Oncolytic virotherapy provides a potent therapy option for squamous bladder cancer

Abstract

Abstract Prognosis for squamous cell carcinoma (SCC) of the bladder is limited mostly because of lack of effective treatment regimens. Oncolytic virotherapy represents a promising option for bladder cancer and received in 2024 FDA therapy designation for the treatment of non-invasive high-grade bladder cancer (BLCA). For muscle-invasive bladder cancer (MIBC), preclinical studies demonstrated high efficacy of the oncolytic adenovirus XVir-N-31 in urothelial carcinoma (UC). We analyzed the potency of XVir-N-31 virotherapy as a novel treatment option in SCC. Replication of XVir-N-31 has been described to be facilitated by high expression level of Y-Box binding protein 1 (YB-1). Increased YB-1-mRNA expression was detected in basal/squamous subtype in TCGA BLCA cohort compared to urothelial and luminal BLCA and correlated with patient outcomes. Furthermore, immunohistochemical staining of 89 SCC on a tissue microarray confirmed strong YB-1 expression in squamous BLCA (sq-BLCA). In vitro, XVir-N-31 showed in subtype-specific cell cultures high rates of infection, replication and cell-killing capacity. In a novel in ovo xenograft model, XVir-N-31 impaired growth of xenografts of patient-derived ex vivo cell lines (p-SCC, p-UC) with growth suppression rates of 39–49%. We provide preclinical evidence ex vivo and in ovo for high efficacy of XVir-N-31 based oncolytic virotherapy as novel SCC therapy.