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

摘要 本申请的目的是提供受保护的研究时间和指导 Chelsea Landon，DVM，PhD必须过渡到独立研究者。兰登医生 一位兽医，在比较医学、肿瘤学和药物方面具有很强的临床和研究背景 交付系统，使她在转化研究的职业生涯中具有独特的资格。指导下 她的导师赫尔曼斯塔茨博士和一个跨学科的咨询委员会，培训和目标概述， 这一提议将使Landon博士扩大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计划奠定坚实的基础 治疗。杜克大学将提供必要的环境，以支持她过渡到独立。 大约90%的癌症相关死亡与转移性扩散和全身性疾病有关。 疾病，而不是原发性肿瘤。对于许多原发性肿瘤，肺是最常见的转移部位。 考虑到需要有效治疗转移性疾病和肺内疾病的常见位置， 我的目标是评估鼻内（IN）免疫策略，以减少转移负荷。作为临床试验， 尽管评估肿瘤疫苗的范围已经扩大，但很明显，最佳的递送方式是未知的。一 针对肺中转移性肿瘤免疫的方法是使用IN免疫以诱导抗原- 特异性细胞免疫应答，优先迁移到粘膜组织。先前的工作已经 证明了通过IN途径有效诱导肿瘤肽特异性免疫;然而，这些研究 常用的基于毒素的佐剂不适合临床开发。本提案的目标是 鉴定最大化诱导肿瘤特异性CTL应答的预防性适用佐剂 以确定用肿瘤特异性肽和非毒素诱导的IN免疫是否 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 用非毒素佐剂和肿瘤特异性肽IN免疫将诱导CTL应答， 提供有效的抗癌治疗，从而减少肺内的转移负荷。这 将按照以下具体目标检验假设： 具体目标#1：鉴定在IN后使表位特异性CTL最大化的临床可翻译佐剂 次免疫 具体目标#2：确定用肿瘤特异性肽+非毒素佐剂进行IN免疫的功效 降低转移负荷。 本提案中概述的工作将为Landon博士提供宝贵的技能，并使她能够 生成出版物和未来R 01应用所需的数据，旨在进一步开发肿瘤疫苗 战略，提供了一个坚实的基础，建立一个独立的研究人员的职业生涯。

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.