Transport of Effector T cells and Nano-DC vaccine in Breast Cancer

项目1-摘要 不受控制的肿瘤生长(癌症)通常是患者免疫无效的结果 对肿瘤的反应。癌症免疫疗法旨在恢复身体对肿瘤的防御系统- 特定的免疫反应。由于树突状细胞(DC)是专业的抗原提呈细胞，可以 处理肿瘤抗原并将其呈递给T细胞以启动免疫反应，DC疫苗是自然选择 进行治疗干预。美国食品和药物管理局批准SiPuleucel-T，一种DC疫苗，用于 晚期前列腺癌是这一前景广阔的领域的一个重要里程碑。DC疫苗通常是 由内化了肿瘤抗原和佐剂的DC组成。一系列物理和生物事件 决定功能树突状细胞疫苗能否成功引发适当的免疫反应：1)树突状细胞疫苗 必须从注射部位迁移到淋巴组织；2)DC疫苗必须保持成熟的刺激作用 持续处理免疫抗原并将其呈递给T细胞的状态；以及3)抗原特异性T细胞 必须走到荷瘤器官，渗透到肿瘤微环境中发挥其抗肿瘤作用 活动。然而，到目前为止，这些事件对于大多数DC疫苗来说往往是不可逾越的障碍。临床研究 研究表明，皮内注射的树突状细胞只有不到5%能到达淋巴结。此外， 体外成熟的DC在体内不能维持刺激信号。此外，肿瘤 微环境阻止细胞毒性T细胞的渗透。因此，克服这些顺序障碍 是研制成功的治疗性DC疫苗的关键，以促进有效的转运 DC疫苗和激活的T细胞。为免疫治疗运输中心的项目1 在物理学(CITO)中，我们假设顺序的物理和生物的成功协商 屏障决定了DC疫苗在淋巴结中的蓄积，特别是在肿瘤引流的淋巴结中。 此外，肿瘤微环境的改变有助于效应T细胞和大分子的运输 与纳米DC疫苗协同作用的药物，用于有效的癌症治疗。我们已经开发出针对HER2的 纳米DC疫苗来验证这一假说。细胞表面HER2蛋白的表达约为20%-30% 在乳腺癌和许多胰腺癌患者中也是如此。我们最近开发了一种多孔硅 基于微粒子(PSM)的DC疫苗(Nano-DC疫苗)开发平台，并展示了 PSM既可作为肿瘤抗原的储存库，又可作为刺激DC细胞的佐剂。我们会 将纳米DC疫苗平台应用于这项研究，并将在乳腺癌小鼠模型中测试我们的假设。 该项目将与依赖于其成像的运输光学物理核心(TOC)紧密结合， 量化、分析和计算传输建模服务，以实现精确的免疫治疗。

PROJECT 1 – SUMMARY Uncontrolled tumor growth (cancer) often results as a consequence of a patient's ineffective immune responses against the tumor. Cancer immunotherapy aims at restoring the body's defense system with tumor- specific immune responses. Since dendritic cells (DCs) are professional antigen-presenting cells that can process and present tumor antigen to T cells to initiate immune responses, DC vaccines are the natural choice for therapeutic intervention. Approval by the US Food and Drug Administration of sipuleucel-T, a DC vaccine for advanced prostate cancer, represented a major milestone in this promising field. A DC vaccine is usually comprised of DCs internalized with tumor antigens and adjuvants. A sequence of physical and biological events determine the success of a functional DC vaccine to elicit the proper immune responses: 1) The DC vaccine must migrate from the injection site to lymphoid tissues; 2) The DC vaccine must maintain a mature stimulatory status to persistently process and present the immunizing antigen to T cells; and 3) The antigen-specific T cells must travel to the tumor-bearing organ and infiltrate into the tumor microenvironment to exert their anti-tumor activity. However, these events are often insurmountable hurdles for most DC vaccines thus far. Clinical studies have shown that only less than 5% of intradermally injected DCs can reach the lymph nodes. In addition, the stimulatory signals of ex vivo matured DCs cannot be maintained in vivo. Furthermore, the tumor microenvironment prevents infiltration of the cytotoxic T cells. Therefore, overcoming these sequential barriers is critical to the development of a successful therapeutic DC vaccine, in order to facilitate effective transport of the DC vaccine and activated T cells. For Project 1 of the Center for Immunotherapeutic Transport Oncophysics (CITO), we hypothesize that successful negotiation of the sequential physical and biological barriers determines accumulation of DC vaccine in the lymph nodes, especially the tumor-draining lymph nodes. Also, modification of the tumor microenvironment facilitates transport of the effector T cells and macromolecular drugs that synergize with the Nano-DC vaccine for effective cancer therapy. We have developed a HER2-specific Nano-DC vaccine to test the hypothesis. The cell surface HER2 protein is expressed in approximately 20-30% of breast cancers and also in many pancreatic cancer patients. We have recently developed a porous silicon microparticle (PSM)-based platform for DC vaccine (Nano-DC vaccine) development, and demonstrated that PSM could serve both as a reservoir for the tumor antigen and as an adjuvant to stimulate the DC cells. We will apply the Nano-DC vaccine platform in this study, and will test our hypothesis in murine models of breast cancer. The project will be tightly integrated with the Transport Oncophysics Core (TOC) hinging on its imaging, quantification, analysis, and computational transport modeling services to enable precision immunotherapy.