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 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源性免疫抑制机制。 对免疫检查点抑制（ICI）的抗性，这在免疫系统中提供了显著和持久的反应。 晚期癌症患者，但不是大多数乳腺癌患者。我们的实验室一直致力于 这表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（MDSCs）是一种新的重要的肿瘤增敏策略， 微环境（TME）和改善乳腺癌对ICI的反应。我们发表了两篇临床前 研究表明，恩替司他，一种I类组蛋白脱乙酰酶抑制剂，降低了MDSC对 此外，将恩替司他与ICI纳武单抗和伊匹单抗组合改善了小鼠T细胞的存活率。 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， 确定了该治疗的推荐II期剂量（RP 2D），给予晚期实体瘤患者 肿瘤，包括10/33的乳腺癌，作为恩替司他的两周预治疗，随后是 恩替司他+纳武单抗+伊匹单抗的组合。此外，总体缓解率（ORR）为30%， 在接受RP 2D的20例晚期乳腺癌患者的扩展队列中观察到。 然而，我们还没有了解恩替诺特如何减少骨髓抑制以实现TME。 这种敏感性导致了对ICIs的显著反应。 临床前模型中的初步数据表明，恩替司他1）降低了细胞内分泌的抑制功能， 肿瘤MDSC; 2）减少STAT 3-NFkB-AP-1信号传导轴的活化;和3）改变肿瘤MDSC的细胞增殖。 表型和/或其他骨髓细胞（包括肿瘤相关巨噬细胞）的TME内浸润 （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 调查结果。因此，我们假设恩替司他降低MDSC免疫抑制，并改变MDSC的免疫功能。 表型和功能的TAM，和DC共同敏化TME，以促进增强的 对ICI的回应具体目的是：1）确定恩替司他对STAT 3-NF κ B-AP-1的影响 轴降低MDSC介导的T细胞抑制;和2）确定恩替司他诱导的T细胞抑制的细胞基础。 TME的致敏性及其如何介导对ICI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，假设驱动 患者的相关研究，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，而新生物标志物的鉴定可能会改善 患者分层，以便将来进行试验。