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: 10359704
• 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/10359704
• 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; Development; Early Diagnosis; Early treatment; Evaluation; Exposure to; Frequencies; Funding; Future; Goals; Grant; Human; Human Biology; Immune; Immune response; Immune system; Immunocompetent; Immunological Models; Immunotherapy; Individual; Infrastructure; 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; 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; base; cancer immunobiology; cancer immunotherapy; cancer therapy; checkpoint therapy; chemoradiation; 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.

早期检测和治疗癌症的进展需要准确的模型系统才能进一步评估 新的，有前途的发现。小动物，尤其是鼠标，模型系统对研究人员有吸引力 由于许多原因，包括它们的易用性和描述良好的平台。免疫疗法具有 彻底改变了临床肿瘤学，但缺乏人类免疫系统和人类癌症的临床前模型 研究治疗方案的新方式和局限性/毒性。增长人类肿瘤的能力 在免疫缺陷型小鼠（所谓的患者衍生异种移植物或PDXS）中，研究人员可以直接与 在受控环境中的人类癌组织。但是，PDX模型受其缺乏完整免疫的限制 系统。该提案的广泛目的是验证一个体内模型来评估人类肿瘤 完全个性化和自体的完整且完整的人类免疫系统的背景 研究癌症免疫疗法的时尚。在此，我们建议：（1）验证人源化的能力 作为癌症免疫疗法治疗反应和毒性的模型的系统 黑色素瘤，包括免疫疗法检查点阻滞和疫苗策略，并扩展我们的电流 通过验证建立人源性小鼠并评估肿瘤生长和白细胞的能力，在黑色素瘤中工作 在人源性小鼠中建立的自体胰腺和结直肠肿瘤的发育。 在这些领域的每个领域中，我们将利用我们的多机构团队的个人专业知识以及我们的 制度基础设施，以最大程度地提高实验目的的成功。这个项目的结果将 可为普通研究社区广泛使用，以供假设驱动的研究未来。在一起， 本研究建议中描述的研究将满足多个目标，并满足几个未满足的需求 在此赠款机会中确定，因此可以显着增强完全自体和的适用性 免疫能力的精确模型系统用于翻译肿瘤学研究。