TY - JOUR
T1 - Intravesical oncolytic virotherapy and immunotherapy for non-muscle-invasive bladder cancer mouse model
AU - Smelser, Woodson W.
AU - Wang, Jian
AU - Ogden, Kristen M.
AU - Chang, Sam S.
AU - Kirschner, Austin N.
N1 - Publisher Copyright:
© 2023 BJU International.
PY - 2023/9
Y1 - 2023/9
N2 - 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.
AB - 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.
KW - Intravesical therapy
KW - Oncolytic therapy
KW - genitourinary cancer/bladder cancer
KW - immunotherapy
KW - organism/animal model of cancer
UR - http://www.scopus.com/inward/record.url?scp=85151935135&partnerID=8YFLogxK
U2 - 10.1111/bju.16012
DO - 10.1111/bju.16012
M3 - Article
C2 - 36961272
AN - SCOPUS:85151935135
SN - 1464-4096
VL - 132
SP - 298
EP - 306
JO - BJU international
JF - BJU international
IS - 3
ER -