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

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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.