Enhancing Oncolytic Immunotherapy through Induction of Immunogenic Cell Death

Abstract

Oncolytic viruses (OVs) are natural or engineered viruses that specifically infect and kill cancer cells without harming healthy tissues. Cancer cells killed by OV infection expose tumor antigens along with viral components and intracellular factors that mediate inflammation. Ideally, this process elicits an anti-tumor immune response that controls tumor growth. Herpes simplex virus type 1 (HSV-1) is a candidate OV that has proven therapeutic efficacy in preclinical cancer models. However, therapeutic efficacy of current oncolytic HSV-1 (oHSV-1) is limited in immunologically hot cancers such as melanoma. Here we showed that oHSV-1 expressing a modified B-box (HMB) of high mobility group box 1 (HMGB1), a potent ligand of toll-like receptor (TLR) 4-MD2, provides marginal therapeutic benefit in mice bearing breast cancer. Comparing with parental oHSV, tumor-bearing mice treated with oHSV-1-HMB showed improved survival and reduced tumor burden. Our results demonstrated the potential to improve oHSV-1 with immunogenic cell death modulators. We anticipate our oHSV-1-HMB to provide additive benefit with the combination of immunological checkpoint blockade.