Abstract
531 Background: Adenoviral delivery of the IFNα2b gene to the bladder urothelium enables prolonged exposure to high levels of IFNα2b protein, relative to intravesically-instilled IFNα protein treatments where short bladder dwell time limits exposure. As such, adenoviral-delivered IFNα2b has demonstrated clinical efficacy in patients with BCG-unresponsive NMIBC. The pleiotropic anti-tumor effects of IFNα include both stimulation of the host immune system and direct cytotoxicity of tumor cells. As clinical efficacy of adenoviral-delivered IFNα2b in the context of bladder cancer could be driven by immune-mediated or direct effects, or both, characterizing the cellular and molecular mechanisms of these activities is warranted. Methods: Here, we investigate the molecular mechanisms of tumor-intrinsic resistance to adenoviral-delivered or recombinant IFNα2b in a panel of bladder cancer cell line and patient-derived bladder cancer organoid models. Adenoviral vectors were constructed that express IFNα2b together with a GFP reporter (Ad-IFNα2b) or GFP alone (Ad-GFP), validated, and benchmarked against in vivo data from the literature. Bladder cancer cells and organoids were treated in vitro with rhIFNα2b, Ad-IFNα2b or conditioned media produced by Ad-IFNα2b infected cells, followed by measurements of cytotoxicity and gene expression in response to treatment. Results: Some bladder cancer models exhibited dose-dependent cytotoxicity in response to IFNα2b treatments, while others were resistant to these effects. Genomic and mRNA features associated with IFNα2b sensitivity/resistance are being evaluated and may inform future investigation of the mechanism of anti-tumor activity in patients. Additional studies to evaluate immune-mediated mechanisms are being conducted. Conclusions: Together, these studies will help to define the molecular mechanisms of response and resistance to IFNa2b treatment in bladder cancer patients.
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