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.

项目概要由巨噬细胞和单核细胞驱动的骨髓免疫抑制是一种已知的内在机制。对免疫检查点抑制（ICI）的抵抗，它在以下方面提供了显着且持久的反应：晚期癌症患者，但不是大多数乳腺癌患者，我们的实验室在这方面发挥了重要作用。证明通过降低未成熟骨髓细胞的功能来靶向骨髓免疫抑制衍生抑制细胞（MDSC）是一种新颖且重要的肿瘤致敏策略我们发表了两篇临床前研究文章。研究表明，entinostat（一种 I 类组蛋白脱乙酰酶抑制剂）可减少 MDSC 抑制此外，恩替司他与 ICI 纳武单抗和易普利姆玛联合使用可改善小鼠的存活率这为我们的 I 期临床试验 (NCI-9844) 提供了强有力的理由。确定了该治疗的推荐 2 期剂量 (RP2D)，给予晚期实体瘤患者肿瘤，包括 10/33 的乳腺癌，用恩替司他进行两周的预处理，然后进行此外，恩替司他 + 纳武单抗 + 伊匹单抗组合的总体缓解率 (ORR) 为 30%。在一项由 20 名接受 RP2D 的晚期乳腺癌患者组成的扩展队列中进行观察。然而，我们尚未了解恩替司他如何减少骨髓抑制以实现 TME 导致对 ICI 做出如此惊人反应的敏感性。临床前模型中的初步数据表明恩替司他 1) 降低了体内的抑制功能肿瘤 MDSC；2) 降低 STAT3-NFkB-AP-1 信号轴的激活；3) 改变其他骨髓细胞（包括肿瘤相关巨噬细胞）在 TME 内的表型和/或浸润 (TAM) 和树突状细胞 (DC) 对我们临床试验中患者样本的初步评估证实了这些。因此，我们研究恩替司他可以减少 MDSC 免疫抑制并改变 MDSC 的免疫抑制。 TAM 和 DC 的表型和功能共同使 TME 敏感，以促进增强对 ICI 的反应具体目标是： 1) 确定恩替司他对 STAT3-NFB-AP-1 的影响。轴减少 MDSC 介导的 T 细胞抑制；2) 确定恩替司他诱导的细胞基础 TME 的敏化及其如何介导 ICI 的抗肿瘤反应我们独特的双向方法。将临床前研究（例如小鼠模型和数学建模）与假设驱动相结合对患者进行相关研究，反之亦然，增强了我们揭示分子和 TME 的能力这些研究将揭示骨髓抑制和/或肿瘤的变化。免疫动力学告知对治疗或生存的反应，而新生物标志物的识别可能会改善未来试验的患者分层。