Advancing Precision Oncology in a Humanized, Fully Autologous Mouse Model

癌症早期发现和治疗的进展需要准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很有吸引力 原因有很多，包括它们的易用性和良好的平台。免疫疗法已经 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。生长人类肿瘤的能力 在免疫缺陷小鼠中(所谓的患者来源的异种移植，或PDX)允许研究人员直接与 在受控环境下的人类癌症组织。然而，PDX模型由于缺乏完整的免疫力而受到限制 系统。这项建议的广泛目标是验证体内模型以评估人类肿瘤 在一个完全个性化和自体的环境中完整和完整的人类免疫系统 研究癌症免疫疗法的时尚。在此，我们建议：(1)验证我们人性化的能力 系统作为癌症免疫治疗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，以及(2)延长我们目前的 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来研究黑色素瘤 在人源化小鼠体内建立的自体人胰腺和结直肠肿瘤的研究进展。 在这些领域中的每一个领域，我们将利用我们多机构团队的个人专业知识以及我们的 制度基础设施，以最大限度地实现试验目标的成功。这个项目的结果将是 广泛提供给普通研究界，用于未来以假设为导向的研究。加在一起， 这项研究提案中描述的研究将达到多个目标，并解决几个未得到满足的需求 在此赠款机会中确定的，从而显著增强了完全自体和 用于翻译肿瘤学研究的免疫活性精确模型系统。

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.