597 In situ vaccination with oncolytic vesicular stomatitis virus improves anti-tumor immune response and outcome in bladder cancer
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".