Abstract 3466: Microbial neoantigen vectors for cancer immunotherapy

Abstract

Abstract Cancers employ a variety of immunosuppressive and evasive mechanisms to avoid detection by the immune system and prevent tumor neoantigen-mediated elimination. In recent years, tumor-specific neoantigen vaccines have shown significant promise—promoting tumor regression and increasing survival benefit in certain malignancies by therapeutically directing the immune system to target previously protected tumor specific antigens. However, despite encouraging preclinical data, objective and durable responses have remained elusive—highlighting a requirement for improved therapeutic platforms that permit delivery and targeting of diverse sets of tumor antigens to enhance the efficacy of cancer vaccines. Through synthetic biology, we have engineered living microbial vectors harboring constructs encoding synthetic arrays of tumor-specific neoantigens that specifically colonize tumors following intravenous injection and deliver high levels of neoantigen cargo—both extracellularly (within the tumor microenvironment) and intracellularly (to the cytosol of tumor-resident phagocytes). These engineered vectors robustly activate innate immune cascades and effectively prime tumor neoantigen-directed T cell responses to promote tumor regression and survival in advanced murine solid tumor and lung metastasis models. Extensive remodeling of the tumor immune microenvironment accompanies therapeutic efficacy, with increased activation of tumor neoantigen-specific CD4+ and CD8+ T cells, broadened stimulation of tumor-infiltrating B and T cells, and reduced numbers of intratumoral myeloid cells exhibiting immunosuppressive phenotypes. This work provides a foundational platform for the development of a new class of next-generation tumor vaccines, leveraging the advantages of living medicines to deliver diverse arrays of tumor-specific neoantigens within the optimal immunostimulatory context to induce potent anti-tumor immunity. Citation Format: Andrew A. Redenti, Tal Danino, Nicholas Arpaia. Microbial neoantigen vectors for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3466.