Abstract
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. © 2019, The Author(s), under exclusive licence to Springer Nature Limited.
Original language | English |
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Pages (from-to) | 1102-1115 |
Number of pages | 14 |
Journal | Leukemia |
Volume | 34 |
Issue number | 4 |
DOIs | |
Publication status | Published - 2020 |
Keywords
- CD19 antigen
- chimeric antigen receptor
- retrovirus vector
- acute lymphoblastic leukemia
- adoptive transfer
- alloimmunity
- animal experiment
- animal model
- antileukemic activity
- antineoplastic activity
- Article
- cell proliferation
- chimeric antigen receptor natural killer cell immunotherapy
- clinical article
- controlled study
- DNA modification
- flow cytometry
- human
- human cell
- in vivo study
- mouse
- natural killer cell
- nonhuman
- peripheral blood mononuclear cell
- pre B lymphocyte
- priority journal
- protein expression
- therapy effect
- tumor xenograft
- adoptive immunotherapy
- animal
- apoptosis
- biological therapy
- cytotoxicity
- drug screening
- immunology
- mononuclear cell
- nonobese diabetic mouse
- pathology
- procedures
- SCID mouse
- transplantation
- tumor cell culture
- Animals
- Antigens, CD19
- Apoptosis
- Cell Proliferation
- Cell- and Tissue-Based Therapy
- Cytotoxicity, Immunologic
- Humans
- Immunotherapy, Adoptive
- Killer Cells, Natural
- Leukocytes, Mononuclear
- Mice
- Mice, Inbred NOD
- Mice, SCID
- Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
- Receptors, Chimeric Antigen
- Tumor Cells, Cultured
- Xenograft Model Antitumor Assays