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Developing and characterizing a two-layered safety switch for cell therapies
Gene edited and engineered cell-based therapies are a promising approach for treating a variety of disorders, including cancer. However, the ability of engineered cells to persist for prolonged periods along with possible toxicity raises concerns over the safety of these approaches. Although a numbe...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10348026/ https://www.ncbi.nlm.nih.gov/pubmed/37439774 http://dx.doi.org/10.1080/15384047.2023.2232146 |
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author | Rossignoli, Filippo Hoffman, Danielle Atif, Emaan Shah, Khalid |
author_facet | Rossignoli, Filippo Hoffman, Danielle Atif, Emaan Shah, Khalid |
author_sort | Rossignoli, Filippo |
collection | PubMed |
description | Gene edited and engineered cell-based therapies are a promising approach for treating a variety of disorders, including cancer. However, the ability of engineered cells to persist for prolonged periods along with possible toxicity raises concerns over the safety of these approaches. Although a number of different one-dimensional suicide systems have been incorporated into therapeutic cell types, the incorporation of a two-layered suicide system that allows controlled killing of therapeutic cells at different time points is needed. In this study, we engineered a variety of therapeutic cells to express two different kill switches, RapaCasp9 and HSV-TK and utilized Rapamycin and Ganciclovir respectively to activate these kill switches. We show that the function of both RapaCasp9 and HSV-TK molecules is preserved and can be activated to induce apoptosis detected early (24 h) and late (48 h) post-activation respectively, with no toxicity. In vivo, we show the eradication of a majority of cells after treatment in subcutaneous and orthotopic models. Furthermore, we demonstrate how both suicide switches work independently and can be activated sequentially for an improved killing, thus ensuring a failsafe mechanism in case the activation of a single one of them is not sufficient to eliminate the cells. Our findings highlight the reliability of the double suicide system, effective on a variety of cells with different biological characteristics, independent of their anatomic presence. |
format | Online Article Text |
id | pubmed-10348026 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-103480262023-07-15 Developing and characterizing a two-layered safety switch for cell therapies Rossignoli, Filippo Hoffman, Danielle Atif, Emaan Shah, Khalid Cancer Biol Ther Research Paper Gene edited and engineered cell-based therapies are a promising approach for treating a variety of disorders, including cancer. However, the ability of engineered cells to persist for prolonged periods along with possible toxicity raises concerns over the safety of these approaches. Although a number of different one-dimensional suicide systems have been incorporated into therapeutic cell types, the incorporation of a two-layered suicide system that allows controlled killing of therapeutic cells at different time points is needed. In this study, we engineered a variety of therapeutic cells to express two different kill switches, RapaCasp9 and HSV-TK and utilized Rapamycin and Ganciclovir respectively to activate these kill switches. We show that the function of both RapaCasp9 and HSV-TK molecules is preserved and can be activated to induce apoptosis detected early (24 h) and late (48 h) post-activation respectively, with no toxicity. In vivo, we show the eradication of a majority of cells after treatment in subcutaneous and orthotopic models. Furthermore, we demonstrate how both suicide switches work independently and can be activated sequentially for an improved killing, thus ensuring a failsafe mechanism in case the activation of a single one of them is not sufficient to eliminate the cells. Our findings highlight the reliability of the double suicide system, effective on a variety of cells with different biological characteristics, independent of their anatomic presence. Taylor & Francis 2023-07-13 /pmc/articles/PMC10348026/ /pubmed/37439774 http://dx.doi.org/10.1080/15384047.2023.2232146 Text en © 2023 The Author(s). Published with license by Taylor & Francis Group, LLC. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent. |
spellingShingle | Research Paper Rossignoli, Filippo Hoffman, Danielle Atif, Emaan Shah, Khalid Developing and characterizing a two-layered safety switch for cell therapies |
title | Developing and characterizing a two-layered safety switch for cell therapies |
title_full | Developing and characterizing a two-layered safety switch for cell therapies |
title_fullStr | Developing and characterizing a two-layered safety switch for cell therapies |
title_full_unstemmed | Developing and characterizing a two-layered safety switch for cell therapies |
title_short | Developing and characterizing a two-layered safety switch for cell therapies |
title_sort | developing and characterizing a two-layered safety switch for cell therapies |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10348026/ https://www.ncbi.nlm.nih.gov/pubmed/37439774 http://dx.doi.org/10.1080/15384047.2023.2232146 |
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