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

Area of Science:

• Oncology
• Virology
• Immunotherapy

Background:

• Lung metastases from solid tumors pose a significant therapeutic challenge.
• Current treatments like radiation, chemotherapy, and surgery lack universal efficacy for all lung metastasis types.

Purpose of the Study:

• To evaluate the efficacy of oncolytic myxoma virus (MYXV) engineered to express human tumor necrosis factor (vMyx-hTNF) against lung metastases.
• To compare different systemic administration strategies for vMyx-hTNF, including naked virus and ex vivo-loaded cells.

Main Methods:

• An immunocompetent mouse model (K7M2-Luc) with pre-seeded lung osteosarcoma metastases was used.
• vMyx-hTNF was administered systemically as naked virus or loaded onto autologous bone marrow leukocytes or peripheral blood mononuclear cells (PBMCs).
• Therapeutic efficacy was assessed by tumor burden reduction and survival time, and potential synergy with immune checkpoint inhibitors was explored.

Main Results:

• The PBMC pre-loaded strategy demonstrated the greatest reduction in tumor burden and increased median survival.
• Sequential intravenous multi-dosing with naked virus showed comparable efficacy to a single infusion of PBMC-loaded virus.
• PBMC-loaded vMyx-hTNF showed potential synergy with immune checkpoint inhibitors (anti-PD-1, anti-PD-L1, anti-CTLA-4).
• vMyx-hTNF induced pro-immune stimulation and enhanced expression of cytokines involved in innate and adaptive immune responses.

Conclusions:

• Systemic ex vivo virotherapy using TNF-α-armed MYXV is a promising strategy for lung metastatic cancers like osteosarcoma.
• This approach can potentially synergize with established checkpoint immunotherapies.
• The engineered virus enhances both direct anti-tumor effects and immune responses.