GSK1324726A

Autologous PBMCs were co-cultured with irradiated tumor cells pre-treated with MYC inhibitors (I-BET726, JQ1) and a STING antagonist (C170) to enhance immunogenicity and train tumor-specific PBMCs. This study provides preliminary evidence supporting the efficacy of a personalized, PBMC-based immunotherapy for neuroblastoma. These findings highlight the potential for further development of this approach as a novel treatment strategy, paving the way for improved clinical outcomes in pediatric oncology.

However, differential effects were observed in response to bromodomain and extraterminal (BET) protein inhibitors (JQ1, GSK1324726A) and to the CDK-7 inhibitor THZ1, with BET inhibitors preferentially affecting chromaffin cells, and THZ1 preferentially affecting neuroblasts. The differential dependence of chromaffin cells and neuroblasts on BET and CDK signaling may indicate different mechanisms during tumor initiation in sympathetic ganglia and adrenal.

Cultured B16F10 cells and human UM cells were treated with the histone deacetylase inhibitor (HDACi) entinostat or BETi JQ1...Co-treatment with the bioavailable BETi iBET726 impaired the immunotherapy effect...Indeed, co-cultures of UM with HLA-matched melanoma-specific tumor-infiltrating lymphocytes (TILs) resulted in higher TIL-mediated melanoma killing when entinostat was added. Further exploration of combined immunotherapy and epigenetic therapy in metastatic melanoma resistant to PD-1 inhibition is warranted.