Clinical-grade, large-scale, feeder-free expansion of highly active human natural killer cells for adoptive immunotherapy using an automated bioreactor

Sütlü, Tolga; Stellan, Birgitta; Gilljam, Mari; Quezada, Hernán Concha; Nahi, Hareth; Gahrton, Gösta; Alici, Evren

doi:10.3109/14653249.2010.504770

Cited by 112 publications

(102 citation statements)

References 222 publications

(244 reference statements)

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“…These expanded NK cells displayed significantly higher cytotoxic capacity and higher NKp44 expression than NK cells expanded in flasks. 169 As described earlier in the present review, allogeneic NK cells activated and expanded in vitro with IL-15/HC were safe and potentially effective in a phase I clinical trial when used in combination with chemotherapy in advanced non-small cell lung cancer patients. 104 NK cell lines Compared with autologous or allogeneic NK cells from PBMCs or stem cells, the large-scale expansion of NK cell lines under GMP conditions is easier and more available for clinical adoptive therapy.…”

Section: Expanding Nk Cells For Clinical Practicementioning

confidence: 94%

NK cell-based immunotherapy for malignant diseases

et al. 2013

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Natural killer (NK) cells play critical roles in host immunity against cancer. In response, cancers develop mechanisms to escape NK cell attack or induce defective NK cells. Current NK cell-based cancer immunotherapy aims to overcome NK cell paralysis using several approaches. One approach uses expanded allogeneic NK cells, which are not inhibited by self histocompatibility antigens like autologous NK cells, for adoptive cellular immunotherapy. Another adoptive transfer approach uses stable allogeneic NK cell lines, which is more practical for quality control and large-scale production. A third approach is genetic modification of fresh NK cells or NK cell lines to highly express cytokines, Fc receptors and/or chimeric tumor-antigen receptors. Therapeutic NK cells can be derived from various sources, including peripheral or cord blood cells, stem cells or even induced pluripotent stem cells (iPSCs), and a variety of stimulators can be used for large-scale production in laboratories or good manufacturing practice (GMP) facilities, including soluble growth factors, immobilized molecules or antibodies, and other cellular activators. A list of NK cell therapies to treat several types of cancer in clinical trials is reviewed here. Several different approaches to NK-based immunotherapy, such as tissue-specific NK cells, killer receptor-oriented NK cells and chemically treated NK cells, are discussed. A few new techniques or strategies to monitor NK cell therapy by non-invasive imaging, predetermine the efficiency of NK cell therapy by in vivo experiments and evaluate NK cell therapy approaches in clinical trials are also introduced.

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Section: Expanding Nk Cells For Clinical Practicementioning

confidence: 94%

NK cell-based immunotherapy for malignant diseases

et al. 2013

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“…In addition, Sutlu et al have designed an automated reactor able to expand NK cells from PB mononuclear cells and demonstrated that large amounts of high reactive NK cells can be produced and used for immunotherapy. 68 Furthermore, the expansion of UCB NK cells using tacrolimus and a low molecular weight heparin-media has been developed by Tanka et al 118 The results showed high NK cell fold expansion and high level of cytotoxicity activity against leukemic cell line K562 and patient's primary AML and chronic myeloid leukemia cells. On the other hand, Spanholtz et al 119,120 have recently published a high log-scale expansion of NK cells from UCB CD34 1 cells using clinical grade protocols.…”

Section: Gmp Proceduresmentioning

confidence: 99%

“…NK cells can be directly isolated from PB or UCB; donor cells are expanded for short or long period of time in vitro, and subsequently infused to treat cancer or hematological diseases. [68][69][70][71] The main advantage of obtaining NK cells from these sources is the immediate availability of cells even after long-term expansion in vitro, compared to de novo production of NK cells. However, the disadvantage of this technique relies in the fact that prolonged exposure of NK cells to cytokines in vitro induces cell exhaustion.…”

Section: Generation Of Natural Killer Cells From Hscs M Luevano Et Almentioning

confidence: 99%

Generation of natural killer cells from hematopoietic stem cells in vitro for immunotherapy

Luevano

Madrigal

2012

Cell Mol Immunol

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“…Sutlu et al recently developed a unique method to expand moderate numbers of clinical-grade NK cells in an automated bioreactor without the need for feeder cells. 36 When this technique was used, human NK cells expanded a median 77-fold after 21 days of cell culture from unsorted PBMCs. These cells were activated ex vivo, being more cytotoxic against K562 target cells than those that were expanded in flasks, and expressed higher levels of the natural cytotoxicity receptor NKp44.…”

Section: Ex Vivo Nk Cell Expansion Without Feeder Cellsmentioning

confidence: 99%

Bringing natural killer cells to the clinic: ex vivo manipulation

Childs

Berg

2013

Hematology

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Recently, there has been a substantial gain in our understanding of the role that natural killer (NK) cells play in mediating innate host immune responses against viruses and cancer. Although NK cells have long been known to be capable of killing cancer cells independently of antigen recognition, the full therapeutic potential of NK cell-based immunotherapy has yet to be realized. Here we review novel methods to activate and expand human NK cells ex vivo for adoptive transfer in humans, focusing on the important phenotypic and functional differences observed among freshly isolated, cytokine activated, and ex vivo-expanded NK populations. Natural killer cell therapy for cancer: a new hopeThe ability of natural killer (NK) cells to kill tumor cells without the need to recognize a tumor-specific antigen provides advantages over T cells and makes them appealing for investigation as effectors for immunotherapy. 1,2 There has recently been a substantial gain in our understanding of the role that NK cells play in mediating innate host immune responses against viruses and cancer. Although NK cells have long been known to be capable of killing cancer cells independently of antigen recognition, the full therapeutic potential of NK cell-based immunotherapy has yet to be realized. Here we review novel methods to activate and expand human NK cells ex vivo for adoptive transfer in humans, focusing on the important phenotypic and functional differences observed among freshly isolated, cytokine activated, and ex vivo-expanded NK populations. Ex vivo NK cell activation and expansionUnlike T cells, NK cells represent only a minor fraction of human lymphocytes. NK cells are defined by their CD3 Ϫ /CD56 ϩ phenotype, comprising 5% to 15% of circulating lymphocytes, and are commonly divided into CD56 dim CD16 ϩ (90%) and CD56 bright CD16 Ϫ (10%) subpopulations with distinct effector functions. Recently, investigators have shown that NK cell tumor cytotoxicity can be enhanced by disrupting NK cell signaling through inhibitory receptors such as KIR, PD-1, and NKG2A. 3,4 Furthermore, exposing tumors to drugs that down-regulate ligands for NK cell inhibitory receptors or up-regulate death receptors for NK cell effector molecules or ligands that bind NK cell-activating receptors can be used as a strategy to sensitize tumors to NK cell-mediated apoptosis. Recently, anti-PD-1 and anti-PD-L1 monoclonal antibodies and the immunomodulatory drug lenalidomide were shown to enhance both NK cell tumor trafficking and NK cell-mediated antibody-dependent cell-mediated cytotoxicity, and cytokine release against tumors while simultaneously suppressing regulatory T cell function. [5][6][7][8] Similarly, anti-CTLA-4 monoclonal antibodies have been shown to augment NK cell antibody-dependent cellmediated cytotoxicity and TNF␣ release against melanoma cells by Fc␥RIII (CD16) binding to antibody-bound tumor cells, as well as through regulatory T cell inactivation. 9-11 These data suggest these agents could be used in conjunction with autologous NK cell inf...

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Clinical-grade, large-scale, feeder-free expansion of highly active human natural killer cells for adoptive immunotherapy using an automated bioreactor

Cited by 112 publications

References 222 publications

NK cell-based immunotherapy for malignant diseases

NK cell-based immunotherapy for malignant diseases

Generation of natural killer cells from hematopoietic stem cells in vitro for immunotherapy

Bringing natural killer cells to the clinic: ex vivo manipulation

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