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

效应 T 细胞和 Nano-DC 疫苗在乳腺癌中的运输

• 批准号: 9187677
• 负责人: Elizabeth Mittendorf
• 金额: $ 50.29万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-29 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9187677
• 关键词: Adjuvant; Affect; Antibodies; Antigen-Presenting Cells; Antigens; Biodistribution; Biological; Breast Cancer Patient; Cancer Center; Cancer Patient; Cancer Vaccines; Cell surface; Cells; Clinical Research; Complement; Computer Analysis; Cytotoxic T-Lymphocytes; Dendritic Cell Vaccine; Dendritic Cells; Development; ERBB2 gene; Event; Goals; Hyperthermia; Image; Immune; Immune response; Immunotherapeutic agent; Immunotherapy; Infiltration; Injection of therapeutic agent; Lymph; Lymphatic vessel; Lymphoid Tissue; Magnetism; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Mammary Neoplasms; Mediating; Mediation; Metastatic breast cancer; Microscopic; Modeling; Modification; Monitor; Monoclonal Antibodies; Mus; Nanotechnology; Organ; Patients; Penetration; Pharmaceutical Preparations; Positron-Emission Tomography; Procedures; Process; Property; Proteins; Route; Services; Shapes; Signal Transduction; Silicon; Site; Solid Neoplasm; Staging; System; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Therapeutic antibodies; Transport Process; Travel; Treatment Efficacy; Tumor Antigens; Tumor Tissue; Tumor-Infiltrating Lymphocytes; United States Food and Drug Administration; Vaccinated; Vaccination; Vaccines; X-Ray Computed Tomography; base; cancer immunotherapy; cancer therapy; cell killing; cytokine; density; immunogenic; improved; in vivo; inhibitor/antagonist; interest; intravenous injection; iron oxide; lymph nodes; magnetic field; malignant breast neoplasm; melanoma; migration; mouse model; nano; nanoparticle; neoplastic cell; prevent; response; success; trafficking; treatment strategy; tumor; tumor growth; tumor microenvironment; vaccine development

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.

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功能低下而导致的 针对肿瘤的反应。癌症免疫疗法旨在恢复人体的肿瘤防御系统 特异性免疫反应。由于树突状细胞（DC）是专业的抗原呈递细胞，可以 处理并向 T 细胞呈递肿瘤抗原以启动免疫反应，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 DC 疫苗 sipuleucel-T 晚期前列腺癌代表了这个充满希望的领域的一个重要里程碑。 DC 疫苗通常是 由内化肿瘤抗原和佐剂的 DC 组成。一系列物理和生物事件 确定功能性 DC 疫苗能否成功引发适当的免疫反应：1) DC 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性 持续处理免疫抗原并将其呈递给 T 细胞的状态； 3) 抗原特异性 T 细胞 必须到达肿瘤器官并渗透到肿瘤微环境中才能发挥抗肿瘤作用 活动。然而，迄今为止，这些事件对于大多数 DC 疫苗来说往往是难以克服的障碍。临床研究 研究表明，只有不到 5% 的皮内注射 DC 能够到达淋巴结。此外， 离体成熟 DC 的刺激信号在体内无法维持。此外，肿瘤 微环境可防止细胞毒性 T 细胞的浸润。因此，克服这些连续的障碍 对于成功开发治疗性 DC 疫苗至关重要，以促进有效运输 DC 疫苗和激活的 T 细胞。免疫治疗运输中心项目1 肿瘤物理学（CITO），我们假设连续的物理和生物学的成功协商 屏障决定了 DC 疫苗在淋巴结中的积累，尤其是肿瘤引流淋巴结。 此外，肿瘤微环境的改变有利于效应T细胞和大分子的运输 与 Nano-DC 疫苗协同作用以有效治疗癌症的药物。我们开发了 HER2 特异性 纳米 DC 疫苗来检验这一假设。细胞表面 HER2 蛋白的表达量约为 20-30% 乳腺癌以及许多胰腺癌患者。我们最近开发出一种多孔硅 基于微粒（PSM）的 DC 疫苗（纳米 DC 疫苗）开发平台，并证明 PSM 既可以作为肿瘤抗原的储存库，也可以作为刺激 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检验我们的假设。 该项目将与传输肿瘤物理核心（TOC）紧密集成，这取决于其成像， 量化、分析和计算传输建模服务，以实现精准免疫治疗。