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

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.

NUT carcinoma in pediatric patients: Characteristics, therapeutic regimens, and outcomes of 11 cases registered with the German Registry for Rare Pediatric Tumors (STEP)

“…This treatment follows preclinical data and a case report of an adult patient, resulting in an OS of 3.5 years after diagnosis and a MR at last follow up (June 2023). 18,19 This patient demonstrated response of nonirradiated tumor sites to chemoimmunovirotherapy, although it is not possible to distinguish which therapy element was responsible for the response. Details of therapy and the outcome will be reported separately.…”

“…After progressive disease with pembrolizumab monotherapy, one patient received a novel treatment strategy with pembrolizumab, conventional chemotherapy, and virotherapy with the oncolytic herpes simplex virus T‐VEC (Imlygic ® ). This treatment follows preclinical data and a case report of an adult patient, resulting in an OS of 3.5 years after diagnosis and a MR at last follow up (June 2023) 18,19 . This patient demonstrated response of nonirradiated tumor sites to chemo‐immunovirotherapy, although it is not possible to distinguish which therapy element was responsible for the response.…”

Case report: Immunovirotherapy as a novel add-on treatment in a patient with thoracic NUT carcinoma

“…The oncolytic virus T-VEC has already shown promising anti-tumoral effects in advanced sarcomas, particularly in a combinatorial treatment with the ICI pembrolizumab ( 38 ). Recently, we presented highly promising in vitro results exhibiting a very profound direct oncolysis in NC cell lines when being infected by T-VEC ( 39 ). Based on these results, we initiated for the first time an immunovirotherapy as a novel add-on treatment in a patient with thoracic NUT carcinoma.…”

“…Since replication of T-VEC in the addressed tumor sites is accompanied by a continuous release of immunostimulatory GM-CSF (being encoded in T-VEC as a transgene ( 39 )) notable changes in the composition of the respective tumor micro-environments are triggered. A post treatment tumor specimen obtained from our NC patient at day 98 revealed (i) a partial necrosis, (ii) a switch from a CD3+CD4+ dominant to a CD3+CD8+ dominant lymphocyte infiltrate as well as (iii) an increased number of tumor infiltrating macrophages ( Figure S1 and S2 ).…”

Role of HOXA9 in solid tumors: mechanistic insights and therapeutic potential

“…Bardini et al reported that another BET inhibitor I-BET151 blocked the growth of MLL-AF4+ leukemic cells through affecting the transcription level of BRD4, HOXA7/HOXA9, and RUNX1 [ 150 ]. At present, fourteen BET inhibitors including AZD5153 [ 151 ], BMS-986158 [ 152 ], BI894999 [ 153 ], GS-5829 [ 154 ], GSK525762 [ 155 ], ABBV-075 [ 156 ], CPI-0610 [ 157 ], INCB057643 [ 158 ], OTX-015 [ 159 ], PLX51107 [ 160 ], INCB054329 [ 161 ], FT-1101 [ 162 ], CC-90010 [ 163 ], and ODM-207 [ 164 ] have been entered in the clinical testing.…”