Intravesical oncolytic virotherapy and immunotherapy for non-muscle-invasive bladder cancer mouse model

BJU Int. 2023 Sep;132(3):298-306. doi: 10.1111/bju.16012. Epub 2023 Apr 4.

Abstract

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.

Keywords: Intravesical therapy; Oncolytic therapy; genitourinary cancer/bladder cancer; immunotherapy; organism/animal model of cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravesical
  • Animals
  • BCG Vaccine / therapeutic use
  • CD8-Positive T-Lymphocytes / pathology
  • Disease Models, Animal
  • Immunotherapy
  • Mice
  • Mice, Inbred C3H
  • Non-Muscle Invasive Bladder Neoplasms*
  • Oncolytic Virotherapy*
  • Tumor Microenvironment
  • Urinary Bladder Neoplasms* / pathology

Substances

  • BCG Vaccine