Combination of the oral histone deacetylase inhibitor resminostat with oncolytic measles vaccine virus as a new option for epi-virotherapeutic treatment of hepatocellular carcinoma (HCC)

Einleitung: Oncolytic viruses represent a novel therapeutic approach (so called virotherapy) in the treatment of malignant neoplasias, employing their ability to selectively infect, replicate in and (onco-) lyse tumor cells without affecting normal tissues. Nevertheless, in monotherapy virotherapeutics were found to face various limitations in recent clinical trials. To address those limitations, epigenetic compounds, especially histone deacetylase inhibitors (HDACi), seem to be qualified for putative combination strategies (i.e. epi-virotherapeutic) in the field of oncolytic virotherapy.

Material und Methoden: Here, we investigated the combination treatment of the state-of-the-art oncolytic measles vaccine virus (MeV-SCD; Berchtold et al., Journal of Virology 2013,87:3484) together with the HDACi resminostat (Res), in three HCC-derived cell lines. Residual tumor cell masses were analyzed by Sulforhodamine B viability assay. Influences on cell cycle profiles and primary infection rates were examined by flow cytometry. Influence of resminostat on viral replication was investigated by working out viral growth curves. Immunoblotting was used to illustrate the impact of resminostat on cellular innate immunity signaling.

Ergebnisse: We found (i) an improved rate of primary infections of human hepatoma cells when using oncolytic MeV under concurrent treatment with resminostat. We further found (ii) a boosted cytotoxic effect of the epi-virotherapeutic combination (Res + MeV) with enhanced induction of apoptosis. Quite importantly, we also found (iii) an absence of any resminostat-induced impairment of MeV replication and spread. Beyond that, we also could show (iv) that resminostat is able to prevent the induction of interferon-stimulated genes (ISG), being highly instrumental in overcoming resistances to MeV-mediated oncolysis.

Schlussfolgerung: Our results clearly demonstrate that co-administration of resminostat with oncolytic measles vaccine viruses could help to overcome current limitations of MeV-based monotherapies, supporting the onset of future epi-virotherapeutic clinical trials in patients exhibiting advanced stages of HCC. Beyond that, further epi-virotherapeutic combination approaches also warrant detailed investigations in other malignancies.