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

John D. Christie, Nicole Appel, Hannah Canter, Jazmin Galvan Achi, Natalie M. Elliott, Ana Lemos de Matos, Lina Franco, Jacquelyn Kilbourne, Kenneth Lowe, Masmudur M. Rahman, Nancy Y. Villa, Joshua Carmen, Evelyn Luna, Joseph Blattman, Grant McFadden

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)539-554
Number of pages16
JournalMolecular Therapy - Oncolytics
Volume22
DOIs
StatePublished - Sep 24 2021

Keywords

  • ICI
  • K7M2
  • PBMCs
  • TNF-alpha
  • armed oncolytic virus
  • bone marrow
  • carrier cells
  • immune checkpoint inhibitors
  • myxoma virus
  • osteosarcoma

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research
  • Pharmacology (medical)

Fingerprint

Dive into the research topics of 'Systemic delivery of TNF-armed myxoma virus plus immune checkpoint inhibitor eliminates lung metastatic mouse osteosarcoma'. Together they form a unique fingerprint.

Cite this