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

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...

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Autores principales: Christie, John D., Appel, Nicole, Canter, Hannah, Achi, Jazmin Galvan, Elliott, Natalie M., de Matos, Ana Lemos, Franco, Lina, Kilbourne, Jacquelyn, Lowe, Kenneth, Rahman, Masmudur M., Villa, Nancy Y., Carmen, Joshua, Luna, Evelyn, Blattman, Joseph, McFadden, Grant
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8433070/
https://www.ncbi.nlm.nih.gov/pubmed/34553039
http://dx.doi.org/10.1016/j.omto.2021.07.014
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author Christie, John D.
Appel, Nicole
Canter, Hannah
Achi, Jazmin Galvan
Elliott, Natalie M.
de Matos, Ana Lemos
Franco, Lina
Kilbourne, Jacquelyn
Lowe, Kenneth
Rahman, Masmudur M.
Villa, Nancy Y.
Carmen, Joshua
Luna, Evelyn
Blattman, Joseph
McFadden, Grant
author_facet Christie, John D.
Appel, Nicole
Canter, Hannah
Achi, Jazmin Galvan
Elliott, Natalie M.
de Matos, Ana Lemos
Franco, Lina
Kilbourne, Jacquelyn
Lowe, Kenneth
Rahman, Masmudur M.
Villa, Nancy Y.
Carmen, Joshua
Luna, Evelyn
Blattman, Joseph
McFadden, Grant
author_sort Christie, John D.
collection PubMed
description 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.
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spelling pubmed-84330702021-09-21 Systemic delivery of TNF-armed myxoma virus plus immune checkpoint inhibitor eliminates lung metastatic mouse osteosarcoma Christie, John D. Appel, Nicole Canter, Hannah Achi, Jazmin Galvan Elliott, Natalie M. de Matos, Ana Lemos Franco, Lina Kilbourne, Jacquelyn Lowe, Kenneth Rahman, Masmudur M. Villa, Nancy Y. Carmen, Joshua Luna, Evelyn Blattman, Joseph McFadden, Grant Mol Ther Oncolytics Original Article 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. American Society of Gene & Cell Therapy 2021-08-06 /pmc/articles/PMC8433070/ /pubmed/34553039 http://dx.doi.org/10.1016/j.omto.2021.07.014 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Original Article
Christie, John D.
Appel, Nicole
Canter, Hannah
Achi, Jazmin Galvan
Elliott, Natalie M.
de Matos, Ana Lemos
Franco, Lina
Kilbourne, Jacquelyn
Lowe, Kenneth
Rahman, Masmudur M.
Villa, Nancy Y.
Carmen, Joshua
Luna, Evelyn
Blattman, Joseph
McFadden, Grant
Systemic delivery of TNF-armed myxoma virus plus immune checkpoint inhibitor eliminates lung metastatic mouse osteosarcoma
title Systemic delivery of TNF-armed myxoma virus plus immune checkpoint inhibitor eliminates lung metastatic mouse osteosarcoma
title_full Systemic delivery of TNF-armed myxoma virus plus immune checkpoint inhibitor eliminates lung metastatic mouse osteosarcoma
title_fullStr Systemic delivery of TNF-armed myxoma virus plus immune checkpoint inhibitor eliminates lung metastatic mouse osteosarcoma
title_full_unstemmed Systemic delivery of TNF-armed myxoma virus plus immune checkpoint inhibitor eliminates lung metastatic mouse osteosarcoma
title_short Systemic delivery of TNF-armed myxoma virus plus immune checkpoint inhibitor eliminates lung metastatic mouse osteosarcoma
title_sort systemic delivery of tnf-armed myxoma virus plus immune checkpoint inhibitor eliminates lung metastatic mouse osteosarcoma
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8433070/
https://www.ncbi.nlm.nih.gov/pubmed/34553039
http://dx.doi.org/10.1016/j.omto.2021.07.014
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