LAUSR

Oncolytic viruses exert an anti‐tumour effect through two mechanisms: direct oncolytic and indirect immune‐mediated mechanisms. Although oncolytic herpes simplex virus type 1 (HSV‐1) has been approved for melanoma treatment and is being examined for its applicability to a broad spectrum of malignancies, it is not known whether it has an anti‐myeloma effect. In the present study, we show that the third‐generation oncolytic HSV‐1, T‐01, had a direct oncolytic effect on five of six human myeloma cell lines in vitro. The anti‐tumour effect was enhanced in the presence of peripheral blood mononuclear cells (PBMCs) from healthy individuals and, to a lesser extent, from patients with myeloma. The enhancing effect of PBMCs was abrogated by blocking type I interferons (IFNs) or by depleting plasmacytoid dendritic cells (pDCs) or natural killer (NK) cells, suggesting that pDC‐derived type I IFNs and NK cells dominated the anti‐tumour effect. Furthermore, the combination of T‐01 and lenalidomide exhibited enhanced cytotoxicity, and the triple combination of T‐01, lenalidomide and IFN‐α had a maximal effect. These data indicate that oncolytic HSV‐1 represents a viable therapy for plasma cell neoplasms through direct oncolysis and immune activation governed by pDCs and NK cells. Lenalidomide is likely to augment the anti‐myeloma effect of HSV‐1.