Clinical-grade ex vivo-expanded human natural killer cells up-regulate activating receptors and death receptor ligands and have enhanced cytolytic activity against tumor cells

Berg, Maria; Lundqvist, Andreas; McCoy, Philip; Samsel, Leigh; Fan, Yong; Tawab, Abdul; Childs, Richard W.

doi:10.1080/14653240902807034

Cited by 262 publications

(257 citation statements)

References 26 publications

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“…21-23 D.A. Lee and co-workers have developed a method for large-scale production of highly potent NK cells using K562 cells engineered to express 4-1BB ligand and membrane bound IL21 (mb21).…”

Section: Introductionmentioning

confidence: 99%

PD-L1 blockade enhances anti-tumor efficacy of NK cells

2018

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Anti-PD-1/anti-PD-L1 therapies have shown success in cancer treatment but responses are limited to ~ 15% of patients with lymphocyte infiltrated, PD-L1 positive tumors. Hence, strategies that increase PD-L1 expression and tumor infiltration should make more patients eligible for PD-1/PD-L1 blockade therapy, thus improving overall outcomes. PD-L1 expression on tumors is induced by IFNγ, a cytokine secreted by NK cells. Therefore, we tested if PM21-particle expanded NK cells (PM21-NK cells) induced expression of PD-L1 on tumors and if anti-PD-L1 treatment enhanced NK cell anti-tumor efficacy in an ovarian cancer model. Studies here showed that PM21-NK cells secrete high amounts of IFNγ and that adoptively transferred PM21-NK cells induce PD-L1 expression on SKOV-3 cells in vivo. The induction of PD-L1 expression on SKOV-3 cells coincided with the presence of regulatory T cells (Tregs) in the abdominal cavity and within tumors. In in vitro experiments, anti-PD-L1 treatment had no direct effect on cytotoxicity or cytokine secretion by predominantly PD-1 negative PM21-NK cells in response to PD-L1+ targets. However, significant improvement of NK cell anti-tumor efficacy was observed in vivo when combined with anti-PD-L1. PD-L1 blockade also resulted in increased in vivo NK cell persistence and retention of their cytotoxic phenotype. These results support the use of anti-PD-L1 in combination with NK cell therapy regardless of initial tumor PD-L1 status and indicate that NK cell therapy would likely augment the applicability of anti-PD-L1 treatment.

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Section: Introductionmentioning

confidence: 99%

PD-L1 blockade enhances anti-tumor efficacy of NK cells

2018

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“…The safety and antitumor effects of autologous NK cells expanded from PBMCs were investigated in a phase I trial in patients with advanced metastatic tumors and hematological malignancies. 164 Large-scale ex vivo alloreactive NK cell expansion suitable for multiple donor lymphocyte infusions in AML was reported. This protocol involved that NK cells purified by CliniMACS were cultured in closed air-permeable culture bags with certified culture medium and other components, including human serum, IL-2, IL-15, anti-CD3 antibody and autologous irradiated feeder cells.…”

Section: Expanding Nk Cells For Clinical Practicementioning

confidence: 99%

“…As summarized in Table 2, Epstein-Barr virustransformed lymphoblastoid cell lines, genetically modified K562 cells, or irradiated autologous cells were used as feeder cells to promote NK cell expansion from PBMCs. [164][165][166][167] The Campana group has developed a master cell bank of K562 feeder cells expressing a membrane-bound form of IL-15 (mbIL15) and 4-1BB ligand (K562-mb15-41BBL) under cGMP guidelines, and demonstrated that large-scale expansion and activation of human NK cells for clinical studies was feasible. 165 These NK cells demonstrated cytotoxic activity toward tumor cells even higher than observed in the initial small-scale experiments.…”

Section: Expanding Nk Cells For Clinical Practicementioning

confidence: 99%

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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“…[11][12][13][14] To overcome these limitations, several methods have been explored to activate and expand NK cells before adoptive transfer. [15][16][17][18][19][20] Alternatively, NK cells can be generated from hematopoietic progenitor cells (HPCs). [21][22][23][24][25] Previously, we reported a good manufacturing practice (GMP)-compliant, cytokine-based culture protocol for the ex vivo generation of allogeneic NK cells from CD34 C HPCs isolated from cryopreserved umbilical cord blood (UCB) units, bone marrow (BM), or G-CSF-mobilized blood (see ref.…”

Section: Introductionmentioning

confidence: 99%

Combined IL-15 and IL-12 drives the generation of CD34⁺-derived natural killer cells with superior maturation and alloreactivity potential following adoptive transfer

et al. 2015

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Adoptive transfer of allogeneic natural killer (NK) cells represents a promising treatment approach against cancer, including acute myeloid leukemia (AML). Previously, we reported a cytokine-based culture method for the generation of NK cell products with high cell number and purity. In this system, CD34C hematopoietic progenitor cells (HPC) were expanded and differentiated into NK cells under stroma-free conditions in the presence of IL-15 and IL-2. We show that combining IL-15 with IL-12 drives the generation of more mature and highly functional NK cells. In particular, replacement of IL-2 by IL-12 enhanced the cytolytic activity and IFNg production of HPC-NK cells toward cultured and primary AML cells in vitro, and improved antileukemic responses in NOD/SCID-IL2Rgnull (NSG) mice bearing human AML cells. Phenotypically, IL-12 increased the frequency of HPC-NK cells expressing NKG2A and killer immunoglobulinlike receptor (KIR), which were more responsive to target cell stimulation. In addition, NK15/12 cell products demonstrated superior maturation potential, resulting in >70% positivity for CD16 and/or KIR within 2 weeks after infusion into NSG mice. We predict that higher functionality and faster in vivo maturation will favor HPC-NK cell alloreactivity toward malignant cells in patients, making this cytokine combination an attractive strategy to generate clinical HPC-NK cell products for cancer adoptive immunotherapy.

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Clinical-grade ex vivo-expanded human natural killer cells up-regulate activating receptors and death receptor ligands and have enhanced cytolytic activity against tumor cells

Cited by 262 publications

References 26 publications

PD-L1 blockade enhances anti-tumor efficacy of NK cells

PD-L1 blockade enhances anti-tumor efficacy of NK cells

NK cell-based immunotherapy for malignant diseases

Combined IL-15 and IL-12 drives the generation of CD34⁺-derived natural killer cells with superior maturation and alloreactivity potential following adoptive transfer

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Clinical-grade ex vivo-expanded human natural killer cells up-regulate activating receptors and death receptor ligands and have enhanced cytolytic activity against tumor cells

Cited by 262 publications

References 26 publications

PD-L1 blockade enhances anti-tumor efficacy of NK cells

PD-L1 blockade enhances anti-tumor efficacy of NK cells

NK cell-based immunotherapy for malignant diseases

Combined IL-15 and IL-12 drives the generation of CD34+-derived natural killer cells with superior maturation and alloreactivity potential following adoptive transfer

Contact Info

Product

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Combined IL-15 and IL-12 drives the generation of CD34⁺-derived natural killer cells with superior maturation and alloreactivity potential following adoptive transfer