New Engineering Strategy for Harnessing Immune System against Head and Neck Cancer

利用免疫系统对抗头颈癌的新工程策略

• 批准号: 10434134
• 负责人: Yu Leo Lei
• 金额: $ 57.83万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10434134
• 关键词: Address; Adjuvant; Affect; Antigen Presentation; Antigen-Presenting Cells; Antigens; Benchmarking; Biocompatible Materials; Biomedical Engineering; CD8-Positive T-Lymphocytes; Cancer Vaccines; Cells; Cichorium intybus; Colon; Combination immunotherapy; Consumption; Dental; Dietary Fiber; Disease; Distant; Drug Delivery Systems; Engineering; Formulation; Genetically Engineered Mouse; Goals; HLA-A2 Antigen; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; High Density Lipoproteins; Human; Human Papillomavirus; Immune; Immune response; Immune system; Immunity; Immunization; Immunologic Memory; Immunological Models; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Incidence; Infiltration; Inulin; Knowledge; Lead; Lymphatic; Modeling; Mus; National Institute of Dental and Craniofacial Research; Oral; Patients; Phenotype; Plant Roots; Public Health; Research; Resistance; Role; Route; Serum; Structure; System; T cell response; T-Lymphocyte; Technology; Toxic effect; Tumor-infiltrating immune cells; Vaccines; base; biomaterial interface; cancer immunotherapy; cell killing; commensal microbes; craniofacial; cytotoxic; delivery vehicle; design; effector T cell; exhaustion; gut microbiome; gut microbiota; human model; immune checkpoint blockade; immunomodulatory strategy; immunoregulation; improved; in vivo; innovative technologies; lymph nodes; nanodisk; nanoparticle; nanovaccine; neoplastic cell; new technology; novel strategies; novel vaccines; oral HPV; prebiotics; programmed cell death ligand 1; programmed cell death protein 1; prototype; success; tool; tumor; uptake; vaccine delivery; vaccinology

Project Summary Head and neck squamous cell carcinoma (HNSCC) is an extremely aggressive disease with poor overall survival. Despite the success of immune checkpoint blockade (ICB), current forms of immunotherapy benefit less than 15% of HNSCC patients. Therefore, there exists a critical need for new strategies for achieving powerful and durable immune responses with minimal toxicity. Our objective in this application is to design and develop new technological tools for inducing and potentiating T-cell responses against HPV+ HNSCC. To this end, we have engineered a nanoparticle vaccine delivery vehicle that can efficiently deliver antigens and adjuvant molecules to antigen-presenting cells and achieve strong T-cell responses with robust cytotoxic potential. In addition, we have identified a novel strategy for harnessing the immune system by altering the gut microbiome to further amplify nanovaccine-primed T-cell responses. Here, we seek to conduct structure-function studies to understand how these biomaterials interface with our immune system and apply the knowledge gained from these basic studies to potentiate T-cell responses against HPV+ HNSCC. In particular, we will address the following questions by applying the principles of drug delivery, bioengineering, and vaccinology. Can we utilize our strategy to promote antigen and adjuvant delivery to antigen-presenting cells, and improve systemic and local T-cell responses in vivo? Can we employ our vaccine delivery technology to unleash the full cytotoxic potential of T- cells and reverse immunosuppression within HNSCC? Can we alter the gut microbiome to boost efficacy of combination immunotherapy? Can we demonstrate their efficacy in orthotopic models of HPV+ HNSCC, including genetically engineered mouse model of HNSCC? These studies may lead to a novel strategy for harnessing our immune system as the potential treatment of HPV+ HNSCC. The proposal is fully responsive to PAR-19-172 as it will: (1) drive the maturation of an innovative technology for precise immune modulation, (2) create technologies for versatile adjuvant delivery, and (3) enhance the immunotherapeutics for an NIDCR priority disease.

项目摘要 头颈部鳞状细胞癌（HNSCC）是一种极为侵略性的疾病，总生存率较差。 尽管免疫检查点封锁（ICB）取得了成功，但当前的免疫疗法形式受益于 15％的HNSCC患者。因此，存在着实现强大和的新策略的迫切需求 耐用的免疫反应具有最小的毒性。我们在此应用程序中的目标是设计和开发新的 用于诱导和增强针对HPV+ HNSCC的T细胞响应的技术工具。为此，我们有 设计了一种纳米粒子疫苗输送车辆，该疫苗输送车辆可以有效地输送抗原和辅助分子 抗原呈递细胞，并具有强大的细胞毒性潜力获得强的T细胞反应。另外，我们 已经确定了通过改变肠道微生物组进一步利用免疫系统的新策略 放大纳米甲虫提出的T细胞响应。在这里，我们试图进行结构功能研究以了解 这些生物材料如何与我们的免疫系统接口并应用从这些基本的知识 针对HPV+ HNSCC增强T细胞反应的研究。特别是，我们将解决以下内容 通过应用药物输送，生物工程和疫苗学原理来进行问题。我们可以利用我们的策略吗 促进抗原和佐剂递送到抗原呈递细胞，并改善全身和局部T细胞 体内反应？我们可以利用我们的疫苗输送技术来释放T-的全部细胞毒性潜力 细胞和HNSCC内的反向免疫抑制？我们可以改变肠道微生物组以提高功效吗 联合免疫疗法？我们可以证明它们在HPV+ HNSCC的原位模型中的功效吗？ 包括HNSCC的基因工程小鼠模型？这些研究可能会导致一种新颖的策略 利用我们的免疫系统作为HPV+ HNSCC的潜在处理。该提议对 佩尔（Par）19-172届：（1）驱动创新技术的成熟，以进行精确的免疫调节，（2） 创建用于多功能辅助输送的技术，（3）增强NIDCR的免疫治疗药 优先疾病。