Towards True Precision Oncology: Validation of a Comprehensively Humanized, Autologous Mouse Model

项目总结/摘要 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 系统该提案的主要目的是验证体内模型，以评估人类肿瘤在 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， 时尚.在此，我们提出：（1）验证从患有以下疾病的患者建立人源化小鼠的能力： 黑色素瘤;（2）评估自体人黑色素瘤肿瘤中的肿瘤生长和淋巴细胞发育 在人源化小鼠中建立;和（3）验证该人源化系统作为以下模型的能力： 癌症免疫治疗反应和毒性。在每一个领域，我们将利用我们的多- 机构团队的个人专业知识沿着我们的机构基础设施，以最大限度地提高成功的 实验目的此外，我们将参加肿瘤模型论坛，并利用NCIP Hub 资源，以确保该项目产生的方法，数据和生物模型系统是 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。

PROJECT SUMMARY/ABSTRACT 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 immunodeficient 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. Herein, we propose to: (1) validate the ability to establish humanized mice from patients with melanoma; (2) evaluate tumor growth and lymphocyte development in autologous human melanoma tumors established in humanized mice; and (3) validate the ability of this humanized system to serve as a model for cancer immunotherapy treatment response and toxicity. 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. Furthermore, we will participate in the Oncology Models Forum and utilize the NCIP Hub resources to ensure that the methodology, data, and biologic model systems that result from this project are 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.