will identify disease subtypes and groups of patients that may be most responsive to AIC-activation and elucidate the biological basis of different treatment responses. 3. A therapeutic Aim will refine the treatment concept by prioritizing targeted hyperactivation of specific components of the BCR pathway and by exploring combinations with established treatment agents.

癌症的靶向疗法通常集中于抑制低于最低的致癌信号的药物生存和增殖所需的阈值。在这里，我们提出了一种克服抗药性的新策略在基于自身免疫检查点（AIC）的靶向激活的B细胞恶性肿瘤中自动反应性B细胞。由于B细胞库的必要性是审查自动反应性克隆的必要性其信号要求与其他细胞类型的基本不同。与其他类型的癌症不同，B细胞恶性肿瘤很容易受到自动反应性过度动态信号引起的克隆缺失 B细胞受体（BCR）。我们小组的三项最新研究表明，可以实现目标的AIC激活是可以实现的通过在最大阈值以上的BCR信号的药理过度激活（Chen等，Nature 2015； Shojaee等人，癌细胞2015； Shojaee等人，自然医学2016）。因此，有针对性的AIC激活可以是利用耐药性B细胞白血病和淋巴瘤克隆的利用。基于这些发现和其他发现，我们提出了三个旨在验证目标自身免疫检查点（AIC） - 激活作为治疗人B细胞恶性肿瘤的新概念： 1。该提案包括基于新观察的机械目的，该观察点可以保护检查点自身免疫性疾病仍然在B细胞恶性肿瘤中起作用。这个目的探讨了如何激活在B细胞恶性肿瘤以及AIC激活如何导致细胞死亡中可以可靠地实现。 2。分层目的将确定可能最有反应的疾病亚型和患者组 AIC激活并阐明了不同治疗反应的生物学基础。 3。治疗目的将通过优先考虑特定的靶向过度激活来完善治疗概念 BCR途径的组成部分，并通过探索与已建立的治疗剂的组合。