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）通常是由于患者免疫系统的无效而导致的。 对肿瘤的反应。癌症免疫疗法旨在恢复身体的防御系统与肿瘤- 特异性免疫反应。由于树突状细胞（DC）是专职抗原呈递细胞， DC疫苗是一种天然的选择，它可以处理肿瘤抗原并将其呈递给T细胞以启动免疫应答， 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， 晚期前列腺癌，代表了这一有前途的领域的一个重要里程碑。DC疫苗通常 由用肿瘤抗原和佐剂内化的DC组成。一系列物理和生物事件 确定功能性DC疫苗成功地引发适当的免疫应答：1）DC疫苗 必须从注射部位迁移到淋巴组织; 2）DC疫苗必须维持成熟的刺激性免疫应答， 持续处理并呈递免疫抗原至T细胞的状态;和3）抗原特异性T细胞 它们必须到达荷瘤器官并渗透到肿瘤微环境中才能发挥其抗肿瘤作用 活动然而，这些事件通常是迄今为止大多数DC疫苗无法克服的障碍。临床研究 已经表明，只有少于5%的皮内注射的DC可以到达淋巴结。此外该 离体成熟DC的刺激信号不能在体内维持。此外，肿瘤 微环境阻止细胞毒性T细胞的浸润。因此，克服这些顺序障碍 对于开发成功的治疗性DC疫苗至关重要，以促进有效的 DC疫苗和活化的T细胞。免疫转运中心1号项目 肿瘤物理学（CITO），我们假设，成功的谈判顺序的物理和生物 屏障决定了DC疫苗在淋巴结，特别是肿瘤引流淋巴结中的积累。 此外，肿瘤微环境的修饰促进效应T细胞和大分子转运。 与Nano-DC疫苗协同作用的药物，用于有效的癌症治疗。我们开发了一种HER2特异性 纳米DC疫苗来验证假设。细胞表面HER2蛋白在约20 - 30%的细胞中表达。 乳腺癌和许多胰腺癌患者中也有。我们最近开发了多孔硅 用于DC疫苗（Nano-DC疫苗）开发的基于微粒（PSM）的平台，并证明 PSM既可以作为肿瘤抗原的储存库，又可以作为刺激DC细胞的佐剂。我们将 在本研究中应用Nano-DC疫苗平台，并将在乳腺癌小鼠模型中验证我们的假设。 该项目将与运输肿瘤物理学核心（TOC）紧密结合， 定量，分析和计算运输建模服务，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.