FT538, iPSC‐derived NK cells, enhance AML cell killing when combined with chemotherapy

• Published in: Journal of cellular and molecular medicine 2025-01, Vol.29 (1), p.e70169-n/a
• Main Authors: Eckstrom, Amanda, Tyagi, Anudishi, Mahmood, Sajid, Wong, Lilly, Valamehr, Bahram, Rao, Adishwar, Agrawal, Akriti, Siddiqui, Maryam, Battula, V. Lokesh
• Format: Article
• Language: English
• Subjects: Acute myeloid leukemia; AML; Antigens; Apoptosis; Apoptosis - drug effects; Bone marrow; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Cancer therapies; CD16 antigen; CD38 antigen; Cell death; Cell fusion; Cell Line, Tumor; Cell lines; Cell therapy; Chemotherapy; Cytarabine; Cytarabine - pharmacology; Cytogenetics; Cytotoxicity; Effector cells; Flow cytometry; Humans; immunotherapy; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - drug effects; Induced Pluripotent Stem Cells - metabolism; Interleukin 15; iPSC‐derived NK cells; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - pathology; Leukemia, Myeloid, Acute - therapy; Natural killer cells; NK cell therapy; NK cell‐mediated apoptosis; Original; Patients; Penicillin; Pluripotency; Remission (Medicine); Response rates; Stem cell transplantation; Sulfonamides - pharmacology; Toxicity
• ISSN: 1582-1838; 1582-4934; 1582-4934
• DOI: 10.1111/jcmm.70169

Induced pluripotent stem cell (iPSC)–derived natural killer (NK) cells offer an opportunity for a standardized, off‐the‐shelf treatment with the potential to treat a wider population of acute myeloid leukaemia (AML) patients than the current standard of care. FT538 iPSC‐NKs express a high‐affinity, noncleavable CD16 to maximize antibody dependent cellular cytotoxicity, a CD38 knockout to improve metabolic fitness, and an IL‐15/IL‐15 receptor fusion preventing the need for cytokine administration, the main source of adverse effects in NK cell–based therapies. Here, we sought to evaluate the potential of FT538 iPSC‐NKs as a therapy for AML through their effect on AML cell lines and primary AML cells. We observed that FT538 iPSC‐NKs induce effector‐to‐target cell ratio dependent apoptosis in cell lines and primary AML cells, including cells from high‐risk patients. Flow cytometric analysis revealed that FT538 iPSC‐NKs induce AML cell death when combined with the AML therapies: cytarabine, venetoclax and gilteritinib. Moreover, cytarabine did not affect FT538 iPSC‐NK viability, suggesting that iPSC‐derived NK therapies and chemotherapy may be a promising treatment combination. This study provides the basis for further study of iPSC‐derived NK cell therapies as a treatment option for high‐risk AML patients, particularly those with disease resistant to standard therapies.