Abstract 6666: Leveraging an obligate anaerobic salmonella strain for targeted cargo delivery in the tumor microenvironment to restore immunotherapy sensitivity

Abstract

Abstract Tumor immunotherapy is often hindered by unresponsive cold tumor microenvironments (TME). Although Salmonella-based immunotherapy has shown potential in overcoming these cold immune environments, safety concerns remain. Our study introduces a genetically reprogrammed Salmonella typhimurium strain (OASL) with a dual safety lock to enhance safety and modify immunosuppressive TME, sensitizing tumors to immunotherapies. We propose using OASL to alter the cold TME and locally release therapeutic cargos such as PDL1 nanobodies and tumor-specific neoantigen peptides identified through bioinformatic algorithms, activating immune cells within the tumor while minimizing side effects. We selected YB1, an obligate anaerobic Salmonella strain that thrives in hypoxic environments, as our base strain and incorporated a self-lysis genetic circuit for controlled bacterial growth and cargo release upon reaching a specific population density within the tumor core. We assembled and evaluated the self-lysis gene circuit in vitro, documenting the event using an optical density (OD) reader and confirming OASL's ability to express genetic cargos through western blot analysis. We then investigated OASL's therapeutic effect in vivo and characterized TME changes using flow cytometry and immunohistochemistry staining. Our results indicate that OASL undergoes lysis and releases cargos upon reaching a specific population density in vitro. Additionally, OASL-delivered neoantigen peptides elicited a tumor-specific immune response in vivo. OASL also demonstrated the capacity to modify the TME and restore sensitivity to PDL1 in previously unresponsive tumors, enhancing therapeutic effects. Citation Format: Yige He, Jiandong Huang. Leveraging an obligate anaerobic salmonella strain for targeted cargo delivery in the tumor microenvironment to restore immunotherapy sensitivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6666.