Congenic Mouse Medels of Melanoma for the Characterization of Tumor Immune Responses

用于表征肿瘤免疫反应的黑色素瘤同源小鼠模型

• 批准号: 9103532
• 负责人: MARCUS W BOSENBERG
• 金额: $ 55.09万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9103532
• 关键词: Address; Animal Model; Antigens; Autoimmune Process; Bladder; Breast; Cancer Immunology Science; Cancer Model; Cell Line; Cells; Clinical Trials; Colon; Congenic Mice; Cytotoxic T-Lymphocyte-Associated Protein 4; Development; Distant; Employee Strikes; Ensure; Evaluation; Flow Cytometry; Generations; Genetic Engineering; Genetic Models; Genetic Variation; Genetically Engineered Mouse; Genotype; Growth; Head and neck structure; Human; Immune; Immune response; Immune system; Immunotherapy; Inbred Mouse; Injection of therapeutic agent; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Malignant neoplasm of urinary bladder; Melanoma Cell; Metastatic Melanoma; Metastatic malignant neoplasm to brain; Modeling; Mus; Mutagenesis; Mutation; Neoplasm Metastasis; Organ; Ovarian; Patients; Play; Research Personnel; Role; Sampling; Secondary to; Series; Signal Transduction; Site; Skin; Skin Cancer; Somatic Mutation; Study models; System; Therapeutic; Time; Translations; Validation; base; cancer cell; cancer therapy; combat; congenic; immunogenicity; inhibitor/antagonist; interest; kidney cell; malignant breast neoplasm; melanocyte; melanoma; mouse model; novel; oncology; partial response; patient subsets; public health relevance; quantitative imaging; recombinase-mediated cassette exchange; research clinical testing; research study; response; therapeutic target; treatment response; tumor; tumor immunology

 DESCRIPTION (provided by applicant): There has been longstanding interest in the relationship between the immune system and malignant melanoma, the deadliest form of skin cancer. Melanoma has been the tumor of choice for the evaluation of a wide variety of therapeutic approaches that rely on stimulation of the immune system to combat cancer. Early clinical trials of modulators of immune checkpoints, including agents that block CTLA-4 and PD-1 signaling, focused on melanoma for the evaluation of clinical responses. The striking responses to immune checkpoint inhibitors noted in some melanoma patients have now been observed in several other malignancies, including renal cell, lung, breast, bladder, and prostate cancer. These findings are very encouraging, however the specific mechanisms of response and reasons why only a subset of patients respond to therapy are not known. Based on the critical role that mouse models played in the identification of CTLA-4 and PD-1 as immune checkpoints and therapeutic targets in cancer, it is likely that human-relevant animal models will be required to understand mechanisms of response and to optimize therapy so that a larger proportion of patients respond. We have generated a series of genetically engineered mouse models that reflect the genetic diversity of human melanoma and isolated corresponding congenic melanoma cells lines that form tumors following injection into immune competent C57Bl/6J mice. The genetic models and series of congenic lines represents an ideal set of models for the study of cancer immunology and response to immune therapies. We propose to characterize and validate these melanoma models, evaluate the effects of tumor genotype and mutational burden, and compare immune responses with those seen in human melanoma. Furthermore, we propose to characterize immune responses in novel melanoma brain metastasis and systemic metastasis models. We will make all of the findings and approaches available through the Oncology Models Forum.

 描述（由申请人提供）：长期以来，人们一直对免疫系统与恶性黑色素瘤（最致命的皮肤癌形式）之间的关系感兴趣。黑色素瘤一直是评估依赖于刺激免疫系统来对抗癌症的各种治疗方法的首选肿瘤。免疫检查点调节剂（包括阻断CTLA-4和PD-1信号传导的药物）的早期临床试验集中在黑色素瘤上，以评估临床反应。在一些黑色素瘤患者中观察到的对免疫检查点抑制剂的显著反应现在已经在其他几种恶性肿瘤中观察到，包括肾细胞癌、肺癌、乳腺癌、膀胱癌和前列腺癌。这些发现是非常令人鼓舞的，但是具体的反应机制和为什么只有一部分患者对治疗有反应的原因尚不清楚。基于小鼠模型在鉴定CTLA-4和PD-1作为免疫检查点和癌症治疗靶点方面发挥的关键作用，可能需要人类相关的动物模型来了解反应机制并优化治疗，以便更大比例的患者有反应。我们已经产生了一系列的基因工程小鼠模型，反映了人类黑色素瘤的遗传多样性，并分离出相应的同源黑色素瘤细胞系，这些细胞系在注射到免疫活性C57 Bl/6 J小鼠后形成肿瘤。遗传模型和一系列同源系代表了研究癌症免疫学和对免疫疗法的反应的理想模型集。我们建议表征和验证这些黑色素瘤模型，评估肿瘤基因型和突变负荷的影响，并将免疫反应与人类黑色素瘤中观察到的免疫反应进行比较。此外，我们建议在新的黑色素瘤脑转移和全身转移模型的免疫反应的特点。我们将通过肿瘤学模型论坛提供所有的发现和方法。