权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Targeting myeloid suppression to enhance anti-tumor immunity in breast cancer

靶向骨髓抑制以增强乳腺癌的抗肿瘤免疫力

基本信息

批准号：
10720795
负责人：
Evanthia Theodosiou Roussos Torres
金额：
$ 57.98万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-21 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10720795
关键词：
Advanced Malignant Neoplasm Antigen Presentation Antitumor Response Automobile Driving Binding Biological Markers Biopsy Breast Breast Cancer Model Breast Cancer Patient Candidate Disease Gene Cell Separation Cells ChIP-seq Clinical Clinical Trials Co-Immunoprecipitations Coculture Techniques Complex Couples Cytometry Data Data Analyses Data Correlations Dendritic Cells Differential Equation Disease Dose Drug Modulation Effector Cell Epigenetic Process Evaluation Flow Cytometry Frequencies Future Gene Expression Genes Genomics Histone Deacetylase Inhibitor Human Immune Immune checkpoint inhibitor Immunosuppression Infiltration Investigation Laboratories Macrophage Malignant Neoplasms Mammary Neoplasms Mediating Metastatic Neoplasm to the Lung Metastatic breast cancer Modeling Molecular Mus Myelogenous Myeloid Cells Myeloid-derived suppressor cells NF-kappa B Neoplasm Metastasis Nivolumab Outcome Patients Phase Phase I Clinical Trials Phenotype Play Pre-Clinical Model Publishing Recommendation Resistance Role Running STAT3 gene Sampling Serum Signal Transduction Site Solid Neoplasm T-Lymphocyte Testing Tissue-Specific Gene Expression Tissues Transcription Factor AP-1 Tumor Immunity Tumor-associated macrophages advanced breast cancer cell type checkpoint inhibition cohort immune cell infiltrate improved innovation ipilimumab loss of function malignant breast neoplasm mathematical model models and simulation monocyte mouse model novel novel strategies patient stratification patient subsets potential biomarker pre-clinical preclinical study predict clinical outcome promoter response single-cell RNA sequencing targeted treatment transcription factor transcriptome sequencing treatment response tumor tumor growth tumor microenvironment

项目摘要

Project Summary Myeloid immune suppression, driven by macrophages and monocytes, is a known mechanism of intrinsic resistance to immune checkpoint inhibition (ICI), which has provided significant and durable responses in patients with advanced cancers, but not in most breast cancer patients. Our laboratory has been instrumental in demonstrating that targeting myeloid immunosuppression via decreasing the function of immature myeloid derived suppressor cells (MDSCs) is a novel and important strategy to sensitize the tumor microenvironment (TME) and improve the response to ICIs in breast cancer. We published two preclinical studies demonstrating that entinostat, a class I histone deacetylase inhibitor, decreased MDSC suppression of T cells; furthermore, combining entinostat with the ICIs nivolumab and ipilimumab improved survival in murine models of breast cancer. This provided a strong rationale for our Phase I clinical trial (NCI-9844) where we determined the recommended phase 2 dose (RP2D) for this treatment, given to patients with advanced solid tumors, including 10/33 with breast cancer, as a two-week pre-treatment with entinostat, followed by the combination of entinostat + nivolumab + ipilimumab. Furthermore, an overall response rate (ORR) of 30% was observed in an expansion cohort of 20 patients with advanced breast cancer, who received the RP2D. Nevertheless, we have yet to understand how entinostat decreases myeloid suppression to achieve TME sensitization that leads to this striking response to ICIs. Preliminary data in preclinical models demonstrate that entinostat 1) decreases suppressive function of intra- tumoral MDSCs; 2) decreases the activation of the STAT3-NFkB-AP-1 signaling axis; and 3) alters the phenotype and/or infiltration within the TME of other myeloid cells, including tumor associated macrophages (TAMs), and dendritic cells (DCs). Preliminary evaluation of patient samples from our clinical trial confirms these findings. Thus, we hypothesize that entinostat decreases MDSC immunosuppression and shifts the phenotype and function of TAMs, and DCs to collectively sensitize the TME to promote an enhanced response to ICIs. The Specific Aims are: 1) to determine the effects of entinostat on the STAT3-NFB-AP-1 axis decreases MDSC-mediated T cell suppression; and 2) to determine the cellular basis of entinostat-induced sensitization of the TME and how it mediates the anti-tumor response to ICIs. Our unique bidirectional approach combining preclinical studies, e.g., mouse models and mathematical modeling, with hypothesis-driven correlative investigations in patients, and vice versa, strengthens our ability to uncover the molecular and TME mechanisms driving clinical responses. These studies will reveal if changes in myeloid suppression and/or tumor- immune dynamics inform response to therapy or survival, while identification of new biomarkers may improve patient stratification for future trials.

项目总结