Efficacy of third-party chimeric antigen receptor modified peripheral blood natural killer cells for adoptive cell therapy of B-cell precursor acute lymphoblastic leukemia

We developed an innovative and efficient, feeder-free culture method to genetically modify and expand peripheral blood-derived NK cells with high proliferative capacity, while preserving the responsiveness of their native activating receptors. Activated peripheral blood NK cells were efficiently tra...

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Bibliographic Details
Published in:	Leukemia Vol. 34; no. 4; pp. 1102 - 1115
Main Authors:	Quintarelli, C., Sivori, S., Caruso, S., Carlomagno, S., Falco, M., Boffa, I., Orlando, D., Guercio, M., Abbaszadeh, Z., Sinibaldi, M., Di Cecca, S., Camera, A., Cembrola, B., Pitisci, A., Andreani, M., Vinti, L., Gattari, S., Del Bufalo, F., Algeri, M., Li Pira, G., Moseley, A., De Angelis, B., Moretta, L., Locatelli, F.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-04-2020 Nature Publishing Group
Subjects:	13/106 13/21 13/31 38 38/5 42 42/44 45/41 631/250/251 64 64/110 692/308/2778 692/699/1541/1990/283/2125 Acute lymphoblastic leukemia Acute lymphocytic leukemia Animal models Animals Anticancer properties Antigens Antigens, CD19 - immunology Apoptosis Biocompatibility Blood Cancer Research Care and treatment CD19 antigen Cell culture Cell Proliferation Cell therapy Cell- and Tissue-Based Therapy - methods Cellular therapy Chimeric antigen receptors Critical Care Medicine Cytotoxicity, Immunologic - immunology Genetic modification Growth Hematology Humans Immunotherapy, Adoptive - methods Intensive Internal Medicine Killer cells Killer Cells, Natural - immunology Killer Cells, Natural - transplantation Leukemia Leukocytes, Mononuclear - immunology Lymphatic leukemia Lymphocytes Lymphocytes B Lymphocytes T Medicine Medicine & Public Health Methods Mice Mice, Inbred NOD Mice, SCID Natural killer cells Oncology Peripheral blood Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - immunology Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - therapy Precursors Receptors Receptors, Chimeric Antigen - immunology Therapy Toxicity Tumor Cells, Cultured Xenograft Model Antitumor Assays Xenografts Xenotransplantation Italy
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Summary:	We developed an innovative and efficient, feeder-free culture method to genetically modify and expand peripheral blood-derived NK cells with high proliferative capacity, while preserving the responsiveness of their native activating receptors. Activated peripheral blood NK cells were efficiently transduced by a retroviral vector, carrying a second-generation CAR targeting CD19. CAR expression was demonstrated across the different NK-cell subsets. CAR.CD19-NK cells display higher antileukemic activity toward CD19 + cell lines and primary blasts obtained from patients with B-cell precursor ALL compared with unmodified NK cells. In vivo animal model data showed that the antileukemia activity of CAR.CD19-NK cell is superimposable to that of CAR-T cells, with a lower xenograft toxicity profile. These data support the feasibility of generating feeder-free expanded, genetically modified peripheral blood NK cells for effective “off-the-shelf” immuno-gene-therapy, while their innate alloreactivity can be safely harnessed to potentiate allogeneic cell therapy.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0887-6924 1476-5551
DOI:	10.1038/s41375-019-0613-7