Advancing Precision Oncology in a Humanized, Fully Autologous Mouse Model

在人性化、完全自体小鼠模型中推进精准肿瘤学

• 批准号: 10611842
• 负责人: Ryan C Fields
• 金额: $ 58.7万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10611842
• 关键词: Adaptive Immune System; Address; Animals; Antigens; Area; Autologous; Biological Models; Biology; Bone Marrow; CD34 gene; Cancer Model; Cells; Clinical Oncology; Collaborations; Colorectal Cancer; Colorectal Neoplasms; Communities; Credentialing; Development; Early Diagnosis; Early treatment; Evaluation; Exposure to; Frequencies; Funding; Future; Goals; Grant; Human; Human Biology; Immune; Immune response; Immune system; Immunocompetent; Immunologic Deficiency Syndromes; Immunological Models; Immunotherapy; Individual; Infrastructure; Innate Immune System; Institution; Leukocytes; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of pancreas; Measures; Modality; Modeling; Monitor; Morbidity - disease rate; Mus; Neoplasm Metastasis; Oncology; Patient-Focused Outcomes; Patients; Phenotype; Pre-Clinical Model; Progressive Disease; Radiation therapy; Regimen; Research; Research Personnel; Research Proposals; Resources; Source; Structure; System; T cell receptor repertoire sequencing; T cell response; T-Lymphocyte; Techniques; Therapeutic; Tissues; Toxic effect; Treatment Protocols; Treatment-related toxicity; Vaccine Design; Work; anti-CTLA4; anti-PD1 therapy; anticancer research; antigen-specific T cells; cancer immunobiology; cancer immunotherapy; cancer therapy; checkpoint therapy; effector T cell; human model; humanized mouse; immune checkpoint blockade; improved; in vivo Model; melanoma; mouse model; mutant; neoantigens; novel; pancreatic neoplasm; patient derived xenograft model; patient response; peptide based vaccine; peptide vaccination; pre-clinical; precision oncology; predicting response; response; success; translational oncology; treatment response; tumor; tumor growth; vaccine strategy

Progress in the early detection and treatment of cancer requires accurate model systems to further evaluate new, promising discoveries. Small animal, and in particular mouse, model systems are attractive to researchers for numerous reasons, including their ease of use and well-described platforms. Immunotherapy has revolutionized clinical oncology, but lacks pre-clinical models of the human immune system and human cancer to investigate new modalities and limitations/toxicities of treatment regimens. The ability to grow human tumors in immune-deficient mice (so-called patient-derived xenografts, or PDXs) allows researchers to work directly with human cancer tissue in a controlled setting. However, PDX models are limited by their lack of an intact immune system. The broad objective of this proposal is to validate an in vivo model to evaluate human tumors in the context of a complete and intact human immune system in a completely personalized and autologous fashion to study cancer immunotherapy. Herein, we propose to: (1) validate the ability of our humanized system to serve as a model for cancer immunotherapy treatment response and toxicity in patients with melanoma, including immunotherapy checkpoint blockade and vaccine strategies, and to (2) extend our current work in melanoma by validating the ability to establish humanized mice and evaluate tumor growth and leukocyte development in autologous human pancreatic and colorectal tumors established in humanized mice. In each of these areas, we will leverage our multi-institutional team's individual expertise along with our institutional infrastructure to maximize the success of the experimental aims. The results from this project will made widely available to the general research community for future, hypothesis-driven research. Taken together, the studies described in this research proposal will meet multiple goals and address several unmet needs identified in this grant opportunity, thus significantly enhancing the applicability of a fully autologous and immunocompetent precision model system for use in translational oncology research.

癌症早期发现和治疗的进展需要精确的模型系统来进一步评估 新的有希望的发现小动物，特别是小鼠，模型系统对研究人员具有吸引力 原因有很多，包括它们的易用性和描述良好的平台。免疫治疗已 革命性的临床肿瘤学，但缺乏人类免疫系统和人类癌症的临床前模型 研究治疗方案的新模式和局限性/毒性。人类肿瘤生长的能力 在免疫缺陷小鼠（所谓的患者来源的异种移植物，或PDX）中， 人类癌症组织的一种控制性的方法。然而，PDX模型受到缺乏完整免疫的限制 系统该提案的广泛目标是验证体内模型，以评估人类肿瘤的生物学特性。 在完全个性化和自体免疫系统中的完整和完整的人类免疫系统的背景下， 研究癌症免疫疗法的时尚。在此，我们建议：（1）验证我们的人性化的能力， 系统作为癌症免疫疗法治疗反应和毒性的模型， 黑色素瘤，包括免疫治疗检查点封锁和疫苗策略，并（2）扩大我们目前的 通过验证建立人源化小鼠和评估肿瘤生长和白细胞的能力， 在人源化小鼠中建立的自体人胰腺和结肠直肠肿瘤中的发育。 在每个领域，我们将利用我们的多机构团队的个人专长，沿着我们的 体制基础设施，以最大限度地成功的实验目标。该项目的成果将 广泛提供给一般研究界，用于未来的假设驱动的研究。综合起来看， 本研究计划中所描述的研究将满足多个目标，并解决几个尚未满足的需求 在这个赠款机会中确定，从而大大提高了完全自体和 用于转化肿瘤学研究的免疫活性精确模型系统。