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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.

癌症的靶向治疗通常侧重于将致癌信号抑制到最低限度以下的药物