Intravesical VSVd51-GM-CSF virotherapy is superior to BCG in treating bladder cancer in preclinical and translational models

Non-muscle-invasive bladder cancer (NMIBC) can progress to muscle-invasive disease, with transurethral resection followed by Bacillus Calmette-Guérin (BCG) immunotherapy reducing this risk. Effective immunotherapies for BCG-resistant NMIBC are lacking. This study directly compares the efficacy of the oncolytic vesicular stomatitis virus (VSVd51) encoding the granulocyte macrophage colony-stimulating factor (GM-CSF) transgene (VSVd51-GM-CSF) to BCG in preclinical and translational models of aggressive bladder cancer. VSVd51-GM-CSF and BCG were tested in mouse and human bladder cancer spheroids and in bladder cancer patient-derived organoids, to evaluate immunogenic cell death biomarkers, cytokine release, and immune cell activation. VSVd51-GM-CSF and BCG treatments were then administered to C57Bl/6 mice with MB49 or N-butyl-N-(4-hydroxybutyl)-nitrosamine(BBN)-induced bladder tumors via intravesical instillation. VSVd51-GM-CSF treatment induced a heightened release of immunogenic factors and cytokines, which then activated M1-like tumor-targeting monocytes. Mice treated with VSVd51-GM-CSF exhibited stronger tumor-infiltrating immune responses, longer survival, and reduced tumor volume compared to BCG-treated mice. Importantly, VSVd51-GM-CSF treatment extends survival in BCG-failed mice. This anti-tumor immunity was also observed in patient-derived organoids, suggesting clinical relevance. These translational findings suggest that VSVd51-GM-CSF has significant potential for early-phase clinical trials in NMIBC patients. As a promising viro-immunotherapy, it could provide an alternative for patients with BCG-resistant disease, marking an important step forward in bladder cancer immunotherapy.