Advancing Precision Oncology in a Humanized, Fully Autologous Mouse Model

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. 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. 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 broad objective of this study 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 will: (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 (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 be widely available to the general research community for future, hypothesis-driven research. Taken together, our study will meet multiple goals and address several unmet needs in cancer immunotherapy, thus significantly enhancing the applicability of a fully autologous and immunocompetent precision model system for use in translational oncology research. ]]>

癌症早期检测与治疗领域的进展，亟需精准的模型系统以进一步评估具有应用前景的新型研究发现。小动物模型，尤其是小鼠模型系统，因诸多优势广受研究者青睐，例如操作便捷、实验平台已被充分表征。在免疫缺陷小鼠体内培育人类肿瘤（即所谓患者来源异种移植模型（patient-derived xenografts，PDXs））的技术，可让研究者在可控环境中直接研究人类癌组织。但PDX模型存在局限性：其缺乏完整的免疫系统。免疫疗法已彻底革新临床肿瘤学，但目前仍缺乏搭载人类免疫系统与人类肿瘤的临床前模型，难以探索新型治疗策略，也无法研究治疗方案的局限性与毒副作用。本研究的核心目标为验证一款体内（in vivo）模型，该模型可在完全个性化、自体同源的场景下，搭载完整的人类免疫系统以研究人类肿瘤，从而助力癌症免疫疗法的探索。据此，本研究将完成两项任务：(1) 验证我们的人源化系统（humanized system）作为模型的有效性，以研究黑色素瘤患者接受癌症免疫疗法后的治疗响应与毒副作用，涵盖免疫检查点阻断与疫苗接种策略；(2) 拓展当前在黑色素瘤领域的研究，通过验证人源化小鼠（humanized mice）的构建能力，并评估在人源化小鼠体内建立的自体同源人类胰腺、结直肠肿瘤的生长情况与白细胞发育进程。在各研究方向中，本团队将依托多中心合作团队的专业技术积累与所属机构的实验平台，最大化实现各项实验目标的成功率。本项目的研究成果将向全球科研社群公开，以供后续基于假说的相关研究使用。综上，本研究将达成多项目标，解决癌症免疫疗法领域中多项尚未被满足的需求，从而大幅提升完全自体同源且免疫健全的精准模型系统在转化肿瘤学研究中的应用价值。