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Poster Presentation
Oncolytic immunotherapy for the treatment of non-muscle invasive bladder cancer using intravesical coxsackievirus A21
  1. Nicola E Annels1,
  2. Guy Simpson1,
  3. Mehreen Arif1,
  4. Mick Denyer1,
  5. Attya Iqbal1,
  6. David Mansfield2,
  7. Sarbjinder Sandhu3,
  8. Alan Melcher4,
  9. Kevin Harrington5,
  10. Gough Au6,
  11. Mark Grose7,
  12. Darren Shafren8,
  13. Hugh Mostafid1 and
  14. Hardev Pandha1
  1. Aff1 grid.5475.30000000404074824University of Surrey Guildford UK
  2. Aff2 grid.18886.3f0000000112714623The Institute of Cancer Research London UK
  3. Aff3 grid.5475.30000000404074824University of surrey Guildford UK
  4. Aff4 grid.443984.6St. James's Institute of OncologySt. James's University Hospital Leeds UK
  5. Aff5 grid.18886.3f0000000112714623Institute of Cancer Research and Royal Marsden Hospital London UK
  6. Aff6 grid.266842.c000000008831109XThe University of Newcastle Newcastle Australia
  7. Aff7 Viralytics Limited Toronto ON Canada
  8. Aff8 Viralytics Sydney Australia

https://doi.org/10.1186/2051-1426-3-S2-P331

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    Meeting abstracts

    Background

    As a clinical setting in which local live biological therapy is already well established, nonmuscle invasive bladder cancer (NMIBC) presents intriguing opportunities for oncolytic virotherapy. Coxsackievirus A21 (CVA21) is a novel intercellular adhesion molecule-1 (ICAM-1) targeted immunotherapeutic virus. Combining CVA21 with low doses of chemotherapy (Mitomycin C) enhances CVA21 viral replication and oncolysis by increasing expression levels of ICAM1 on bladder cancer cells. As well as initiating oncolysis, oncolytic viruses can also induce immunogenic cell death (ICD) determinants which is thought to be the optimal way to trigger a tumour-specific response and crucial for long-term therapeutic success. This study set out to confirm the enhanced cytotoxicity in vitro of bladder cancer cell lines and tissues following combined treatment of mitomycin C and CVA21 and to demonstrate the induction of immunogenic cell death determinants.

    Methods

    Characterization of CVA21 cytotoxicity in a panel of 6 bladder cancer cell lines yielded a range of sensitivities. CVA21 cytotoxicity largely correlated with expression of the viral receptor ICAM-1. CAV21 in combination with Mitomycin C resulted in up-regulation of ICAM-1 and significantly increased cytotoxicity over CVA21 alone. Furthermore, CVA21 induced the expression of multiple ICD determinants (calreticulin, ATP and HMGB1 release) and the immunogenic cell marker, Fas, associated with susceptibility to immune attack. The expression of these immunogenic markers was up-regulated in the CVA21 and combination treated cells as compared to Mitomycin C only and untreated cells. The caspase-glow 3/7 assay revealed apoptosis as the primary mode of death. This was further confirmed with the use of an apoptotic inhibitor (Z-VAD-FMK) which significantly inhibited cell-death of CVA21 infected cells.

    Results

    The above data provided the rationale for a two stage Phase I study in which patients with NMIBC receive neoadjuvant CVA21 or low dose Mitomycin C plus CVA21 prior to routine surgical removal (TURBT). The Phase I/II CANON (CAVATAK in NONMuscle invasive bladder cancer: NCT02316171) study investigating the tolerance of multiple escalating intravesicular doses of CVA21 has shown general tolerance of the intravesicular CVA21 treatment. Serial photography has identified possible evidence of viral induced surface haemorrhage and inflammation of the tumour micro-environment. Potential multicycle virus replication within the tumour was highlighted by detection of secondary viral load peaks in the urine as evidenced by RTPCR and infectious TCID50 assays.

    Conclusions

    TURBT tissue analysis displayed marked tumour specific cytoplasmic viral protein expression and widespread evidence of viral-induced apoptotic cell death.