Developing a Human in Mouse Cancer Model with a Completely Humanized Stroma

摘要 小鼠癌症模型易于使用，可重复，成本可控。老鼠也可以 基因工程来研究特定的致癌途径。鉴于许多阳性与鼠 在小鼠模型中，绝大多数临床前抗癌治疗研究都是在小鼠中进行的。 不幸的是，绝大多数在小鼠肿瘤研究中有效的肿瘤药物（约94%）将 最终在人体试验中失败。这些失败花费了数十亿美元，浪费了医生和病人 资源显然，目前的临床前小鼠肿瘤模型不能准确预测患者的反应 接受治疗因此，目前的小鼠模型需要改进，以更准确地反映人类疾病。每个 目前可用的人类癌症小鼠模型具有明显的优势，但也存在严重的缺陷。一 所有可用的临床前模型的关键缺陷是缺乏人肿瘤基质。然而，我们的工作 研究小组和其他人证明了人类肿瘤间质是人类肿瘤的关键成分， 促进人肿瘤生长、转移，抑制抗肿瘤免疫，和 诱导治疗抗性。 我们的长期目标是开发一种人类肿瘤模型，通过更好地代表人类肿瘤， 在人类临床试验中观察到更好的癌症治疗反应。我们假设一个人类肿瘤模型 与人类癌细胞和人类肿瘤基质两者的组合将更好地代表原发性人类疾病。因此，在本发明中， 这将是一个更好/更严格的临床前药物筛选模型， 注定无法用于临床试验我们进一步假设，人类肿瘤间质将更好地 维持肿瘤细胞随时间的异质性，以更准确地反映治疗性肿瘤的自然演变。 阻力最后，这样的模型将是用于评估人肿瘤间质对新肿瘤的影响的理想模型。 免疫细胞疗法我们建议使用人类成体干细胞和癌症相关的组合， 干细胞来创建具有人类癌细胞和基质细胞的人类肿瘤模型。我们将执行 广泛的组织学和分子特征分析，以证实该模型反映原发性肿瘤。最后，我们将（i） 在回顾性研究中评估模型预测患者对疾病反应的能力，以及（ii）评估 使用该模型评估使用靶向卵巢癌的新型CAR T细胞构建体的新型免疫疗法， 癌细胞

Abstract Mouse models of cancer are easy to use, reproducible, and have manageable costs. Mice can also be genetically engineered to study specific oncogenic pathways. Given the many positives associated with murine models, the vast majority of pre-clinical anti-cancer therapeutic studies are performed in a mouse. Unfortunately, the vast majority of oncology drugs (~94%) that are effective in murine tumor studies will ultimately fail when tested in humans. These failures cost billions of dollars and waste physician and patient resources. Clearly, current preclinical mouse tumor models are not accurately predicting a patients’ response to therapy. Thus current mouse models need to be improved to more accurately reflect human disease. Each of the currently available mouse models of human cancer has distinct strengths, but also critical flaws. One critical flaw in all available preclinical models is the lack of human tumor stroma. However, work from our group and others demonstrates that human tumor stroma is a critical component of the human tumor microenvironment which promotes human tumor growth, metastasis, suppresses anti-tumor immunity, and induces therapeutic resistance. Our long term goal is to develop a human tumor model that will, by better representing human tumors, will better cancer therapeutic response seen in human clinical trials. We hypothesize that a human tumor model with both human cancer cells and human tumor stroma will better represent primary human disease. As such, it will be a better/more stringent model for preclinical drug screening that could ultimately prevent a drug which is destined to fail from being used in clinical trials. We further hypothesize that human tumor stroma will better maintain tumor cell heterogeneity over time to more accurately reflect the natural evolution of therapeutic resistance. Finally such a model will be ideal for evaluating the impact of human tumor stroma on novel immune cell therapies. We propose to use a combination of human adult stem cells and cancer associated stem cells to create human tumor model with both human cancer cells and stromal cells. We will perform extensive histological and molecular profiling to confirm this model reflects primary tumor. Finally, we will (i) evaluate the models ability to predict patient response to disease in a retrospective study and (ii) assess the use of this model to evaluate novel immunotherapies using a novel CAR T-cell construct targeting ovarian cancer cells.