Systemic delivery of TNF-armed myxoma virus plus immune checkpoint inhibitor eliminates lung metastatic mouse osteosarcoma

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.

Oncolytic Viruses: Newest Frontier for Cancer Immunotherapy

“…For example, a live attenuated ZIKV vaccine candidate and a recombinant orthopoxvirus (CF33) oncolytic activity was enhanced by immunotherapy [ 118 , 119 ]. Oncolytic HSV-1 (ONCR-177), adenovirus (TILT-123), and MYXV (vMyx-hTNF) expressing single or multiple immune stimulatory cytokines enhanced oncolytic activity when combined with ICIs [ 120 , 121 , 122 ].…”

Systemic Delivery of mLIGHT-Armed Myxoma Virus Is Therapeutic for Later-Stage Syngeneic Murine Lung Metastatic Osteosarcoma

“…Previous studies using the K7M2 lung metastatic osteosarcoma model have shown that immune checkpoint inhibitors anti-PD-L1 and anti-CTLA-4 are efficacious when treatment is initiated very early after tumor seeding [ 11 , 12 ]. However, these immunotherapies lose efficacy when used in later-stage disease [ 13 ]. One way to improve and complement immunotherapy is to combine ICIs with an oncolytic virus [ 14 ].…”

“…Oncolytic virotherapy, on the whole, is currently exploring questions based around the genetic arming of the virus, and how to effectively deliver the virus to metastatic sites of tumors that are not amenable to direct intratumoral injection delivery [ 15 , 16 ]. One virus being studied both for optimal design, through transgene arming, and for systemic delivery to hard-to-reach cancer is oncolytic myxoma virus (MYXV) [ 13 , 17 , 18 ]. MYXV is a member of the poxvirus family poxviridae , and the genus leporipoxvirus [ 19 , 20 ].…”

“…Recently, oncolytic virotherapy using MYXV armed with human Tumor Necrosis Factor (vMyx-hTNF) delivered systemically by leukocyte carrier cells was used alone and in combination with immunotherapy in the luciferase-tagged K7M2 lung metastatic osteosarcoma model [ 13 ]. This study showed that anti-PD-L1 and vMyx-hTNF each can act as successful monotherapies for lung metastatic osteosarcoma, but only if animals are treated relatively early after tumor seeding.…”

“…Furthermore, when anti-PD-L1 therapy is used in combination with vMYX-hTNF the two modalities can act together to treat established tumors (as defined by threshold criteria of tumor cell luciferase expression levels of 5 × 10 5 luminescence units in the lung) at treatment start times, under conditions where both of the monotherapies were shown to be ineffective. These studies give powerful evidence that the combination of oncolytic viral therapy and ICIs is a potential new way forward in treatment in lung metastatic tumors [ 13 , 27 ]. However, even this combination loses efficacy in later-stage disease, thus stimulating further exploration for more effective transgenes expressed by oncolytic MYXV constructs.…”