Utilizing intranasal immunization to induce a cytotoxic T lymphocyte response and reduce metastatic burden in the lung

利用鼻内免疫诱导细胞毒性 T 淋巴细胞反应并减少肺转移负担

• 批准号: 10090666
• 负责人: Chelsea Dawn Landon
• 金额: $ 11.72万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10090666
• 关键词: 4T1; Adjuvant; Advisory Committees; Animals; Antigens; Antineoplastic Agents; Award; Bacterial Toxins; CD8-Positive T-Lymphocytes; CD8B1 gene; CYP1B1 gene; Cancer Vaccines; Cessation of life; Clinical; Clinical Research; Clinical Trials; Communities; Cytotoxic T-Lymphocytes; Data; Development; Disease; Doctor of Philosophy; Drug Delivery Systems; Drug Targeting; Effectiveness; Environment; Epitopes; Foundations; Funding Opportunities; Future; Goals; HLA-A2 Antigen; Human; Immune response; Immunity; Immunization; Immunize; Immunology; Immunotherapy; Institution; Knowledge; Laboratories; Ligands; Location; Luciferases; Lung; Malignant Neoplasms; Medicine; Mentors; Mentorship; Metastatic Neoplasm to the Lung; Modeling; Mucous Membrane; Mus; Nasal cavity; Neoplasm Metastasis; Oncology; Peptides; Phenotype; Population; Primary Neoplasm; Publications; Research; Research Personnel; Research Training; Route; Scientist; Site; Solid; Spleen; Systemic disease; TLR4 gene; TLR9 gene; Testing; Thrombopoietin; Time; Toxin; Training; Transgenic Organisms; Translating; Translational Research; Tumor Antigens; Tumor Burden; Tumor Specific Peptide; United States; Universities; Vaccination; Vaccine Adjuvant; Vaccines; Veterinarians; Work; anti-CTLA4; base; cancer cell; cancer therapy; career; clinical development; clinically translatable; comparative; design; doctoral student; draining lymph node; effective therapy; interest; neoplasm immunotherapy; novel; post-doctoral training; programmed cell death ligand 1; programmed cell death protein 1; programs; response; skills; targeted treatment; tumor

Abstract The purpose of this SERCA application is to provide the protected research time and mentorship necessary for Chelsea Landon, DVM, PhD to make the transition to an independent investigator. Dr. Landon is a veterinarian with a strong clinical and research background in comparative medicine, oncology, and drug delivery systems, making her uniquely qualified for a career in translational research. Under the guidance of her mentor Dr. Herman Staats and an interdisciplinary advisory committee, the training and aims outlined in this proposal will allow Dr. Landon to expand her knowledge in the field of tumor vaccines and immunotherapy and to establish a solid foundation for her own independent research program focused on novel cancer treatments. Duke University will provide the environment necessary to support her transition to independence. Approximately 90% of cancer-related deaths are associated with metastatic spread and systemic disease, and not the primary tumor. For many primary tumors, lungs are the most common site of metastasis. Given the need for effective treatment of metastatic disease and common location of disease within the lungs, my goal is to assess an intranasal (IN) immunization strategy to reduce metastatic burden. As clinical trials to evaluate tumor vaccines have expanded, it is clear that the optimal means of delivery is unknown. One approach for immunizing against metastatic tumors in the lung is the use of IN immunization to induce antigen- specific cellular immune responses that preferentially migrate to mucosal tissues. Previous work has demonstrated effective induction of tumor-peptide specific immunity via the IN route; however, these studies commonly used toxin-based adjuvants not suitable for clinical development. The goals of this proposal are to identify translationally applicable adjuvants that maximize the induction of tumor-specific CTL responses induced by IN immunization and to determine if IN immunization with tumor-specific peptides and non-toxin adjuvants induce protection against metastatic tumor disease. The central hypothesis of the proposed studies is that IN immunization with a non-toxin adjuvant and tumor-specific peptide will induce CTL responses that provide effective anti-cancer therapy, resulting in a reduction of metastatic burden within the lungs. This hypothesis will be tested with the following specific aims: Specific Aim #1: Identify clinically translatable adjuvants that maximize epitope-specific CTL after IN immunization. Specific Aim #2: Determine the efficacy of IN immunization with a tumor-specific peptide + non-toxin adjuvant combination in reducing metastatic burden. The work outlined in this proposal will provide Dr. Landon with a valuable skill set and allow her to generate data needed for publications and a future R01 application aimed at further developing tumor vaccine strategies, providing a solid foundation to build a career as an independent researcher.

抽象的 此 SERCA 申请的目的是提供受保护的研究时间和指导 Chelsea Landon（DVM、PhD）对于转变为独立调查员来说是必要的。兰登博士是 一位在比较医学、肿瘤学和药物方面拥有深厚临床和研究背景的兽医 交付系统，使她具有从事转化研究职业的独特资格。在指导下 她的导师 Herman Staats 博士和一个跨学科咨询委员会，概述了培训和目标 该提案将使兰登博士能够扩展她在肿瘤疫苗和免疫治疗领域的知识 并为她自己专注于新型癌症的独立研究项目奠定坚实的基础 治疗。杜克大学将提供必要的环境来支持她向独立过渡。 大约 90% 的癌症相关死亡与转移扩散和全身性相关 疾病，而不是原发肿瘤。对于许多原发性肿瘤来说，肺部是最常见的转移部位。 鉴于需要有效治疗转移性疾病和肺部常见的疾病部位， 我的目标是评估鼻内 (IN) 免疫策略以减少转移负担。作为临床试验 评估肿瘤疫苗已经扩大，很明显，最佳的递送方式尚不清楚。一 针对肺部转移性肿瘤的免疫方法是使用IN免疫来诱导抗原- 优先迁移至粘膜组织的特异性细胞免疫反应。之前的作品有 证明通过 IN 途径有效诱导肿瘤肽特异性免疫；然而，这些研究 常用的毒素类佐剂不适合临床开发。该提案的目标是 确定可翻译应用的佐剂，最大限度地诱导肿瘤特异性 CTL 反应 通过IN免疫诱导并确定是否用肿瘤特异性肽和非毒素进行IN免疫 佐剂诱导针对转移性肿瘤疾病的保护。拟议研究的中心假设 是用非毒素佐剂和肿瘤特异性肽进行IN免疫将诱导CTL反应， 提供有效的抗癌治疗，从而减少肺部转移负担。这 假设将通过以下具体目标进行检验： 具体目标#1：鉴定可在 IN 后最大化表位特异性 CTL 的临床可翻译佐剂 免疫接种。 具体目标#2：确定使用肿瘤特异性肽+非毒素佐剂进行IN免疫的效果 联合用药可减少转移负担。 本提案中概述的工作将为兰登博士提供宝贵的技能，并使她能够 生成出版物和未来 R01 应用所需的数据，旨在进一步开发肿瘤疫苗 战略，为建立独立研究人员的职业生涯提供坚实的基础。