Related Experiment Video
Updated: Jun 27, 2026
An Orthotopic Bladder Tumor Model and the Evaluation of Intravesical saRNA Treatment
Published on: July 28, 2012
Intravesical oncolytic virotherapy and immunotherapy for non-muscle-invasive bladder cancer mouse model
Woodson W Smelser1,2, Jian Wang3, Kristen M Ogden4,5
1Department of Surgery, Division of Urology, Washington University in St. Louis, St. Louis, MI, USA.
Objectives:
To test if intravesical instillation of both an anti-programmed cell death protein 1 (PD-1) inhibitor and an oncolytic reovirus would demonstrate a greater effect than either treatment alone, as non-muscle-invasive bladder cancer that is refractory to intravesical bacillus Calmette-Guérin can be treated by systemic anti-PD-1 immunotherapy and we previously demonstrated improved overall survival (OS) with six once-weekly instillations of intravesical anti-PD-1 in a murine model.
Materials And Methods:
Using an orthotopic syngeneic C3H murine model of MBT2 urothelial bladder cancer, groups of 10 mice were compared between no treatment, intravesical anti-PD-1, intravesical oncolytic reovirus, or intravesical reovirus + anti-PD-1. A single intravesical treatment session was given. The primary outcome was OS, and the secondary outcomes included long-term immunity and tumour-immune profile.
Results:
With a median follow-up of 9 months, all mice that received no treatment died with a median survival of 41 days, while the comparison median OS was not reached for reovirus (hazard ratio [HR] 14.4, 95% confidence interval [CI] 3.9-32.6; P < 0.001), anti-PD-1 (HR 28.4, 95% CI 7.0-115.9; P < 0.001), and reovirus + anti-PD-1 (HR 28.4, 95% CI 7.0-115.9; P < 0.001). Monotherapy with anti-PD-1 or reovirus demonstrated no significant differences in survival (P = 0.067). Mass cytometry showed that reovirus + anti-PD-1 treatment enriched monocytes and decreased myeloid-derived suppressor cells, generating an immuno-responsive tumour microenvironment. Depletion of CD8+ T cells eliminated the survival advantage provided by the intravesical treatment.
Conclusions:
Treatment of murine orthotopic bladder tumours with a single instillation of intravesical reovirus, anti-PD-1 antibody, or the combination confers superior survival compared to controls. Tumour-immune microenvironment differences indicated myeloid-derived suppressor cells and CD8+ T cells mediate the treatment response.
Insights
Combining intravesical oncolytic reovirus and anti-programmed cell death protein 1 (PD-1) therapy significantly improves survival in a murine bladder cancer model. This combination enhances the tumor immune microenvironment, offering a promising strategy for refractory cancers.
Area of Science:
- Oncology
- Immunotherapy
- Virology
Background:
- Non-muscle-invasive bladder cancer (NMIBC) refractory to bacillus Calmette-Guérin (BCG) can be treated with systemic anti-programmed cell death protein 1 (PD-1) immunotherapy.
- Previous studies demonstrated improved overall survival (OS) with intravesical anti-PD-1 in a murine model.
Purpose of the Study:
- To evaluate the efficacy of combining intravesical anti-PD-1 inhibitor and oncolytic reovirus compared to monotherapy.
- To assess the impact of combination therapy on survival and the tumor-immune microenvironment.
Main Methods:
- An orthotopic syngeneic C3H murine model of MBT2 urothelial bladder cancer was utilized.
- Mice received either no treatment, intravesical anti-PD-1, intravesical oncolytic reovirus, or a combination of both.
- Primary outcome was overall survival (OS); secondary outcomes included long-term immunity and tumor-immune profile analysis via mass cytometry.
Main Results:
- Combination therapy (reovirus + anti-PD-1) significantly improved OS compared to controls and monotherapy (P < 0.001).
- Monotherapy with either agent showed no significant difference in survival (P = 0.067).
- Mass cytometry revealed that combination treatment enriched monocytes, decreased myeloid-derived suppressor cells, and generated an immuno-responsive tumor microenvironment. Depletion of CD8+ T cells abrogated the survival benefit.
Conclusions:
- Intravesical instillation of oncolytic reovirus and anti-PD-1 antibody, alone or in combination, confers superior survival in a murine bladder cancer model.
- The combination therapy modulates the tumor-immune microenvironment, involving myeloid-derived suppressor cells and CD8+ T cells, which mediate the treatment response.
