Synergized Immune and Tumor Cell Bone Marrow Biomarkers to Predict Recurrence in Triple Negative Breast Cancer

协同免疫和肿瘤细胞骨髓生物标志物可预测三阴性乳腺癌的复发

• 批准号: 10279058
• 负责人: Rebecca L. Aft
• 金额: $ 62.98万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10279058
• 关键词: Address; Affect; Biological; Biological Assay; Biological Markers; Bone Marrow; Breast Cancer Patient; Breast Cancer therapy; Carboplatin; Cell Communication; Cells; Clinical; Cytotoxic Chemotherapy; Data; Dendritic Cells; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Resistance; Distant; Enrollment; Environment; Funding; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Goals; Heterogeneity; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunologic Markers; Immunotherapy; In complete remission; Individual; Intervention; Lead; Macrophage Colony-Stimulating Factor Receptor; Methods; Molecular; Molecular Profiling; Neoadjuvant Therapy; Neoplasm Metastasis; Newly Diagnosed; Nivolumab; Paclitaxel; Pathologic; Pathway interactions; Patients; Phase; Phenotype; Population; Primary Neoplasm; Randomized; Recurrence; Recurrent disease; Relapse; Residual Tumors; Residual state; Risk; Selection for Treatments; Specimen; T-Lymphocyte; Testing; Therapeutic Intervention; Therapeutic Trials; Tumor-infiltrating immune cells; Validation; base; biobank; biomarker development; biomarker panel; checkpoint therapy; chemotherapy; cohort; combinatorial; cytotoxic; diagnostic assay; digital; gene panel; improved; insight; malignant breast neoplasm; metastatic process; molecular phenotype; mortality; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; phase II trial; prevent; prognostic; prospective; response; risk stratification; single cell sequencing; standard of care; targeted treatment; therapy resistant; tool; triple-negative invasive breast carcinoma; tumor; tumor-immune system interactions

Project Summary/Abstract Triple negative breast cancer (TNBC) is aggressive and a large percentage of patients develop metastatic disease. Disseminated tumor cells (DTCs) found in the bone marrow (BM) of TNBC patients may be the intermediaries of the metastatic process. Data from our lab as well as others suggest that the immune landscape of BM may influence DTC latency, treatment resistance, and metastatic potential. We have already defined and validated an 8 gene expression-based biomarker panel that can detect DTCs in the BM of treatment naïve TNBC patients and that predicts development of distant metastatic disease. Our recent data indicate that TNBC patients with DTC-positive BM have altered populations of immune cell precursors and this is associated with recurrent disease development. Based on these findings, we hypothesize that immune checkpoint inhibitors will facilitate the elimination of BM DTCs in TNBC patients by altering the immune microenvironment in patients with specific DTC and/or BM immune cell populations, and that cell population-specific gene expression signatures can predict which patients will benefit most from aggressive immunotherapy to prevent metastatic disease relapse. We will test this hypothesis using our extensive biorepository of BM specimens collected from TNBC patients who received conventional chemotherapy, as well as prospectively collected specimens from TNBC patients participating in an independently funded institutional phase II immune checkpoint inhibitor (ICI) trial of carboplatin/paclitaxel/nivolumab with or without cabiralizumab. Our goals are: 1. To evaluate the ability of our 8- gene DTC gene panel to predict distant disease development in TNBC patients enrolled in our ICI therapeutic trial of carboplatin/paclitaxel/nivolumab with or without cabiralizumab; 2. To understand the specific subpopulations of BM DTCs in TNBC patients treated with conventional chemotherapy and ICI therapy which are resistant to therapy, and; 3. To understand alterations in specific T cell and conventional dendritic cell (cDC) populations in the BM when DTCs are present, and how this is impacted by conventional and ICI therapy. The results of this proposal will lead to a greater understanding of immune escape and heterogeneity of BM micrometastatic disease as well as biomarkers for improving conventional and ICI therapy in TNBC patients.

项目摘要/摘要 三阴性乳腺癌(TNBC)具有侵袭性，很大比例的患者发生转移。 疾病。在TNBC患者骨髓中发现的播散性肿瘤细胞(DTC)可能是 转移过程的中间体。来自我们实验室和其他实验室的数据表明，免疫环境 BM的发生可能影响DTC潜伏期、治疗耐药和转移潜能。我们已经定义了 验证了一个基于8基因表达的生物标志物小组，该小组可以检测治疗初治TNBC的骨髓中的DCs 这预示着远处转移性疾病的发展。我们最近的数据表明，TNBC患者 在DTC阳性的骨髓中，免疫细胞前体的数量发生了变化，这与复发有关 疾病的发展。基于这些发现，我们假设免疫检查点抑制剂将 通过改变免疫微环境促进TNBC患者骨髓DTCs的消除 具有特定DTC和/或BM免疫细胞群以及该细胞群特定基因的患者 表情特征可以预测哪些患者将从积极的免疫治疗中受益最大 防止转移的疾病复发。 我们将使用我们从TNBC患者收集的大量BM样本来验证这一假设 世卫组织接受了常规化疗，并预期从TNBC患者那里收集样本 参与一项独立资助的机构第二阶段免疫检查点抑制剂(ICI)试验 卡铂/紫杉醇/尼伏单抗加或不加Cabiralizumab。我们的目标是：1.评估我们的8- 基因DTC基因面板用于预测接受ICI治疗的TNBC患者的远处疾病发展 卡铂/紫杉醇/尼伏鲁单抗与或不与Cabiralizumab联合试验；2.了解特异性 接受常规化疗和ICI治疗的TNBC患者的骨髓DTCs亚群 耐药，以及；3.了解特定T细胞和常规树突状细胞(CDC)的变化 当DTC存在时，骨髓中的人群，以及这是如何受到常规和ICI治疗的影响的。这个 这一建议的结果将有助于更好地理解骨髓的免疫逃逸和异质性 微转移疾病以及改善TNBC患者常规和ICI治疗的生物标志物。