Solid cancers that metastasize to the lungs represent a major therapeutic challenge. Current treatment paradigms for lung metastases consist of radiation therapy, chemotherapies, and surgical resection, but there is no single treatment or combination that is effective for all tumor types. To address this, oncolytic myxoma virus (MYXV) engineered to express human tumor necrosis factor (vMyx-hTNF) was tested after systemic administration in an immunocompetent mouse K7M2-Luc lung metastatic osteosarcoma model. Virus therapy efficacy against pre-seeded lung metastases was assessed after systemic infusion of either naked virus or ex vivo -loaded autologous bone marrow leukocytes or peripheral blood mononuclear cells (PBMCs). Results of this study showed that the PBMC pre-loaded strategy was the most effective at reducing tumor burden and increasing median survival time, but sequential intravenous multi-dosing with naked virus was comparably effective to a single infusion of PBMC-loaded virus. PBMC-loaded vMyx-hTNF also potentially synergized very effectively with immune checkpoint inhibitors anti-PD-1, anti-PD-L1, and anti-cytotoxic T lymphocyte associated protein 4 (CTLA-4). Finally, in addition to the pro-immune stimulation caused by unarmed MYXV, the TNF transgene of vMyx-hTNF further induced the unique expression of numerous additional cytokines associated with the innate and adaptive immune responses in this model. We conclude that systemic ex vivo virotherapy with TNF-α-armed MYXV represents a new potential strategy against lung metastatic cancers like osteosarcoma and can potentially act synergistically with established checkpoint immunotherapies.

Immediate vitrectomy with endolaser for PDR-associated VH (< 30 days) decreases time spent with vision loss and the need for adjunctive PRP. Modern vitrectomy is safe and may be considered earlier in VH management.

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T cells are essential in controlling and clearing viral pathogens, but they also have the potential to induce immunopathology. We have previously shown that this balance between protection and pathology is dependent on the number of virus-specific T cells. Specifically, intermediate numbers of CD8 T cells result in lethal hemorrhagic disease, while lower doses result in exhaustion, and higher doses in viral clearance. Increasing the number of virus-specific CD4 T cells also leads to lethal hemorrhagic disease, however the mechanism by which T cells mediate this pathology remains unclear. Using lymphocytic choriomeningitis virus (LCMV) and an in vivo adoptive transfer mouse model, we found that lethal pathology induced by CD8 T cells is dependent on tumor necrosis factor (TNF). The absence of TNF signaling abrogates pathology without impeding viral clearance. Interestingly, CD4 T cell induced pathology, while dependent on CD8 T cells, still occurs in the absence of TNF. Furthermore, IL-2 produced by CD4 T cells modulates CD8 T cell responses to generate hemorrhagic disease that is TNF-dependent. Our findings show that TNF plays a significant role in T cell mediated hemorrhagic disease, and further implies that CD4 T cells modulate CD8 T cells to follow a different mechanism of pathology in the absence of this potent pro-inflammatory cytokine.