Efficacy of Oncolytic Herpes Simplex Virus T-VEC Combined with BET Inhibitors as an Innovative Therapy Approach for NUT Carcinoma

SIMPLE SUMMARY: Since T-VEC is already approved for treatment of melanoma, its promising efficacy shown here also for NUT carcinoma (NC) cell lines may create a rapid transition to individual treatments as well as clinical trials in NC patients. The idea of combining T-VEC immunotherapy with BET inhibitors is strengthened by the assumption that the initial rapid response of NC to BET inhibitor therapy and the additional direct tumor cell lysis triggered by virotherapeutics may be able to effectively stabilize or even shrink the tumor cell mass to bridge the time gap until the durable immune response, induced by immunovirotherapy, can lead to complete tumor remission. This would signify a real breakthrough for patients suffering from this extremely aggressive tumor, whose average survival time is currently in the range of only six months. ABSTRACT: NUT carcinoma (NC) is an extremely aggressive tumor and current treatment regimens offer patients a median survival of six months only. This article reports on the first in vitro studies using immunovirotherapy as a promising therapy option for NC and its feasible combination with BET inhibitors (iBET). Using NC cell lines harboring the BRD4-NUT fusion protein, the cytotoxicity of oncolytic virus talimogene laherparepvec (T-VEC) and the iBET compounds BI894999 and GSK525762 were assessed in vitro in monotherapeutic and combinatorial approaches. Viral replication, marker gene expression, cell proliferation, and IFN-β dependence of T-VEC efficiency were monitored. T-VEC efficiently infected and replicated in NC cell lines and showed strong cytotoxic effects. This implication could be enhanced by iBET treatment following viral infection. Viral replication was not impaired by iBET treatment. In addition, it was shown that pretreatment of NC cells with IFN-β does impede the replication as well as the cytotoxicity of T-VEC. T-VEC was found to show great potential for patients suffering from NC. Of note, when applied in combination with iBETs, a reinforcing influence was observed, leading to an even stronger anti-tumor effect. These findings suggest combining virotherapy with diverse molecular therapeutics for the treatment of NC.