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Updated: Oct 25, 2025
Advances in Human Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor-Expressing Natural Killer Cells
Published on: February 14, 2025
Improved Activity against Acute Myeloid Leukemia with Chimeric Antigen Receptor (CAR)-NK-92 Cells Designed to Target
Michael A Morgan1,2, Arnold Kloos3, Daniela Lenz1
1Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany.
Abstract:
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.
Insights
Engineered natural killer (NK) cells expressing chimeric antigen receptors (CARs) targeting CD123 show potent anti-acute myeloid leukemia (AML) activity. Interleukin-15 (IL-15) expression enhances CAR-NK cell persistence and efficacy in vivo.
Area of Science:
- Immunology
- Oncology
- Gene Therapy
Background:
- Chimeric antigen receptor (CAR) engineering enhances immune cell anti-cancer activity.
- Retroviral vectors enable stable transgene expression for CAR therapies.
- Acute myeloid leukemia (AML) expresses the tumor-associated antigen CD123.
Purpose of the Study:
- To engineer NK-92 cells with a CD123-specific CAR using alpharetroviral vectors.
- To evaluate the anti-AML efficacy of CAR-NK-92 cells in vitro and in vivo.
- To assess the role of IL-15 co-expression in CAR-NK cell persistence and function.
Main Methods:
- Alpharetroviral vector transduction of NK-92 cells with a CD123-targeting CAR and IL-15.
- In vitro cytotoxicity assays using CD123+ AML cell line KG-1a.
- In vivo efficacy studies in a patient-derived xenotransplantation AML model.
Main Results:
- CAR-NK-92 cells demonstrated stable transgene expression and constitutive IL-15 secretion.
- Enhanced anti-AML activity was observed in vitro and in vivo compared to control groups.
- IL-15 expression was crucial for the in vivo persistence of NK-92 cells.
Conclusions:
- Anti-CD123 CAR-NK-92 cells are a promising therapeutic strategy for AML.
- IL-15 co-expression is vital for improving the in vivo persistence and efficacy of CAR-NK cells.
- Further optimization of CAR-NK cell therapy holds potential for enhanced AML treatment.
