Abstract 1673: Advancing bladder cancer treatment with live attenuated salmonella ZH9: from monotherapy to combination strategies

Abstract For over 30 years, microbial immunotherapy with Bacillus Calmette-Guérin (BCG) has been the standard-of-care for non-muscle invasive bladder cancer (NMIBC). Global demand for BCG however exceeds supply and BCG therapy is associated with disease recurrence and high treatment burden. Most novel bladder cancer treatments in development either target BCG unresponsive patients as second line or are administered in combination with BCG and thus share its shortcomings. There remains a significant need for innovative therapies to replace BCG in bladder cancer treatment, and live-attenuated Salmonella Typhi ZH9 presents a promising alternative, both as a monotherapy and as a combination partner. Efficacy of ZH9 was investigated in syngeneic mouse MB49 and p53-/Pten- GEMM orthotopic tumor models in which animals were treated in the bladder via catheterization, with or without combination intraperitoneal anti-PD-L1 or anti-PD-1 treatment. Immune responses were characterized by flow cytometry and histology analyses of bladder tissue. Intravesical ZH9 monotherapy following orthotopic MB49 tumor inoculation demonstrated significant survival benefit compared to both vehicle control and BCG treatments. A single administration of ZH9 was sufficient for efficacy, inducing far greater magnitude and duration of immune responses than standard-of-care BCG, and resulting in systemic anti-tumor immunity that protected against both local bladder and distant MB49 tumors. Combination of local ZH9 treatment with regimens of checkpoint inhibitor antibodies anti-PD-L1 (MB49 model) and anti-PD-1 (GEMM model) that were otherwise ineffective, led to significant efficacy, suggesting local Salmonella ZH9 treatment can synergize with systemic immunotherapies. These data support Salmonella ZH9 as an effective first-line monotherapy and checkpoint inhibitor combination therapy for bladder cancer, with potential to reduce treatment burden on patients, lower associated healthcare costs and to ease microbial therapy supply constraints due to a scalable manufacturing process. Clinical evaluation of ZH9 in a Phase 1b study evaluating safety, pharmacology, and early efficacy in NMIBC is ongoing. Citation Format: Nicholas Glanville, Claudia Prevosto, Sonia Domingos-Pereira, Lenka Polak, Victoria Morel, Marine Leblond, Gregory Verdeil, Denise Nardelli-Haefliger, Livija Deban. Advancing bladder cancer treatment with live attenuated salmonella ZH9: from monotherapy to combination strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1673.