3D Models of Immunotherapy

免疫疗法的 3D 模型

• 批准号: 9283025
• 负责人: FRANK S HODI
• 金额: $ 57.44万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9283025
• 关键词: Address; Adjuvant; Angiogenic Factor; Animals; Antigen-Presenting Cells; Antigens; Award; Biocompatible Materials; Biological Models; Blocking Antibodies; Blood Vessels; Cancer Vaccines; Cancerous; Cell Communication; Cell Culture Techniques; Cell physiology; Cell surface; Cells; Cellular biology; Cessation of life; Complement; Cytotoxic T-Lymphocyte-Associated Protein 4; Cytotoxic T-Lymphocytes; Dendritic Cells; Development; Devices; Distant; Experimental Models; Failure; Future; Gene Expression; Generations; Human; Human Biology; Immune; Immune response; Immunotherapy; Impairment; In Vitro; Malignant Neoplasms; Modeling; Mus; Neoplasms in Vascular Tissue; Patients; Perfusion; Phase I Clinical Trials; Pre-Clinical Model; Printing; Role; Site; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Tissues; Vaccination; Vaccines; Work; antitumor effect; base; cancer immunotherapy; humanized mouse; immune checkpoint blockade; immune function; immunoregulation; in vitro Model; in vivo; lymph nodes; melanoma; mouse model; neoplastic cell; novel; novel vaccines; preclinical study; response; success; therapeutic vaccine; three-dimensional modeling; tool; trafficking; tumor; vaccination strategy

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.

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。但是，大多数 患者中仍然没有对当前的免疫疗法反应 无法产生对癌症抗原的有效细胞毒性T淋巴细胞（CTL）反应， 肿瘤的耐受作用。可能需要治疗疫苗来产生强大的CTL反应，并且 我们最近制定了一种新的生物材料疫苗策略，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。但是，下一代疫苗的开发 基于这个概念和治疗性癌症疫苗，更普遍地受到了严重损害 当前模型系统可用于探索和测试这些类型的疗法的局限性。临床前研究 通常使用鼠标模型，但即使人性化的鼠标模型也不会捕获人类的关键方面 与免疫疗法有关的生物学。细胞培养研究可用于探索人类免疫细胞生物学， 但是标准的人类细胞培养模型并没有重现指导免疫的3D多细胞相互作用 对癌症的反应或决定疫苗接种成功的肿瘤细胞免疫细胞相互作用。这 应用建议创建人类生物学的3D模型，使人们能够研究 疫苗接种。这些模型将在体外复制疫苗部位本身，其中对癌症的免疫反应 启动抗原，肿瘤，免疫细胞会遇到癌细胞，以及 免疫细胞通常由肿瘤内的细胞下调。为了彻底表征和 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体外模型与相同类型的体内组织之间的直接比较。这些研究将是 验证模型的关键。然后，我们将使用肿瘤，血管和免疫细胞创建人类模型 来自同一患者。这些人类模型将用于开始探索几个关键问题 治疗性癌症疫苗接种，包括检查点阻滞和血管生成因子在肿瘤中的作用， 肿瘤内疫苗接种对免疫细胞反应的影响。该项目完成时，我们 将开发并彻底表征小鼠和人类生物学的新颖的3D模型 复制疫苗接种部位和血管化肿瘤。这些模型将使我们能够探索关键问题 与人类癌症免疫疗法相关，并提供了一种筛查免疫调节影响的方法 随着我们和其他人发展新的癌症免疫疗法，代理（例如各种辅助者）将来。