Mechanisms of immunomodulation with epigenetic therapy

表观遗传学治疗的免疫调节机制

• 批准号: 10408082
• 负责人: Nilofer Azad
• 金额: $ 30.68万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10408082
• 关键词: Affect; Biological Models; Biology; Biopsy; Biopsy Specimen; Cell physiology; Cells; Chemoresistance; Clinical; Clinical Data; Clinical Trials; Collaborations; Combination immunotherapy; Combined Modality Therapy; Cytometry; Data; Epigenetic Process; Foundations; Funding; Future; Goals; Histone Deacetylase; Histone Deacetylase Inhibitor; Human; Immune; Immune System Diseases; Immune Targeting; Immune checkpoint inhibitor; Immune response; Immune system; Immunization; Immunohistochemistry; Immunology procedure; Immunosuppression; Immunotherapy; Inflammatory; Investigation; Learning; Ligands; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metastatic Pancreatic Adenocarcinoma; Molecular; Mus; Mutation; Myelogenous; Myeloid-derived suppressor cells; Natural Selections; Nivolumab; Pancreatic Adenocarcinoma; Pathway interactions; Patients; Population; Pre-Clinical Model; Process; Regulation; Reporting; Role; STAT3 gene; Signal Pathway; Signal Transduction; Stromal Cells; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Therapeutic Trials; Tissues; Transcriptional Regulation; Translating; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; Vaccines; Work; anti-PD-1; anti-PD1 therapy; antitumor effect; base; cell stroma; cell type; epigenetic silencing; epigenetic therapy; experience; human model; immunoregulation; improved outcome; in vivo Model; inhibitor; inhibitor therapy; mouse model; neoantigens; neoplastic cell; novel; pancreatic cancer cells; pancreatic cancer model; pancreatic cancer patients; pre-clinical; programmed cell death protein 1; resistance mechanism; responders and non-responders; response; single cell analysis; synergism; targeted agent; trafficking; transcriptome sequencing; tumor; tumor microenvironment; tumor-immune system interactions; vaccine development

Project Summary/Abstract Immune checkpoint inhibitors (ICI) targeting programmed cell death protein 1 (PD-1) or its ligand have produced unprecedented clinical benefit for some cancers but have failed in others including pancreatic adenocarcinoma (PDA). PDAs display low T cell infiltration and high numbers of immunosuppressive cell types including myeloid- derived suppressor cells (MDSCs). Combination approaches that reverse the intrinsic immunosuppressive biology of PDA will be key to converting PDA into an ICI-sensitive tumor type. Our group and others reported that epigenetic therapies can influence both tumors and other cells in the tumor microenvironment (TME), including immune and stromal cells. We reported that the histone deacetylase inhibitor (HDACi) entinostat modulates myeloid-derived suppressor cells (MDSCs), resulting in a less immunosuppressive population. We have translated these preclinical findings into an ongoing clinical trial of entinostat in combination with the PD-1 inhibitor nivolumab, on which we have observed multiple clinical responses in metastatic PDA patients. The current proposal builds upon our existing pre-clinical data to answer important mechanistic questions as to how epigenetic modulatory therapies reprogram the TME for systemic immunotherapy. We hypothesize that HDACi therapy can modulate multiple inflammatory, stromal and tumor cells in the PDA TME, converting PDA tumors from immune excluding into immune responsive cancers. We will first evaluate HDACi modified pathways from our preclinical findings to further identify specific pathways that are altered by HDACi. This work will specifically test the hypothesis generated from our preliminary data that STAT3 modulation mediates entinostat’s effects on MDSC function through regulation of multiple inflammatory pathways, resulting in the antitumor effect seen when given in combination with anti-PD1 therapy. We will also expand our investigation of the immunomodulatory effects of HDACi to evaluate the effect of entinostat on focused immune populations that receive signals from MDSCs. We will use our preclinical models to test the hypothesis that entinostat uncovers mutation-associated pancreatic cancer neoantigens that can augment antitumor immunity alone or in combination with systemic immunotherapies. We will confirm our preclinical findings using our unique biospecimens collected from our ongoing clinical trial of entinostat in combination with anti-PD1 therapy in PDA that is banking serial biopsies at baseline, after entinostat monotherapy and after combination therapy, allowing assessment of the immune impact of HDACi alone and in combination with ICI on the TME. In addition, we hope to build upon our clinical experience with entinostat plus nivolumab by studying rational combinations of additional novel agents, providing a preclinical basis for future therapeutic trials.

项目总结/摘要 靶向程序性细胞死亡蛋白1（PD-1）或其配体的免疫检查点抑制剂（ICI）已经产生了 对某些癌症有前所未有的临床益处，但对包括胰腺癌在内的其他癌症却失败了 （PDA）。PDA显示低T细胞浸润和高数量的免疫抑制细胞类型，包括髓样细胞。 衍生的抑制细胞（MDSC）。逆转内在免疫抑制的联合方法 PDA的生物学特性将是将PDA转化为ICI敏感性肿瘤类型的关键。我们小组和其他人报告说， 表观遗传疗法可以影响肿瘤和肿瘤微环境（TME）中的其他细胞， 包括免疫细胞和基质细胞。我们报道了组蛋白去乙酰化酶抑制剂（HDACi）恩替诺特， 调节骨髓来源的抑制细胞（MDSC），导致免疫抑制性较低的群体。我们 已经将这些临床前发现转化为正在进行的恩替司他与PD-1联合的临床试验 抑制剂nivolumab，我们已经在转移性PDA患者中观察到多种临床反应。的 目前的建议建立在我们现有的临床前数据，以回答重要的机制问题， 表观遗传调节疗法重新编程TME用于全身免疫疗法。我们假设HDACi 治疗可以调节PDA TME中的多种炎性细胞、基质细胞和肿瘤细胞， 从免疫排斥转变为免疫反应性癌症。我们将首先评估HDACi修饰的途径， 我们的临床前研究结果，以进一步确定特定的途径，改变了HDACi。这项工作将具体 检验从我们的初步数据中产生的假设，即STAT 3调节介导恩替司他的作用， MDSC通过调节多种炎症途径发挥作用，导致在以下情况下观察到的抗肿瘤作用： 与抗PD 1治疗联合给药。我们还将扩大对免疫调节的研究， HDACi的作用，以评估恩替司他对接收来自HDACi的信号的聚焦免疫群体的作用。 MDSC。我们将使用我们的临床前模型来检验恩替司他揭示突变相关性的假设。 胰腺癌新抗原可单独或与全身性抗肿瘤免疫联合增强抗肿瘤免疫 免疫疗法我们将使用从我们的研究中心收集的独特生物标本来确认我们的临床前发现。 正在进行的恩替司他联合抗PD 1治疗PDA的临床试验，正在进行系列活检 基线、恩替司他单药治疗后和联合治疗后，允许评估免疫 HDACi单独和与ICI组合对TME的影响。此外，我们希望建立在我们的临床 通过研究其他新型药物的合理组合，获得恩替司他加纳武利尤单抗的经验， 为未来的治疗试验奠定了临床前基础。