Abstract
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.
Highlights
The results of this study demonstrate the outstanding potential of TNF-armed myxoma virus (MYXV) as an oncolytic therapy for lung metastatic tumors, the use of mixed leukocyte carrier cells to improve the efficacy of treatment, and the ability of TNF-armed MYXV to synergize with approved immune checkpoint inhibitors (ICIs)
Tumors were allowed to engraft in the recipient lungs for 3 days before animals were treated with 2 Â 106 bone marrow (BM) cells ex vivo pre-loaded for 1 h with one of three test viruses: vMyx-M135 knockout (M135KO), vMyx-M11 knockout (M11KO), or vMyx-hTNF (MYXV expressing human TNF) (Figure 1A)
The unarmed knockout vMyx-M135KO and vMyx-M11LKO viruses were selected for screening based on previous oncolytic efficacy results in other tumor models.[31,38,39] vMyx-hTNF was selected for screening because we hypothesized that a generalized immune-enhancing cytokine ligand such as TNF, when preferentially expressed in the context of a tumor bed, might allow increased anti-tumor efficacy compared to unarmed viruses, while avoiding the toxic effects associated with systemic delivery of the purified cytokine
Summary
Cancer is the current second leading cause of death in Americans today, killing almost 600,000 Americans in 2020.1,2 As of 2020, cancer was only second to heart disease as cause of death in the United States.[2,3,4] While normally associated as a disease of advanced age, cancer is currently the fourth leading cause of death in adolescents and young adults.[5,6] commonly grouped together, malignant neoplasms of younger populations and those of older populations differ extensively in their incidence rates, origin, development, mutation load, and their response to therapies.[7,8] Osteosarcoma is one such cancer that is much more common in adolescents and young adults, but with a second peak in older populations.[9,10] It is currently the eighth most common childhood malignancy and is poorly treated after it has metastasized out of the primary site in the bone. Osteosarcoma is the most common form of primary malignancy arising in the bones[11,12] and develops from osteoblastic cells, especially during times of rapid bone growth, usually associated with the dysregulation of common tumor suppressors, including p53 and pRB.[9,13,14] there is a total gross survival rate of 68% over 5 years, treatment, prognosis, and survival are still dependent on many factors.[13] Current treatment strategies for osteosarcoma are highly dependent on the stage of the cancer at which the treatment is administered, with early intervention having positive outcomes; the prognosis for metastatic osteosarcoma is considerably worse, with the 5-year survival rate being 17% and the 10-year survival rate being 15%.15,16. Current treatment strategies for osteosarcoma are highly dependent on the stage of the cancer at which the treatment is administered, with early intervention having positive outcomes; the prognosis for metastatic osteosarcoma is considerably worse, with the 5-year survival rate being 17% and the 10-year survival rate being 15%.15,16 Given the poor prognosis associated with later stage osteosarcoma, the development of new treatment strategies is necessary
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