Oncolytic virus therapy for hematological malignancies

Abstract

Oncolytic virus therapy has been emerging as an important modality of cancer immunotherapy. Oncolytic viruses exert an antitumor effect through two mechanisms: direct oncolytic and indirect immune-mediated mechanisms. Recombinant herpes simplex virus type 1 (HSV-1) has been leading the fi eld of oncolytic virus therapy, and has been approved for the treatment of advanced melanoma in the United States and Europe and of glioblastoma in Japan. Human hematopoietic cells are resistant to HSV-1 replication and thus oncolytic HSV-1 has been considered unsuitable to treat hematological malignancies. However, we showed that more than half of human hematological tumor cell lines and primary tumor cells derived from various lineages were susceptible to oncolytic HSV-1. The expression of an HSV-1 receptor, nectin-1, was critical to the susceptibility. In an immunocompetent mouse model, intratumoral injection of HSV-1 into lymphoma induced regression of injected, as well as non-injected, contralateral tumors accompanied by abundant infi ltration of antigen-specifi c CD8+ T cells. In addition, HSV-1 exerted an anti-myeloma effect in vitro through direct oncolysis and immune activation governed by plasmacytoid dendritic cells and NK cells. Lenalidomide augmented the anti-myeloma effect of HSV-1. These data suggest that intratumoral injection of oncolytic HSV-1 may be applicable to systemic hematological malignancies. Combination with other treatments, particularly immune checkpoint blockade, and further elucidation of antitumor mechanisms of oncolytic virus therapy are expected to advance the effi cacy of this promising modality of cancer immunotherapy.