Enhancing local adaptive immune control of lung cancer using a systemic + mucosal vaccination strategy 3019

Abstract Description Immune checkpoint blockade (ICB) has revolutionized lung cancer treatment by reinvigorating dysfunctional anti-tumor T cell responses in situ. However, ICB efficacy is limited for many patients due to insufficient T cell presence within the tumor microenvironment. Expanding the current immunotherapeutic repertoire with strategies to enhance local anti-tumor T cell responses is crucial for overcoming this challenge. Focusing on lung anti-viral immunity, we have demonstrated that a systemic-prime + mucosal-boost vaccination strategy amplifies respiratory adaptive immune responses in healthy mice. Building on these findings, we hypothesize that engineering a systemic-prime + mucosal-boost vaccine strategy to therapeutically target lung tumor antigens will improve disease control. As a proof-of-concept, we have validated a systemic mRNA-prime + mucosal adenoviral-boost vaccine strategy targeting the tumor antigen, HELLO, expressed by the lung cancer cell line KP-HELLO. Vaccination of healthy mice results in robust HELLO-specific T cell activation in the lung, as assessed by ex vivo peptide stimulation. Moreover, we have shown that mucosal boosting moderately prolongs survival compared to systemic boosting in mice bearing intratracheally established KP-HELLO tumors. Ongoing work seeks to optimize mouse survival and elucidate the cellular and molecular components responsible for mucosal-boost efficacy, with the goal of identifying synergistic combination therapy candidates. Funding Sources Supported by NIH/NCI T32 5T32CA009109-47; UVA Lung Translational Research Team Pilot Project Award Topic Categories Vaccines and Immunotherapy (VAC)