Development of oncolytic virus combination immunotherapy for the treatment of multiple myeloma

Multiple Myeloma (MM) is a haematological malignancy characterised by a clonal expansion of malignant plasma cells within the bone marrow that culminates in disseminated disease. MM has a high rate of relapse from current therapies and is currently considered incurable.
Oncolytic viruses (OV) selectively infect and kill malignant cells over healthy cells. This is due to a number of mechanisms, including their natural tropism and/or synthetic genetic modifications. In addition to selective tumour cell killing, OV also activate an anti-tumour immune response. Several OV were screened before reovirus was selected as the OV of interest for this study. Reovirus can reduce tumour burden and increase the immunogenicity of MM cells in both in vitro and in vivo studies. Clinical trials of reovirus have noted potent infection of MM cells within the bone marrow, but an absence of lytic cell death. Thus, the overall aim of this study was to evaluate potential combination partners to improve the effectiveness of reovirus in MM.
Histone deacetylase (HDAC) inhibitors (e.g., panobinostat) are a class of compounds used to treat MM. While they have poor efficacy as solo agents, they can alter the expression of a wide array of genes, potentiating the efficacy of other compounds. Herein, pre-treatment with HDAC inhibitors increased the rate of reovirus infection of MM cells, increasing reovirus-mediated cell death. The results obtained also established that panobinostat and reovirus in combination elicits a similar immune response to reovirus alone and may improve antigen-specific immune responses. Importantly, this is the first study to evidence the effectiveness of panobinostat/reovirus combination treatment using MM patient samples alongside an immunocompetent mouse model of MM.
In conclusion, HDAC inhibitors can potentiate the key anti-tumour mechanisms of OV therapy. This combination has the potential to improve outcomes in MM patients and synergise with other immunotherapy treatments.