Oncolytic viruses (OV) are an emerging class of anticancer bio-therapeutics that induce antitumor immunity through selective replication in tumor cells. However, the efficacy of OVs as single agents remains limited. We introduce a strategy that boosts the therapeutic efficacy of OVs by combining their activity with immuno-modulating, small molecule protein tyrosine phosphatase inhibitors. We report that vanadium-based phosphatase inhibitors enhance OV infection in vitro and ex vivo, in resistant tumor cell lines. Furthermore, vanadium compounds increase antitumor efficacy in combination with OV in several syngeneic tumor models, leading to systemic and durable responses, even in models otherwise refractory to OV and drug alone. Mechanistically, this involves subverting the antiviral type I IFN response toward a death-inducing and pro-inflammatory type II IFN response, leading to improved OV spread, increased bystander killing of cancer cells, and enhanced antitumor immune stimulation. Overall, we showcase a new ability of vanadium compounds to simultaneously maximize viral oncolysis and systemic anticancer immunity, offering new avenues for the development of improved immunotherapy strategies.

Resistance to oncolytic virotherapy is frequently associated with failure of tumor cells to get infected by the virus. Dimethyl fumarate (DMF), a common treatment for psoriasis and multiple sclerosis, also has anticancer properties. We show that DMF and various fumaric and maleic acid esters (FMAEs) enhance viral infection of cancer cell lines as well as human tumor biopsies with several oncolytic viruses (OVs), improving therapeutic outcomes in resistant syngeneic and xenograft tumor models. This results in durable responses, even in models otherwise refractory to OV and drug monotherapies. The ability of DMF to enhance viral spread results from its ability to inhibit type I interferon (IFN) production and response, which is associated with its blockade of nuclear translocation of the transcription factor nuclear factor κB (NF-κB). This study demonstrates that unconventional application of U.S. Food and Drug Administration-approved drugs and biological agents can result in improved anticancer therapeutic outcomes.

The poor prognosis of patients with advanced bone and soft-tissue sarcoma has not changed in the past several decades, highlighting the necessity for new therapeutic approaches. Immunotherapies, including oncolytic viral (OV) therapy, have shown great promise in a number of clinical trials for a variety of tumor types. However, the effective application of OV in treating sarcoma still remains to be demonstrated. Although few pre-clinical studies using distinct OVs have been performed and demonstrated therapeutic benefit in sarcoma models, a side-by-side comparison of clinically relevant OV platforms has not been performed. Four clinically relevant OV platforms (Reovirus, Vaccinia virus, Herpes-simplex virus and Rhabdovirus) were screened for their ability to infect and kill human and canine sarcoma cell lines in vitro, and human sarcoma specimens ex vivo. In vivo treatment efficacy was tested in a murine model. The rhabdovirus MG1 demonstrated the highest potency in vitro. Ex vivo, MG1 productively infected more than 80% of human sarcoma tissues tested, and treatment in vivo led to a significant increase in long-lasting cures in sarcoma-bearing mice. Importantly, MG1 treatment induced the generation of memory immune response that provided protection against a subsequent tumor challenge. This study opens the door for the use of MG1-based oncolytic immunotherapy strategies as treatment for sarcoma or as a component of a combined therapy. Sarcomas are a rare and heterogeneous group of aggressive malignant solid tumors that, unlike carcinomas originating from epithelium, arise from a variety of mesenchymal tissues, such as muscle, connective tissue and bone. Sarcomas require a multimodal therapeutic approach that consists of multiagent chemotherapy, surgical resection and radiation. According to the National Cancer Institute, the overall 5-year survival rate for sarcoma patients is 50%, which drops to <20% for cases involving distant metastatic spread. As such, new treatment options for recurrent/metastatic sarcoma are direly needed.Immunotherapy could provide an alternative to chemotherapy yet there has been little focus on sarcoma in this field. This is likely due to sarcoma's heterogeneous nature and the relatively smaller number of patients it affects compared to carcinomas. However, immune checkpoint inhibitors, which have revolutionized the immunotherapy field and that have been very successful to date in melanoma (e.g., anti-CTLA4, anti-PD-1), have so far failed as monotherapies for sarcoma. 1Oncolytic viruses (OVs) constitute another form of an immunotherapy platform that has showed promising results in a broad range of cancers. OVs are engineered to take advantage of several hallmarks of cancer in order to preferentially replicate in tumor cells. Cancer-selective infection by OVs leads to cancer cell lysis and the parallel production of inflammatory cytokines, leading to innate and adaptive immune responses against both virus and tumor.2 OV treatment can lead to profound anti-tumor immune responses and cure...