The oncolytic vesicular stomatitis virus VSV-GP shows profound oncolytic activity in NUT-carcinoma cell lines.

NUT carcinoma (NC) is a rare, yet aggressive disease (median survival of 6.5 months) of the young defined by a translocation of the nuclear protein in testis gene 1 (NUTM1). Neither surgery nor radiochemotherapy or targeted therapies provide effective disease control, thereby creating a need for innovative therapeutic strategies. Recently, the recombinant oncolytic virus (OV) VSV-GP entered phase I clinical testing (NCT05155332). We (1) visualized VSV-GPs' replication cycle in transmission electron microscopy; (2) analyzed VSV-GP's oncolytic efficacy and replication kinetics using viability assays, xCELLigence analyses, RT-qPCR, TCID50 assays, and FACS analysis; as well as (3) explored potential resistance mechanisms in seven human NC cell lines. Upon infection with VSV-GP, we noticed profound oncolysis, apoptosis, and high replication kinetics in five out of seven NC cell lines. Investigations of molecular determinants of resistance showed that VSV-GPs' entry receptor α-dystroglycan was equally expressed by VSV-GP-permissive and -resistant cell lines. While synthesis of intrinsic interferon (IFN)-β was found to be suppressed in VSV-GP-infected NC cell lines, intracellular IFN-β signaling was functional. Since VSV-GP is a promising compound for virotherapy of NC patients, exploration of virus-induced immunogenicity and identification of resistance mechanisms could pave the way for additional combination treatment regimes in NC.