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Improved Activity against Acute Myeloid Leukemia with Chimeric Antigen Receptor (CAR)-NK-92 Cells Designed to Target CD123

Anti-cancer activity can be improved by engineering immune cells to express chimeric antigen receptors (CARs) that recognize tumor-associated antigens. Retroviral vector gene transfer strategies allow stable and durable transgene expression. Here, we used alpharetroviral vectors to modify NK-92 cell...

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Autores principales: Morgan, Michael A., Kloos, Arnold, Lenz, Daniela, Kattre, Nadine, Nowak, Juliette, Bentele, Marco, Keisker, Maximilian, Dahlke, Julia, Zimmermann, Katharina, Sauer, Martin, Heuser, Michael, Schambach, Axel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310147/
https://www.ncbi.nlm.nih.gov/pubmed/34372571
http://dx.doi.org/10.3390/v13071365
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author Morgan, Michael A.
Kloos, Arnold
Lenz, Daniela
Kattre, Nadine
Nowak, Juliette
Bentele, Marco
Keisker, Maximilian
Dahlke, Julia
Zimmermann, Katharina
Sauer, Martin
Heuser, Michael
Schambach, Axel
author_facet Morgan, Michael A.
Kloos, Arnold
Lenz, Daniela
Kattre, Nadine
Nowak, Juliette
Bentele, Marco
Keisker, Maximilian
Dahlke, Julia
Zimmermann, Katharina
Sauer, Martin
Heuser, Michael
Schambach, Axel
author_sort Morgan, Michael A.
collection PubMed
description Anti-cancer activity can be improved by engineering immune cells to express chimeric antigen receptors (CARs) that recognize tumor-associated antigens. Retroviral vector gene transfer strategies allow stable and durable transgene expression. Here, we used alpharetroviral vectors to modify NK-92 cells, a natural killer cell line, with a third-generation CAR designed to target the IL-3 receptor subunit alpha (CD123), which is strongly expressed on the surface of acute myeloid leukemia (AML) cells. Alpharetroviral vectors also contained a transgene cassette to allow constitutive expression of human IL-15 for increased NK cell persistence in vivo. The anti-AML activity of CAR-NK-92 cells was tested via in vitro cytotoxicity assays with the CD123(+) AML cell line KG-1a and in vivo in a patient-derived xenotransplantation CD123(+) AML model. Unmodified NK-92 cells or NK-92 cells modified with a truncated version of the CAR that lacked the signaling domain served as controls. Alpharetroviral vector-modified NK-92 cells stably expressed the transgenes and secreted IL-15. Anti-CD123-CAR-NK-92 cells exhibited enhanced anti-AML activity in vitro and in vivo as compared to control NK-92 cells. Our data (1) shows the importance of IL-15 expression for in vivo persistence of NK-92 cells, (2) supports continued investigation of anti-CD123-CAR-NK cells to target AML, and (3) points towards potential strategies to further improve CAR-NK anti-AML activity.
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spelling pubmed-83101472021-07-25 Improved Activity against Acute Myeloid Leukemia with Chimeric Antigen Receptor (CAR)-NK-92 Cells Designed to Target CD123 Morgan, Michael A. Kloos, Arnold Lenz, Daniela Kattre, Nadine Nowak, Juliette Bentele, Marco Keisker, Maximilian Dahlke, Julia Zimmermann, Katharina Sauer, Martin Heuser, Michael Schambach, Axel Viruses Article Anti-cancer activity can be improved by engineering immune cells to express chimeric antigen receptors (CARs) that recognize tumor-associated antigens. Retroviral vector gene transfer strategies allow stable and durable transgene expression. Here, we used alpharetroviral vectors to modify NK-92 cells, a natural killer cell line, with a third-generation CAR designed to target the IL-3 receptor subunit alpha (CD123), which is strongly expressed on the surface of acute myeloid leukemia (AML) cells. Alpharetroviral vectors also contained a transgene cassette to allow constitutive expression of human IL-15 for increased NK cell persistence in vivo. The anti-AML activity of CAR-NK-92 cells was tested via in vitro cytotoxicity assays with the CD123(+) AML cell line KG-1a and in vivo in a patient-derived xenotransplantation CD123(+) AML model. Unmodified NK-92 cells or NK-92 cells modified with a truncated version of the CAR that lacked the signaling domain served as controls. Alpharetroviral vector-modified NK-92 cells stably expressed the transgenes and secreted IL-15. Anti-CD123-CAR-NK-92 cells exhibited enhanced anti-AML activity in vitro and in vivo as compared to control NK-92 cells. Our data (1) shows the importance of IL-15 expression for in vivo persistence of NK-92 cells, (2) supports continued investigation of anti-CD123-CAR-NK cells to target AML, and (3) points towards potential strategies to further improve CAR-NK anti-AML activity. MDPI 2021-07-14 /pmc/articles/PMC8310147/ /pubmed/34372571 http://dx.doi.org/10.3390/v13071365 Text en © 2021 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
Morgan, Michael A.
Kloos, Arnold
Lenz, Daniela
Kattre, Nadine
Nowak, Juliette
Bentele, Marco
Keisker, Maximilian
Dahlke, Julia
Zimmermann, Katharina
Sauer, Martin
Heuser, Michael
Schambach, Axel
Improved Activity against Acute Myeloid Leukemia with Chimeric Antigen Receptor (CAR)-NK-92 Cells Designed to Target CD123
title Improved Activity against Acute Myeloid Leukemia with Chimeric Antigen Receptor (CAR)-NK-92 Cells Designed to Target CD123
title_full Improved Activity against Acute Myeloid Leukemia with Chimeric Antigen Receptor (CAR)-NK-92 Cells Designed to Target CD123
title_fullStr Improved Activity against Acute Myeloid Leukemia with Chimeric Antigen Receptor (CAR)-NK-92 Cells Designed to Target CD123
title_full_unstemmed Improved Activity against Acute Myeloid Leukemia with Chimeric Antigen Receptor (CAR)-NK-92 Cells Designed to Target CD123
title_short Improved Activity against Acute Myeloid Leukemia with Chimeric Antigen Receptor (CAR)-NK-92 Cells Designed to Target CD123
title_sort improved activity against acute myeloid leukemia with chimeric antigen receptor (car)-nk-92 cells designed to target cd123
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310147/
https://www.ncbi.nlm.nih.gov/pubmed/34372571
http://dx.doi.org/10.3390/v13071365
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