Combination of oncolytic Maraba virus with immune checkpoint blockade overcomes therapy resistance in an immunologically cold model of advanced melanoma with dysfunctional T cell receptor signalling

Oncolytic viruses are promising immunotherapeutic agents, but their efficacy, particularly following intra-tumoural injection, in relation to the size of the targeted tumour, is unclear. Here we show that an oncolytic rhabdovirus, maraba, activates an immune response in human as well as mouse pre-clinical systems, which targets viral as well as tumour-associated antigens. The addition of immune checkpoint blockade to virotherapy is apparent only on the treatment of larger tumours, which have an inherently more immunosuppressive tumour microenvironment, including skewing of T cell receptor engagement with antigen from conventional to regulatory CD4+ cells. Maraba converts the immunologically cold tumour to hot, thus priming the tumour microenvironment for effective αPD1 combination therapy. This study supports the use of maraba oncolytic virotherapy in combination with immune checkpoint inhibitors in melanoma and highlights the impact of the tumour burden on the immune microenvironment and benefit of single agent and combination treatment. To investigate therapeutic effects of Maraba oncolytic viral treatment, we used five- to six-week-old female C57Bl/6 mice (Charles River, UK) or Nr4a3 Tocky mice (C57Bl/6 background), inoculated with 4434 thyroid cancer murine melanoma tumour cells.