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TGF-β Inhibition Improves Oncolytic Herpes Viroimmunotherapy in Murine Models of Rhabdomyosarcoma
Oncolytic viruses are an emerging class of cancer therapeutics that couple cytotoxicity with the induction of an anti-tumor immune response. Host-virus interactions are complex and modulated by a tumor microenvironment whose immunosuppressive activities can limit the effectiveness of cancer immunoth...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Society of Gene & Cell Therapy
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633823/ https://www.ncbi.nlm.nih.gov/pubmed/29034312 http://dx.doi.org/10.1016/j.omto.2017.09.001 |
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author | Hutzen, Brian Chen, Chun-Yu Wang, Pin-Yi Sprague, Les Swain, Hayley M. Love, Julia Conner, Joe Boon, Louis Cripe, Timothy P. |
author_facet | Hutzen, Brian Chen, Chun-Yu Wang, Pin-Yi Sprague, Les Swain, Hayley M. Love, Julia Conner, Joe Boon, Louis Cripe, Timothy P. |
author_sort | Hutzen, Brian |
collection | PubMed |
description | Oncolytic viruses are an emerging class of cancer therapeutics that couple cytotoxicity with the induction of an anti-tumor immune response. Host-virus interactions are complex and modulated by a tumor microenvironment whose immunosuppressive activities can limit the effectiveness of cancer immunotherapies. In an effort to improve this aspect of oncolytic virotherapy, we combined the oncolytic herpes virus HSV1716 with the transforming growth factor beta receptor 1 (TGF-βR1) inhibitor A8301 to treat syngeneic models of murine rhabdomyosarcoma. Mice that received HSV1716 or A8301 alone showed little to no benefit in efficacy and survival over controls. Conversely, mice given combination therapy exhibited tumor stabilization throughout the treatment regimen, which was reflected in significantly prolonged survival times including some complete responses. In vitro cell viability and virus replication assays showed that the rhabdomyosarcoma cell lines were generally insensitive to HSV1716 and A8301. Likewise, in vivo virus replication assays showed that HSV1716 titers moderately decreased in the presence of A8301. The enhanced efficacy instead appears to be dependent on the generation of an improved anti-tumor T cell response as determined by its loss in athymic nude mice and following in vivo depletion of either CD4(+) or CD8(+) cells. These data suggest TGF-β inhibition can augment the immunotherapeutic efficacy of oncolytic herpes virotherapy. |
format | Online Article Text |
id | pubmed-5633823 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-56338232017-10-13 TGF-β Inhibition Improves Oncolytic Herpes Viroimmunotherapy in Murine Models of Rhabdomyosarcoma Hutzen, Brian Chen, Chun-Yu Wang, Pin-Yi Sprague, Les Swain, Hayley M. Love, Julia Conner, Joe Boon, Louis Cripe, Timothy P. Mol Ther Oncolytics Article Oncolytic viruses are an emerging class of cancer therapeutics that couple cytotoxicity with the induction of an anti-tumor immune response. Host-virus interactions are complex and modulated by a tumor microenvironment whose immunosuppressive activities can limit the effectiveness of cancer immunotherapies. In an effort to improve this aspect of oncolytic virotherapy, we combined the oncolytic herpes virus HSV1716 with the transforming growth factor beta receptor 1 (TGF-βR1) inhibitor A8301 to treat syngeneic models of murine rhabdomyosarcoma. Mice that received HSV1716 or A8301 alone showed little to no benefit in efficacy and survival over controls. Conversely, mice given combination therapy exhibited tumor stabilization throughout the treatment regimen, which was reflected in significantly prolonged survival times including some complete responses. In vitro cell viability and virus replication assays showed that the rhabdomyosarcoma cell lines were generally insensitive to HSV1716 and A8301. Likewise, in vivo virus replication assays showed that HSV1716 titers moderately decreased in the presence of A8301. The enhanced efficacy instead appears to be dependent on the generation of an improved anti-tumor T cell response as determined by its loss in athymic nude mice and following in vivo depletion of either CD4(+) or CD8(+) cells. These data suggest TGF-β inhibition can augment the immunotherapeutic efficacy of oncolytic herpes virotherapy. American Society of Gene & Cell Therapy 2017-09-08 /pmc/articles/PMC5633823/ /pubmed/29034312 http://dx.doi.org/10.1016/j.omto.2017.09.001 Text en © 2017 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Hutzen, Brian Chen, Chun-Yu Wang, Pin-Yi Sprague, Les Swain, Hayley M. Love, Julia Conner, Joe Boon, Louis Cripe, Timothy P. TGF-β Inhibition Improves Oncolytic Herpes Viroimmunotherapy in Murine Models of Rhabdomyosarcoma |
title | TGF-β Inhibition Improves Oncolytic Herpes Viroimmunotherapy in Murine Models of Rhabdomyosarcoma |
title_full | TGF-β Inhibition Improves Oncolytic Herpes Viroimmunotherapy in Murine Models of Rhabdomyosarcoma |
title_fullStr | TGF-β Inhibition Improves Oncolytic Herpes Viroimmunotherapy in Murine Models of Rhabdomyosarcoma |
title_full_unstemmed | TGF-β Inhibition Improves Oncolytic Herpes Viroimmunotherapy in Murine Models of Rhabdomyosarcoma |
title_short | TGF-β Inhibition Improves Oncolytic Herpes Viroimmunotherapy in Murine Models of Rhabdomyosarcoma |
title_sort | tgf-β inhibition improves oncolytic herpes viroimmunotherapy in murine models of rhabdomyosarcoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633823/ https://www.ncbi.nlm.nih.gov/pubmed/29034312 http://dx.doi.org/10.1016/j.omto.2017.09.001 |
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