Combining Oncolytic HSV-1 with Immunogenic Cell Death-Inducing Drug Mitoxantrone Breaks Cancer Immune Tolerance and Improves Therapeutic Efficacy

Abstract

Although antitumor activity of herpes simplex virus 1 (HSV-1) ICP0 null oncolytic vectors has been validated in murine breast cancer models, oncolytic virus treatment alone is insufficient to break immune tolerance. Thus, we investigated enhancing efficacy through combination therapy with the immunogenic cell death-inducing chemotherapeutic drug, mitoxantrone. Despite a lack of enhanced cytotoxicity in vitro, HSV-1 ICP0 null oncolytic virus KM100 with 5 mmol/L mitoxantrone provided significant survival benefit to BALB/c mice bearing Her2/neu TUBO-derived tumors. This protection was mediated by increased intratumoral infiltration of neutrophils and tumor antigen-specific CD8 þ T cells. Depletion studies verified that CD8-, CD4-, and Ly6G-expressing cells are essential for enhanced efficacy of the combination therapy. Moreover, the addition of mitoxantrone to KM100 oncolytic virus treatment broke immune tolerance in BALB-neuT mice bearing TUBO-derived tumors. This study suggests that oncolytic viruses in combination with immunogenic cell death-inducing chemotherapeutics enhance the immunogenicity of the tumorassociated antigens, breaking immunologic tolerance established toward these antigens.

Anticancer metal drugs and immunogenic cell death

“…Mitoxantrone, as an anthracendione, is a structurally related DNA-intercalating compound clinically used for treatment of acute myeloid leukemia, non-Hodgkin's lymphoma and several solid tumors including breast and prostate cancer [38]. ICD induction by mitoxantrone in combination with an oncolytic virus was recently demonstrated to overcome immunologic tolerance established toward cancer antigens [39]. Bugaut et al reported about the ICD activity of the glycopeptide bleomycin, commonly employed for the treatment of testis cancer and Hodgkin lymphoma and acting comparable to anthracyclines primarily via ROS-mediated ER stress [40].…”

Immunogenic HSV-mediated Oncolysis Shapes the Antitumor Immune Response and Contributes to Therapeutic Efficacy

“…The values are average of three wells that used pooled splenocytes from five mice. of potent oncolytic viruses, along with the selection of appropriate combination therapies to enhance immunogenicity 34. …”

Genome-wide lentiviral shRNA screen identifies serine/arginine-rich splicing factor 2 as a determinant of oncolytic virus activity in breast cancer cells

“…4 Studies in preclinical murine tumor models showed that the antitumor activity of the prototype HSV-1 ICP0-null OV KM100 depends on whether the tumor model is tolerized. 4,6 Although in vitro tumor cell cytotoxicity mirrors the in vivo therapeutic efficacy of some OVs, 7 we fail to observe a similar correlation with our herpesvirus-based OVs, 5,6,8 despite the requirement for replication of competent vectors. 4 Thus, the complex molecular interactions that dictate permissivity of oncolytic HSVs in cancer cells remain elusive.…”

“…3 We have developed and tested the efficacy of HSV-1 deleted for the viral protein ICP0 as oncolytic vectors. [4][5][6] These OVs show modest in vitro oncolysis mainly in cancer cell types with impaired abilities to mount anti-viral responses. 4 Studies in preclinical murine tumor models showed that the antitumor activity of the prototype HSV-1 ICP0-null OV KM100 depends on whether the tumor model is tolerized.…”