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

摘要 小鼠癌症模型使用方便，重复性好，成本可控。老鼠也可以 通过基因工程研究特定的致癌途径。考虑到与小鼠有关的许多积极因素 在模型中，绝大多数临床前抗癌治疗研究都是在小鼠身上进行的。 不幸的是，绝大多数(~94%)在小鼠肿瘤研究中有效的肿瘤学药物将 在人类身上测试时，最终会失败。这些失败花费了数十亿美元，浪费了医生和患者 资源。显然，目前的临床前小鼠肿瘤模型并不能准确预测患者的反应 去接受治疗。因此，目前的小鼠模型需要改进，以更准确地反映人类疾病。每个人 目前可用的人类癌症小鼠模型有明显的优点，但也有关键的缺陷。一 所有可用的临床前模型的关键缺陷是缺乏人类肿瘤间质。然而，来自我们的工作 证明了人类肿瘤间质是人类肿瘤的重要组成部分 促进人类肿瘤生长、转移、抑制抗肿瘤免疫的微环境，以及 会导致治疗抵抗。 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，将 在人类临床试验中看到更好的癌症治疗反应。我们假设一个人类肿瘤模型 对于人类癌细胞和人类肿瘤，基质将更好地代表人类的原发疾病。因此， 这将是一个更好/更严格的临床前药物筛选模式，最终可以防止一种药物 在临床试验中使用注定会失败。我们进一步假设人类肿瘤间质将会更好 随着时间的推移保持肿瘤细胞的异质性，以更准确地反映治疗的自然演变 抵抗。最后，这样的模型将是评估人类肿瘤间质对新陈代谢的影响的理想方法。 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 干细胞利用人类癌细胞和基质细胞建立人类肿瘤模型。我们将表演 广泛的组织学和分子图谱证实这一模型反映了原发肿瘤。最后，我们将(一) 在回顾研究中评估模型预测患者对疾病的反应的能力，以及(Ii)评估 利用该模型评价以卵巢为靶点的新型CAR T细胞构建物的免疫治疗效果 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.