Newly Characterized Murine Undifferentiated Sarcoma Models Sensitive to Virotherapy with Oncolytic HSV-1 M002

Abstract

Despite advances in conventional chemotherapy, surgical techniques, and radiation, outcomes for patients with relapsed, refractory, or metastatic soft tissue sarcomas are dismal. Survivors often suffer from lasting morbidity from current treatments. New targeted therapies with less toxicity, such as those that harness the immune system, and immunocompetent murine sarcoma models to test these therapies are greatly needed. We characterized two new serendipitous murine models of undifferentiated sarcoma (SARC-28 and SARC-45) and tested their sensitivity to virotherapy with oncolytic herpes simplex virus 1 (HSV-1). Both models expressed high levels of the primary HSV entry molecule nectin-1 (CD111) and were susceptible to killing by interleukin-12 (IL-12) producing HSV-1 M002 in vitro and in vivo. M002 resulted in a significant intratumoral increase in effector CD4+ and CD8+ T cells and activated monocytes, and a decrease in myeloid-derived suppressor cells (MDSCs) in immunocompetent mice. Compared to parent virus R3659 (no IL-12 production), M002 resulted in higher CD8:MDSC and CD8:T regulatory cell (Treg) ratios, suggesting that M002 creates a more favorable immune tumor microenvironment. These data provide support for clinical trials targeting sarcomas with oncolytic HSV-1. These models provide an exciting opportunity to explore combination therapies for soft tissue sarcomas that rely on an intact immune system to reach full therapeutic potential.

Tumor Cells Modified with Newcastle Disease Virus Expressing IL-24 as a Cancer Vaccine

“…LX/IL-24-modified tumor vaccine treatment also enhanced the function of the CD8 + T cells, as indicated by significantly higher proportion and numbers of IFN-γ-producing CD8 + T cells. The increased T cell infiltration in the tumor microenvironment is often correlated with improved clinical outcome in several cancers 31, 32, 33, 34. Recent studies also suggested that antitumor effects of immunotherapy by NDV could be enhanced when combined with immune checkpoint antibodies 35, 36.…”

Oncolytic Virus Encoding a Master Pro-Inflammatory Cytokine Interleukin 12 in Cancer Immunotherapy

“…Because an important control group is missing in this experimental setup (i.e., unarmed OHSV-infected irradiated tumor cells), it is not clear whether this anti-cancer vaccine effect in neuroblastoma was due to OHSV, local IL-12 expression, or both. In syngeneic sarcoma models, M002 did not produce any survival benefit compared to its parental virus R3659 (no IL-12 expression) [96], despite M002 inducing a significant anti-tumor immune effect over R3659 treatment, such as an increased percentage of intra-tumoral CD8 + T cells and activated monocytes, a decreased percentage of myeloid-derived suppressor cells (MDSCs), and increased CD8:MDSC and CD8:T regulatory cell ratios [96]. In recently performed pilot experiments in an ovarian cancer metastatic model, systemic intraperitoneal application of M002 resulted in a robust tumor-antigen specific CD8 + T cell response in the peritoneal cavity and the omentum [97], which are the primary sites of ovarian cancer metastasis [98].…”

Localized Interleukin-12 for Cancer Immunotherapy

“…Treatment was associated with tumor antigen-specific CD8 + T cell infiltration (238). Against flank SARC-043 and SARC-045 sarcomas, oHSV-IL-12 extended survival compared to saline injections (239). Although there was no difference is survival between control and IL-12 encoding oHSV, the oHSV-IL-12 was found to increase tumor-infiltrating effector T cells while decreasing immunosuppressive MDSC and T reg populations (239).…”