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.

项目概要 头颈鳞状细胞癌（HNSCC）是一种侵袭性极强的疾病，总体生存率较差。 尽管免疫检查点阻断 (ICB) 取得了成功，但当前形式的免疫疗法的获益仍低于 15% 的 HNSCC 患者。因此，迫切需要新的战略来实现强大和 持久的免疫反应且毒性最小。我们在此应用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 细胞反应的技术工具。为此，我们有 设计了一种纳米颗粒疫苗递送载体，可以有效递送抗原和佐剂分子 抗原呈递细胞并实现具有强大细胞毒性潜力的强烈 T 细胞反应。此外，我们 已经确定了一种通过改变肠道微生物群来进一步利用免疫系统的新策略 增强纳米疫苗引发的 T 细胞反应。在这里，我们寻求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相互作用并应用从这些基础知识中获得的知识 增强 T 细胞针对 HPV+ HNSCC 反应的研究。我们将特别解决以下问题 通过应用药物输送、生物工程和疫苗学的原理来回答问题。我们可以利用我们的策略吗 促进抗原和佐剂递送至抗原呈递细胞，并改善全身和局部T细胞 体内反应？我们能否利用我们的疫苗输送技术来释放 T- 的全部细胞毒性潜力？ HNSCC 中的细胞和反向免疫抑制？我们能否改变肠道微生物组来提高功效 联合免疫治疗？我们能否证明它们在 HPV+ HNSCC 原位模型中的功效？ 包括 HNSCC 基因工程小鼠模型？这些研究可能会带来一种新的策略 利用我们的免疫系统作为 HPV+ HNSCC 的潜在治疗方法。该提案充分响应 PAR-19-172 将：(1) 推动精确免疫调节创新技术的成熟，(2) 创造多功能佐剂递送技术，以及 (3) 增强 NIDCR 的免疫治疗 优先疾病。