Development of an autologous humanized model of melanoma exploring human thymic education capacity

开发黑色素瘤自体人源化模型，探索人类胸腺教育能力

• 批准号: 9752259
• 负责人: Antonio Jimeno
• 金额: $ 58.08万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752259
• 关键词: Address; Adult; Affect; Antigens; Autologous; Benchmarking; Biological Assay; Biological Models; Biology; Biopsy; Bone Marrow; CD34 gene; CD8-Positive T-Lymphocytes; CSF3 gene; CTLA4 gene; Cells; Clinical Data; Clinical Trials; Data; Development; Education; Engraftment; Enrollment; Epithelium; Exposure to; Fibrous capsule of kidney; Gene Expression; Genetic; Genetic Drift; Goals; Graft vs Tumor Effect; Growth; Hematopoietic stem cells; Home environment; Human; Immune; Immune Targeting; Immune checkpoint inhibitor; Immune response; Immune system; Immunity; Immunotherapy; Implant; Malignant Neoplasms; Mediating; Melanoma Cell; Mesenchymal; Mesenchymal Stem Cells; Modeling; Monitor; Morphology; Mus; Natural Killer Cells; Nivolumab; Pathway interactions; Patient Education; Patients; Plasma; Play; Predisposition; Refractory; Resistance; Role; SLEB2 gene; Signal Transduction; Source; System; T-Lymphocyte; Testing; Therapy trial; Thymic Tissue; Thymus Gland; Time; Transplantation; Treatment Efficacy; Tumor Cell Line; Validation; anti-tumor immune response; cancer cell; cohort; cytokine; drug efficacy; experimental study; hematopoietic differentiation; host neoplasm interaction; human disease; human model; humanized mouse; improved; improved outcome; in vivo; in vivo Model; induced pluripotent stem cell; inhibitor/antagonist; macrophage; melanoma; mouse model; neoplastic cell; novel strategies; patient response; personalized medicine; precursor cell; predicting response; prevent; prospective; reconstitution; resistance mechanism; response; reverse genetics; self-renewal; therapy outcome; treatment response; tumor; tumor growth

SUMMARY A constraint to studying human cancer is the limited availability of models with appropriate human stroma and immunity. This caveat is particularly relevant for melanoma, given the pivotal role the immune system plays in its development. To address these limitations, we plan to study melanoma biology and therapy in a humanized mouse (HM) model. We initially developed a mis-matched HM (mHM; tumor and hematopoietic stem cells [HSCs] from different sources), and now have generated an autologous HM (aHM; tumor, HSCs and mesenchymal stem cells [MSCs] from the same patient). In HM bearing tumors the human immune and mesenchymal cells from the patient's bone marrow homed into the growing tumor, migrated into the pre- existing mouse stroma, and interacted with the human cancer cells. Tumors grown in HM more closely resembled the originator tumor than those grown in non-HM mice, and the drift in gene expression caused by prior passaging was partially reversed. Signaling in key immune and stroma pathways was more prominent and closely resembled the originator patient in HM vs. non-HM models. The immune cells mounted effective tumor-specific immune responses, mediated by human immune cells including T cells. Significantly, immune responses upon immune therapies in the HM melanoma models showed a correlation with the patient's therapy results. Two salient and under-studied issues limit the wider application of HM: The relevance of the degree of tumor and immune matching, which can affect the faithfulness of immune response, and that can only be appreciated by comparing mHM and aHM. A second criticism to HM is xenogenic education of human T cells on mouse thymic cells, resulting from the lack of a functional human thymus in such models. In this application we will further address the relevance of an autologous versus mis-matched HM to test which approach gives rise to a more representative model of melanoma; secondly, using the same precursor cells from the patient we will reconstitute a functional thymus. The overarching goal of this proposal is to conduct a co-clinical trial where we will accomplish the following: 1) prospectively generate and characterize aHM and mHM from 20 melanoma patients, 2) test which approach yields a more representative melanoma HM model, 3) test in HM the immune drugs (cytotoxic T-lymphocyte-associated protein 4 [CTLA4] and programmed cell death protein 1 [PD-1] inhibitors) that each patient received and correlate with the clinical data, 4) identify the mechanisms involved in resistance to CTLA4/PD-1 inhibitors; and finally as an exploratory Aim in selected cases, we will 5) generate thymic epithelium from the same patient's HSCs that will result in HM with a fully autologous melanoma, thymus and immune system, thus enabling immune cell education in a strictly human context. This project will advance our understanding of the tumor-host interaction in melanoma and human cancer, by better characterizing the interplay between melanoma cells and the immune and stroma systems, leading to the discovery of new approaches to improve personalization of therapy and improve outcomes.

概括 研究人类癌症的限制是具有适当人类基质和的模型的有限可用性 免疫。考虑到免疫系统在 它的发展。为了解决这些局限性，我们计划研究人性化的黑色素瘤生物学和治疗 鼠标（HM）模型。我们最初开发了不匹配的HM（MHM；肿瘤和造血干细胞 [HSC]来自不同来源），现在已经产生了自体HM（AHM；肿瘤，HSC和 来自同一患者的间充质干细胞[MSC]）。在HM轴承肿瘤中，人类免疫和 来自患者骨髓中的间充质细胞被归入生长的肿瘤，迁移到前 现有的小鼠基质，并与人类癌细胞相互作用。在HM中生长的肿瘤更接近 比在非HM小鼠中生长的肿瘤类似于发起肿瘤，并且基因表达的漂移是由 先前的传言部分扭转了。密钥免疫和基质途径中的信号传导更为突出 在HM与非HM模型中与发起人患者非常相似。免疫细胞安装有效 肿瘤特异性免疫反应，由包括T细胞在内的人类免疫细胞介导。显着，免疫 HM黑色素瘤模型中对免疫疗法的反应显示与患者的相关性 治疗结果。两个突出和研究不足的问题限制了HM的更广泛应用： 肿瘤和免疫匹配程度，可能影响免疫反应的忠诚，这可以 只能通过比较MHM和AHM来赞赏。对HM的第二种批评是对人类的特种教育 小鼠胸腺细胞上的细胞是由于在这种模型中缺乏功能性人胸腺所致。在这个 应用程序我们将进一步解决自动群和错误匹配的HM的相关性，以测试哪个 方法引起了更具代表性的黑色素瘤模型。其次，使用相同的前体细胞 从患者那里，我们将重建功能性胸腺。该提议的总体目标是进行 我们将完成以下任务的共同临床试验：1）前瞻性生成和表征Ahm和 来自20名黑色素瘤患者的MHM，2）测试方法产生更具代表性的黑色素HM模型， 3）在HM中测试免疫药物（细胞毒性T淋巴细胞相关蛋白4 [CTLA4]和程序性细胞 死亡蛋白1 [PD-1]抑制剂）每个患者接受并与临床数据相关，4）确定 抗CTLA4/PD-1抑制剂的抗性机制；最后是选定的探索目标 案例，我们将5）从同一患者的HSC产生胸腺上皮，这将导致HM充分 自体黑色素瘤，胸腺和免疫系统，从而实现严格人类的免疫细胞教育 语境。该项目将促进我们对黑色素瘤和人类肿瘤宿主相互作用的理解 通过更好地表征黑色素瘤细胞与免疫和基质系统之间的相互作用，癌症， 导致发现了改善治疗个性化并改善预后的新方法。