Autologous Humanized Mouse Model of Non-Small Cell Lung Cancer (NSCLC) to Investigate the Tumor-Immune Landscape and Its Response to Treatment

非小细胞肺癌 (NSCLC) 自体人源化小鼠模型，用于研究肿瘤免疫景观及其对治疗的反应

• 批准号: 10019482
• 负责人: Michael Chiorazzi
• 金额: $ 14.82万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-17 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10019482
• 关键词: Active Immunotherapy; Address; Allogenic; Animal Model; Antibody Therapy; Antineoplastic Agents; Aspirate substance; Autologous; B-Lymphocytes; Biological; Biopsy; Blood; Bone Marrow; Cancer Etiology; Cancer Patient; Cells; Clinical; Clinical Trials; Complex; Data; Development; Doctor of Philosophy; Drug usage; Engraftment; Exhibits; Failure; Flow Cytometry; Functional disorder; Genetic; Genetic Transcription; Genomic approach; Genomics; Goals; Growth; Growth Factor; Harvest; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic System; Hematopoietic stem cells; Human; Immune; Immune System Diseases; Immune system; Immunofluorescence Immunologic; Immunooncology; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Individual; Innate Immune System; Institutional Review Boards; Intervention; Knowledge; Light; Location; Manuscripts; Medical Oncology; Mentorship; Methods; Minority; Modeling; Mus; Myeloid Cells; Natural Killer Cells; Non-Small-Cell Lung Carcinoma; Operative Surgical Procedures; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Physicians; Physiological; Population; Postdoctoral Fellow; Pre-Clinical Model; Preparation; Principal Investigator; Proteomics; Protocols documentation; Research; Research Personnel; Role; Sampling; Scientist; System; T-Lymphocyte; Time; Tissues; Training; Treatment Failure; Tumor Promotion; Tumor-associated macrophages; Tumor-infiltrating immune cells; Vascular Endothelial Growth Factors; Xenograft Model; Xenograft procedure; anti-PD-L1; bevacizumab; career; drug action; drug efficacy; exhaust; exhaustion; genomic data; humanized mouse; improved; improved outcome; individual patient; macrophage; melanoma; mortality; mouse development; mouse model; neoplastic cell; patient response; peripheral blood; receptor; response; single cell analysis; treatment response; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions

PROJECT SUMMARY Non-small cell lung cancer (NSCLC) remains the major cause of cancer mortality across the globe, despite exciting advances in immune-based therapies. These therapies, while dramatically effective in some patients, are ineffective in the majority of NSCLC patients. The causes of treatment failure remain incompletely understood, as is the role of the local tumor microenvironment (TME) in influencing tumor growth, both in the presence and absence of these therapies. To better study human tumor-immune interactions and immunotherapeutics, we have developed a humanized mouse model that supports the engraftment of mice bearing a matched human hematopoietic system and tumor from an individual NSCLC patient. In addition, this model is unique in its support of functional myeloid cells as part of the innate immune system. We propose to use these autologously-engrafted humanized NSCLC PDX models to study the TME in detail, employing flow cytometric, immunostaining and single cell genomic analyses to characterize the transcriptional and proteomic states of the cells present. We will correlate tumor growth to specific cell populations identified with these methods, enhancing our understanding of the pathways active in tumor- vs blood-resident immune cells, and identifying established and possibly new networks of immune dysfunction in the TME. Armed with this knowledge, we will probe the pathways active in these patient models using drugs specific to the immune exhaustion and tumor promoting mechanisms we identify. Our goal is to gain a deeper understanding of how the TME and immunotherapeutics interact, and to develop these immune avatar mice as models that may predict a patient’s response to a particular immunotherapy. The principal investigator is a physician-scientist, with a PhD in genetics and post-doctoral and clinical training in Medical Oncology. His career goal is to become an independent investigator studying tumor-immune interactions. The proposed K08 training plan will provide the candidate with mentorship and coursework to build the expertise necessary to execute the proposed project and become independent in the field of translational immuno-oncology.

项目概要 尽管非小细胞肺癌（NSCLC）仍然是全球癌症死亡的主要原因 这些疗法虽然对某些患者非常有效，但在免疫疗法方面取得了令人兴奋的进展。 对大多数 NSCLC 患者无效 治疗失败的原因仍不完全清楚， 局部肿瘤微环境 (TME) 在影响肿瘤生长方面的作用，无论是存在还是存在 缺乏这些疗法。 为了更好地研究人类肿瘤免疫相互作用和免疫治疗，我们开发了一种人源化药物 支持携带匹配的人类造血系统和肿瘤的小鼠植入的小鼠模型 此外，该模型的独特之处在于它支持功能性骨髓细胞 我们建议使用这些自体移植的人源化 NSCLC PDX。 利用流式细胞仪、免疫染色和单细胞基因组分析详细研究 TME 的模型 为了表征存在的细胞的转录和蛋白质组状态，我们将把肿瘤生长与相关联。 用这些方法鉴定出特定的细胞群，增强了我们对活跃通路的理解 肿瘤免疫细胞与血液驻留免疫细胞，并识别已建立的和可能新的免疫网络 有了这些知识，我们将探索这些患者模型中的活跃通路。 我们的目标是使用针对免疫耗竭药物和我们确定的肿瘤促进机制的药物。 更深入地了解 TME 和免疫治疗如何相互作用，并开发这些免疫化身 小鼠作为模型可以预测患者对特定免疫疗法的反应。 主要研究者是一位医师科学家，拥有遗传学博士学位以及博士后和临床培训 他的职业目标是成为研究肿瘤免疫的独立研究者。 拟议的 K08 培训计划将为候选人提供指导和课程作业来构建。 执行拟议项目并在翻译领域独立所需的专业知识 免疫肿瘤学。