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.
Vaccination remains one of the most effective strategies for preventing human diseases caused by infectious pathogens, yet developing an efficacious vaccine for persistent viral infections such as HIV remains a difficult aim of much research. Vaccines expressing pathogen T cell epitopes has been a widely employed strategy to try and improve the efficacy of vaccines against chronic viral infections. However, selectively engaging T cells has the potential to increase rather than prevent pathology during subsequent infection, consequently shifting a mild disease to a lethal one. Thus, determining the immune parameters that lead to protection versus those that mediate pathology is critical for developing a safe and effective vaccine against persistent viral infections. Using lymphocytic choriomeningitis virus (LCMV) we investigated how the precursor frequency of CD8 T cells affects the balance of protection vs. pathology during chronic viral infection. We found that the balance is based largely on the number of T cells responding to the pathogen. Intermediate numbers of responding CD8 T cells resulted in maximum pathology. We have also observed that increasing vaccine-induced CD4 T cell responses, unlike CD8 T cells, never leads to protection, but instead high host mortality. We have now began to study the interaction of CD8 and CD4 T cells during infection to determine what effect CD4 T cells have in protective versus pathologic vaccine-induced immunity and what exactly mediates such responses.
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.
Vaccines expressing pathogen T cell epitopes have been a widely pursued strategy for improving the efficacy of vaccines against persistent viral infections such as HIV. However, selectively engaging T cells also has the potential to increase rather than prevent pathology, consequently shifting a mild disease to a lethal one after subsequent infection. Thus, determining the immune and viral parameters that lead to protection versus those that mediate pathology is critical for developing a safe and effective vaccine against persistent viral infections. Using lymphocytic choriomeningitis virus (LCMV) and an in vivo adoptive transfer mouse model, we investigated how the precursor frequency of CD8 T cells affected the balance of protection vs. pathology during chronic viral infection. We found that the balance is based largely on the number of T cells responding to the pathogen. Intermediate numbers of responding CD8 T cells results in maximum pathology while high numbers provide full protection. We also looked at CD4 T cells and unlike CD8 T cells, increasing the number of pathogen specific CD4 T cells never provides a protective response and instead leads to high host mortality. We have now begun to study the interaction of CD8 and CD4 T cells simultaneously during viral infection to determine the effects of CD4 T cells on CD8 T cell protective versus pathologic vaccine-induced immunity and what exactly mediates such responses.
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