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

Affiliation
Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany; REBIRTH Research Center for Translational Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany
Morgan, Michael;
GND
1034493086
Affiliation
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany
Kloos, Arnold;
Affiliation
Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany
Lenz, Daniela;
Affiliation
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany
Kattre, Nadine;
ORCID
0009-0001-5234-7554
Affiliation
Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany
Nowak, Juliette;
Affiliation
Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany
Bentele, Marco;
ORCID
0000-0002-8306-9235
Affiliation
Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany
Keisker, Maximilian;
GND
1265719470
Affiliation
Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany; REBIRTH Research Center for Translational Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany
Dahlke, Julia;
Affiliation
Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany.
Zimmermann, Katharina;
Affiliation
Department of Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, Germany.
Sauer, Martin;
GND
130051918
Affiliation
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany
Heuser, Michael;
GND
128643250
ORCID
0000-0003-2743-0070
Affiliation
Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany; REBIRTH Research Center for Translational Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
Schambach, Axel

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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