Background The majority of nonmuscle invasive bladder cancer (NMIBC) cases progress towards muscle invasive disease. Transurethral resection followed by chemotherapy and/or BCG immunotherapy can stall progression in the minority of NMIBC cases. Cystectomy prior to muscle invasion provides the best option for survival. However, bladder removal significantly affects morbidity and quality of life. There are no effective treatment options for patients with chemo/BCG-resistant and late stage disease. Compared to other solid cancer types, the urinary bladder is an ideal organ to evaluate oncolytic virotherapies due to the urgent medical need for alternative bladder-sparing therapies and its established immunosensitivity to BCG therapy. The current study will determine whether a novel oncolytic Vesicular Stomatitis Virus (VSVd51) containing human immune transgenes can treat NMIBC.
Methods A novel recombinant OV containing a human immune transgene was rescued on the VSVd51 backbone. Features of immunogenic cell death (ICD) on mouse and human bladder cancer cell lines were measured by microscopy, flow cytometry, immunoblot, luminometry, qRT-PCR and ELISA following infection by recombinant VSVd51. The mediating role of immune effector cells was evaluated through pharmacologic in vivo depletion, while combination injection of recombinant VSVd51 following BCG failure was performed in the C57Bl/6-MB49 model. Measurements of ICD was additionally carried out in human BC spheroids and bladder cancer patient tissue following recombinant VSVd51 infection ex vivo.
Results Recombinant VSVd51 liberated danger signals (calreticulin, HMGB1, ATP) and immunogenic cytokines/chemokines were detected from infected mouse and human BC cell lines. Intravesical instillation of recombinant VSVd51 promoted enhanced activation of systemic and bladder infiltrating natural killer (NK) and cytotoxic CD8+ T cells. The increased functionality of NK and CD8+ T cells was associated with improved survival as determined through depletion studies. Moreover, improved survival and reduced bladder tumor volume was observed in recombinant VSVd51 treated mice who failed BCG therapy. In parallel, VSVd51-induced inflammation of the tumor microenvironment was recapitulated in human BC cell lines, spheroids and patient tissue exposed to recombinant VSVd51 infection.
Conclusions These translational results suggest that a recombinant VSVd51 is a promising immunotherapy that could provide a bladder-sparing therapeutic benefit in individuals diagnosed with NMIBC each year.
Ethics Approval The study was approved by the CIUSSS de l’Estrie CHUS Ethics Board, approval number 2018-2465.
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