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Retroviral Replicating Vector Toca 511 (Vocimagene Amiretrorepvec) for Prodrug Activator Gene Therapy of Lung Cancer
SIMPLE SUMMARY: A unique gene therapy strategy based on tumor-selectively replicating retroviral vectors has shown promising results in clinical trials for glioma and gastrointestinal cancers. Here, we applied this strategy to the treatment of lung cancer, the leading cause of cancer deaths worldwid...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9736610/ https://www.ncbi.nlm.nih.gov/pubmed/36497300 http://dx.doi.org/10.3390/cancers14235820 |
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author | Kushiya, Hiroki Hiraoka, Kei Suzuki, Tomohiro Inoko, Kazuho Inagaki, Akihito Niwa, Hiroki Sasaki, Katsunori Nakamura, Toru Tsuchikawa, Takahiro Shichinohe, Toshiaki Jolly, Douglas J. Kasahara, Noriyuki Hirano, Satoshi |
author_facet | Kushiya, Hiroki Hiraoka, Kei Suzuki, Tomohiro Inoko, Kazuho Inagaki, Akihito Niwa, Hiroki Sasaki, Katsunori Nakamura, Toru Tsuchikawa, Takahiro Shichinohe, Toshiaki Jolly, Douglas J. Kasahara, Noriyuki Hirano, Satoshi |
author_sort | Kushiya, Hiroki |
collection | PubMed |
description | SIMPLE SUMMARY: A unique gene therapy strategy based on tumor-selectively replicating retroviral vectors has shown promising results in clinical trials for glioma and gastrointestinal cancers. Here, we applied this strategy to the treatment of lung cancer, the leading cause of cancer deaths worldwide. Our results demonstrate that retroviral replicating vectors can achieve highly efficient delivery of reporter genes and prodrug activator genes to lung cancer cells in vitro and in vivo, with the latter enabling highly effective cancer cell killing upon exposure to prodrug, achieving significant therapeutic benefit in both subcutaneous and orthotopic pleural dissemination models of lung cancer. Retroviral replicating vector-based gene therapy thus represents a novel strategy with potential to address the unmet medical need for more effective ways to treat lung cancer. ABSTRACT: Therapeutic efficacy of retroviral replicating vector (RRV)-mediated prodrug activator gene therapy has been demonstrated in a variety of tumor models, but clinical investigation of this approach has so far been restricted to glioma and gastrointestinal malignancies. In the present study, we evaluated replication kinetics, transduction efficiency, and therapeutic efficacy of RRV in experimental models of lung cancer. RRV delivering GFP as a reporter gene showed rapid viral replication in a panel of lung cancer cells in vitro, as well as robust intratumoral replication and high levels of tumor transduction in subcutaneous and orthotopic pleural dissemination models of lung cancer in vivo. Toca 511 (vocimagene amiretrorepvec), a clinical-stage RRV encoding optimized yeast cytosine deaminase (yCD) which converts the prodrug 5-fluorocytosine (5-FC) to the active drug 5-fluorouracil (5-FU), showed potent cytotoxicity in lung cancer cells upon exposure to 5-FC prodrug. In vivo, Toca 511 achieved significant tumor growth inhibition following 5-FC treatment in subcutaneous and orthotopic pleural dissemination models of lung cancer in both immunodeficient and immunocompetent hosts, resulting in significantly increased overall survival. This study demonstrates that RRV can serve as highly efficient vehicles for gene delivery to lung cancer, and indicates the translational potential of RRV-mediated prodrug activator gene therapy with Toca 511/5-FC as a novel therapeutic strategy for pulmonary malignancies. |
format | Online Article Text |
id | pubmed-9736610 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-97366102022-12-11 Retroviral Replicating Vector Toca 511 (Vocimagene Amiretrorepvec) for Prodrug Activator Gene Therapy of Lung Cancer Kushiya, Hiroki Hiraoka, Kei Suzuki, Tomohiro Inoko, Kazuho Inagaki, Akihito Niwa, Hiroki Sasaki, Katsunori Nakamura, Toru Tsuchikawa, Takahiro Shichinohe, Toshiaki Jolly, Douglas J. Kasahara, Noriyuki Hirano, Satoshi Cancers (Basel) Article SIMPLE SUMMARY: A unique gene therapy strategy based on tumor-selectively replicating retroviral vectors has shown promising results in clinical trials for glioma and gastrointestinal cancers. Here, we applied this strategy to the treatment of lung cancer, the leading cause of cancer deaths worldwide. Our results demonstrate that retroviral replicating vectors can achieve highly efficient delivery of reporter genes and prodrug activator genes to lung cancer cells in vitro and in vivo, with the latter enabling highly effective cancer cell killing upon exposure to prodrug, achieving significant therapeutic benefit in both subcutaneous and orthotopic pleural dissemination models of lung cancer. Retroviral replicating vector-based gene therapy thus represents a novel strategy with potential to address the unmet medical need for more effective ways to treat lung cancer. ABSTRACT: Therapeutic efficacy of retroviral replicating vector (RRV)-mediated prodrug activator gene therapy has been demonstrated in a variety of tumor models, but clinical investigation of this approach has so far been restricted to glioma and gastrointestinal malignancies. In the present study, we evaluated replication kinetics, transduction efficiency, and therapeutic efficacy of RRV in experimental models of lung cancer. RRV delivering GFP as a reporter gene showed rapid viral replication in a panel of lung cancer cells in vitro, as well as robust intratumoral replication and high levels of tumor transduction in subcutaneous and orthotopic pleural dissemination models of lung cancer in vivo. Toca 511 (vocimagene amiretrorepvec), a clinical-stage RRV encoding optimized yeast cytosine deaminase (yCD) which converts the prodrug 5-fluorocytosine (5-FC) to the active drug 5-fluorouracil (5-FU), showed potent cytotoxicity in lung cancer cells upon exposure to 5-FC prodrug. In vivo, Toca 511 achieved significant tumor growth inhibition following 5-FC treatment in subcutaneous and orthotopic pleural dissemination models of lung cancer in both immunodeficient and immunocompetent hosts, resulting in significantly increased overall survival. This study demonstrates that RRV can serve as highly efficient vehicles for gene delivery to lung cancer, and indicates the translational potential of RRV-mediated prodrug activator gene therapy with Toca 511/5-FC as a novel therapeutic strategy for pulmonary malignancies. MDPI 2022-11-25 /pmc/articles/PMC9736610/ /pubmed/36497300 http://dx.doi.org/10.3390/cancers14235820 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Kushiya, Hiroki Hiraoka, Kei Suzuki, Tomohiro Inoko, Kazuho Inagaki, Akihito Niwa, Hiroki Sasaki, Katsunori Nakamura, Toru Tsuchikawa, Takahiro Shichinohe, Toshiaki Jolly, Douglas J. Kasahara, Noriyuki Hirano, Satoshi Retroviral Replicating Vector Toca 511 (Vocimagene Amiretrorepvec) for Prodrug Activator Gene Therapy of Lung Cancer |
title | Retroviral Replicating Vector Toca 511 (Vocimagene Amiretrorepvec) for Prodrug Activator Gene Therapy of Lung Cancer |
title_full | Retroviral Replicating Vector Toca 511 (Vocimagene Amiretrorepvec) for Prodrug Activator Gene Therapy of Lung Cancer |
title_fullStr | Retroviral Replicating Vector Toca 511 (Vocimagene Amiretrorepvec) for Prodrug Activator Gene Therapy of Lung Cancer |
title_full_unstemmed | Retroviral Replicating Vector Toca 511 (Vocimagene Amiretrorepvec) for Prodrug Activator Gene Therapy of Lung Cancer |
title_short | Retroviral Replicating Vector Toca 511 (Vocimagene Amiretrorepvec) for Prodrug Activator Gene Therapy of Lung Cancer |
title_sort | retroviral replicating vector toca 511 (vocimagene amiretrorepvec) for prodrug activator gene therapy of lung cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9736610/ https://www.ncbi.nlm.nih.gov/pubmed/36497300 http://dx.doi.org/10.3390/cancers14235820 |
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