3D Models of Immunotherapy

癌症免疫疗法目前正在为患者提供令人兴奋的新治疗选择。然而，大多数人 的患者仍然对目前的免疫疗法没有反应，这种失败可能至少部分是由于 无法产生针对癌症抗原的强大的细胞毒性T淋巴细胞(CTL)反应，以及 肿瘤的耐受性。可能需要治疗性疫苗来产生强大的CTL反应，以及 我们最近开发了一种新的疫苗接种生物材料战略，这导致了前所未有的能力 根除临床前模型中已建立的肿瘤。然而，下一代疫苗的发展 基于这一概念，更广泛地说，治疗性癌症疫苗受到 目前可用于探索和测试这些类型的疗法的模型系统的局限性。临床前研究 通常使用老鼠模型，但即使是人性化的老鼠模型也不能捕捉到人类的关键方面 与免疫疗法相关的生物学。细胞培养研究可以用来探索人类免疫细胞生物学， 但标准的人类细胞培养模型不能重建引导免疫的3D、多细胞相互作用 对癌症的反应，以及决定疫苗接种成功的肿瘤细胞-免疫细胞相互作用。这 应用程序建议创建人体生物学的3D模型，使人们能够研究 接种疫苗。这些模型将在体外复制疫苗部位本身，在那里对癌症的免疫反应 抗原是启动的，肿瘤是免疫细胞与癌细胞相遇的地方，而 免疫细胞通常被肿瘤内的细胞下调。为了彻底地描述和描述 验证我们的方法，我们将首先创建疫苗部位和肿瘤的3D小鼠模型，因为这将允许 3D体外模型与同类型体内组织的直接比较。这些研究将是 验证模型的关键。然后，我们将创建人类模型，使用肿瘤、血管和免疫细胞 来自同一个病人。这些人体模型将用于开始探索以下几个关键问题 治疗性癌症疫苗接种，包括检查点封锁和血管生成因子对肿瘤的作用， 以及瘤内接种疫苗对免疫细胞反应的影响。在这个项目完成后，我们 将开发并彻底描述老鼠和人类生物学的新型3D模型，将 复制接种部位和带血管的肿瘤。这些模型将使我们能够探索关键问题 与人类癌症免疫治疗相关，并提供了一种筛选免疫调节影响的手段 随着我们和其他人开发新的癌症免疫疗法，未来可能会有更多的药物(如各种佐剂)。

Cancer immunotherapy is currently providing exciting new treatment options for patients. However, the majority of patients still do not respond to current immunotherapies, and this failure likely results, at least in part, from an inability to generate potent cytotoxic T lymphocyte (CTL) responses against cancer antigens, and the tolerizing effects of the tumors. Therapeutic vaccines may be needed to generate robust CTL responses, and we have recently developed a new biomaterials strategy for vaccination that led to unprecedented ability to eradicate established tumors in preclinical models. However, the development of next generation vaccines based on this concept, and therapeutic cancer vaccines more generally, is significantly impaired by the limitations of current model systems available to explore and test these types of therapies. Preclinical studies typically utilize mouse models, but even humanized mouse models do not capture key aspects of human biology relevant to immunotherapies. Cell culture studies can be used to explore human immune cell biology, but standard human cell culture models do not recreate the 3D, multicellular interactions that direct the immune response against cancer nor the tumor cell-immune cell interactions that dictate vaccination success. This application proposes to create 3D models of human biology that enable one to study key aspects of vaccination. These models will replicate, in vitro, the vaccine site itself, where the immune response to cancer antigens is initiated, and the tumor, where immune cells encounter cancerous cells, and the function of the immune cells is typically down-regulated by the cells within the tumor. In order to thoroughly characterize and validate our approach, we will first create 3D mouse models of the vaccine site and the tumor, as this will allow direct comparison between the 3D in vitro model and the in vivo tissue of the same type. These studies will be key to validate the models. We will then create the human models, using tumor, vascular and immune cells all derived from the same patient. These human models will be used to begin exploring several key issues in therapeutic cancer vaccination, including the role of checkpoint blockade and angiogenic factors on the tumors, and the impact of vaccination intratumorally on the immune cell response. At the completion of this project we will have developed and thoroughly characterized novel, 3D models of both mouse and human biology that will replicate the vaccination site and vascularized tumors. These models will allow us to explore key questions relevant to human cancer immunotherapy, and provide a means to screen the impact of immunomodulatory agents (e.g., various adjuvants) in the future as we and others develop new cancer immunotherapies.