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

• 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
• 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

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.

项目摘要 髓系免疫抑制由巨噬细胞和单核细胞驱动，是一种已知的内在机制。 对免疫检查点抑制(ICI)的抵抗，这在 晚期癌症患者，但大多数乳腺癌患者不是。我们的实验室在 证明通过降低未成熟髓系的功能来靶向髓系免疫抑制 摘要衍生抑制细胞是一种新的、重要的肿瘤增敏策略。 改善乳腺癌患者的微环境(TME)和改善对ICIS的反应。我们发表了两篇临床前研究报告 研究表明，组蛋白脱乙酰酶I类抑制剂Eninostat可降低MDSC对 此外，内抑素与ICIS nivolumab和ipilimumab联合使用可提高小鼠的存活率 乳腺癌的模型。这为我们的I期临床试验(NCI-9844)提供了强有力的理由，在该试验中，我们 确定了这种治疗的推荐第二阶段剂量(RP2D)，给予晚期固体患者 肿瘤，包括10/33的乳腺癌患者，作为内抑素治疗前两周，随后 恩替比妥+尼伏卢单抗+伊普利单抗联合用药。此外，总应答率(ORR)为30% 在接受RP2D治疗的20名晚期乳腺癌患者的扩大队列中观察。 然而，我们尚未了解内抑素是如何减少髓系抑制以实现TME的。 敏感化导致了对ICIS的这种引人注目的反应。 临床前模型中的初步数据显示，内抑素1)降低了血管内皮细胞的抑制功能 肿瘤MDSCs；2)减少STAT3-NFkB-AP-1信号轴的激活；3)改变STAT3-NFkB-AP-1信号轴 其他髓系细胞，包括肿瘤相关巨噬细胞的表型和/或在TME内的渗透 (TAMS)和树突状细胞(DC)。对我们临床试验的患者样本的初步评估证实了这些 调查结果。因此，我们假设内抑素减少了对MDSC的免疫抑制并转移了 TAMs的表型和功能，以及DC集体敏化TME以促进增强 对ICIS的回应。具体目的是：1)确定内抑素对STAT3-NFB-AP-1的影响 AXIS减少MDSC介导的T细胞抑制；2)确定内抑素诱导的细胞基础 TME的增敏作用及其如何介导ICIS的抗肿瘤反应。我们独特的双向方法 结合临床前研究，例如小鼠模型和数学建模，与假设驱动 在患者中的相关研究，反之亦然，加强了我们发现分子和TME的能力 驱动临床反应的机制。这些研究将揭示如果髓系抑制和/或肿瘤的变化- 免疫动力学为治疗或生存反应提供信息，而新生物标记物的识别可能会有所改善 为将来的试验进行患者分层。