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Increased Activity of a NK-Specific CAR-NK Framework Targeting CD3 and CD5 for T-Cell Leukemias
SIMPLE SUMMARY: Chimeric antigen receptors (CAR) can redirect the activity of NK cells to target T-cell malignancies. Our results identify that recognition of CD5 molecules in malignant T cells by the CAR leads to improved antitumor response compared to targeting CD3, due to strong downregulation of...
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/PMC8833462/ https://www.ncbi.nlm.nih.gov/pubmed/35158792 http://dx.doi.org/10.3390/cancers14030524 |
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author | Voynova, Elisaveta Hawk, Nga Flomerfelt, Francis A. Telford, William G. Gress, Ronald E. Kanakry, Jennifer A. Kovalovsky, Damian |
author_facet | Voynova, Elisaveta Hawk, Nga Flomerfelt, Francis A. Telford, William G. Gress, Ronald E. Kanakry, Jennifer A. Kovalovsky, Damian |
author_sort | Voynova, Elisaveta |
collection | PubMed |
description | SIMPLE SUMMARY: Chimeric antigen receptors (CAR) can redirect the activity of NK cells to target T-cell malignancies. Our results identify that recognition of CD5 molecules in malignant T cells by the CAR leads to improved antitumor response compared to targeting CD3, due to strong downregulation of the CD3 antigen after CD3-CAR treatment. We have also identified that a specific CAR-NK framework has superior activity than a CAR-T framework on NK effector cells. ABSTRACT: NK effector cells expressing a CAR construct may be used to target T-lineage markers. In this work, we compared the activity of a NK-specific CAR-NK and a CAR-T framework when expressed on NK effector cells to target CD3 and CD5 in T-cell malignancies. Our results show that CD3-CAR-T is more active than CD5-CAR-T to eliminate malignant T cells in vitro, however, CD3-CAR-T were less efficient to eliminate tumor cells in vivo, while CD5-CAR-T had antitumor activity in a diffuse xenograft model. Lack of in vivo efficacy correlated with downregulation of CD3 levels in target T cells after coculture with CD3-CAR effector cells. The CAR-NK framework greatly improved the efficacy of CARs leading to increased degranulation, cytokine secretion and elimination of the tumor xenograft by CD5-CAR-NK effector cells. Finally, all CAR constructs were similarly effective to eliminate malignant T cells in vitro. Our results show that the NK-CAR framework improves the activity of CARs in NK cells and that CD5 would be a better target than CD3 for T-cell malignancies, as dynamic downregulation of target expression may affect in vivo efficacy. |
format | Online Article Text |
id | pubmed-8833462 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-88334622022-02-12 Increased Activity of a NK-Specific CAR-NK Framework Targeting CD3 and CD5 for T-Cell Leukemias Voynova, Elisaveta Hawk, Nga Flomerfelt, Francis A. Telford, William G. Gress, Ronald E. Kanakry, Jennifer A. Kovalovsky, Damian Cancers (Basel) Article SIMPLE SUMMARY: Chimeric antigen receptors (CAR) can redirect the activity of NK cells to target T-cell malignancies. Our results identify that recognition of CD5 molecules in malignant T cells by the CAR leads to improved antitumor response compared to targeting CD3, due to strong downregulation of the CD3 antigen after CD3-CAR treatment. We have also identified that a specific CAR-NK framework has superior activity than a CAR-T framework on NK effector cells. ABSTRACT: NK effector cells expressing a CAR construct may be used to target T-lineage markers. In this work, we compared the activity of a NK-specific CAR-NK and a CAR-T framework when expressed on NK effector cells to target CD3 and CD5 in T-cell malignancies. Our results show that CD3-CAR-T is more active than CD5-CAR-T to eliminate malignant T cells in vitro, however, CD3-CAR-T were less efficient to eliminate tumor cells in vivo, while CD5-CAR-T had antitumor activity in a diffuse xenograft model. Lack of in vivo efficacy correlated with downregulation of CD3 levels in target T cells after coculture with CD3-CAR effector cells. The CAR-NK framework greatly improved the efficacy of CARs leading to increased degranulation, cytokine secretion and elimination of the tumor xenograft by CD5-CAR-NK effector cells. Finally, all CAR constructs were similarly effective to eliminate malignant T cells in vitro. Our results show that the NK-CAR framework improves the activity of CARs in NK cells and that CD5 would be a better target than CD3 for T-cell malignancies, as dynamic downregulation of target expression may affect in vivo efficacy. MDPI 2022-01-21 /pmc/articles/PMC8833462/ /pubmed/35158792 http://dx.doi.org/10.3390/cancers14030524 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 Voynova, Elisaveta Hawk, Nga Flomerfelt, Francis A. Telford, William G. Gress, Ronald E. Kanakry, Jennifer A. Kovalovsky, Damian Increased Activity of a NK-Specific CAR-NK Framework Targeting CD3 and CD5 for T-Cell Leukemias |
title | Increased Activity of a NK-Specific CAR-NK Framework Targeting CD3 and CD5 for T-Cell Leukemias |
title_full | Increased Activity of a NK-Specific CAR-NK Framework Targeting CD3 and CD5 for T-Cell Leukemias |
title_fullStr | Increased Activity of a NK-Specific CAR-NK Framework Targeting CD3 and CD5 for T-Cell Leukemias |
title_full_unstemmed | Increased Activity of a NK-Specific CAR-NK Framework Targeting CD3 and CD5 for T-Cell Leukemias |
title_short | Increased Activity of a NK-Specific CAR-NK Framework Targeting CD3 and CD5 for T-Cell Leukemias |
title_sort | increased activity of a nk-specific car-nk framework targeting cd3 and cd5 for t-cell leukemias |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8833462/ https://www.ncbi.nlm.nih.gov/pubmed/35158792 http://dx.doi.org/10.3390/cancers14030524 |
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