Ex Vivo Expanded Adaptive NK Cells Effectively Kill Primary Acute Lymphoblastic Leukemia Cells

• Published in: Cancer immunology research 2017-08, Vol.5 (8), p.654-665
• Main Authors: Liu, Lisa L, Béziat, Vivien, Oei, Vincent Y S, Pfefferle, Aline, Schaffer, Marie, Lehmann, Sören, Hellström-Lindberg, Eva, Söderhäll, Stefan, Heyman, Mats, Grandér, Dan, Malmberg, Karl-Johan
• Format: Article
• Language: English
• Subjects: Adaptive Immunity; Cell Line, Tumor; Cell- and Tissue-Based Therapy; Child; Cytomegalovirus - immunology; Cytotoxicity, Immunologic; Histocompatibility Antigens Class I - immunology; Histocompatibility Antigens Class I - therapeutic use; HLA-E Antigens; Humans; Immunotherapy; Killer Cells, Natural - immunology; Medicin och hälsovetenskap; NK Cell Lectin-Like Receptor Subfamily C - immunology; NK Cell Lectin-Like Receptor Subfamily C - therapeutic use; Precursor Cell Lymphoblastic Leukemia-Lymphoma - immunology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - therapy; Receptors, KIR - immunology; Receptors, KIR - therapeutic use
• ISSN: 2326-6066; 2326-6074; 2326-6074
• DOI: 10.1158/2326-6066.CIR-16-0296

Manipulation of human natural killer (NK) cell repertoires promises more effective strategies for NK cell-based cancer immunotherapy. A subset of highly differentiated NK cells, termed adaptive NK cells, expands naturally in response to human cytomegalovirus (HCMV) infection, carries unique repertoires of inhibitory killer cell immunoglobulin-like receptors (KIR), and displays strong cytotoxicity against tumor cells. Here, we established a robust and scalable protocol for generation and expansion of adaptive NK cells for cell therapy against pediatric acute lymphoblastic leukemia (ALL). Culture of polyclonal NK cells together with feeder cells expressing HLA-E, the ligand for the activating NKG2C receptor, led to selective expansion of adaptive NK cells with enhanced alloreactivity against HLA-mismatched targets. The expanded adaptive NK cells gradually obtained a more differentiated phenotype and were specific and highly efficient killers of allogeneic pediatric T- and precursor B-cell acute lymphoblastic leukemia (ALL) blasts, previously shown to be refractory to killing by autologous NK cells and the NK-cell line NK92 currently in clinical testing. Selective expansion of NK cells that express one single inhibitory KIR for self-HLA class I would allow exploitation of the full potential of NK-cell alloreactivity in cancer immunotherapy. In summary, our data suggest that adaptive NK cells may hold utility for therapy of refractory ALL, either as a bridge to transplant or for patients that lack stem cell donors. .