scholarly journals Retargeting of natural killer–cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction

Blood ◽  
2002 ◽  
Vol 100 (4) ◽  
pp. 1265-1273 ◽  
Author(s):  
Christoph Uherek ◽  
Torsten Tonn ◽  
Barbara Uherek ◽  
Sven Becker ◽  
Barbara Schnierle ◽  
...  
Keyword(s):  
Natural Killer ◽  
Chimeric Antigen Receptor ◽  
Nk Cell ◽  
Killer Cell ◽  
Antigen Receptor ◽  
Antibody Fragment ◽  
Cytolytic Activity ◽  
Antitumoral Activity ◽  
Adoptive Therapy ◽  
Normal Human

The continuously growing natural killer (NK) cell line NK-92 is highly cytotoxic against malignant cells of various origins without affecting normal human cells. Based on this selectivity, the potential of NK-92 cells for adoptive therapy is currently being investigated in phase I clinical studies. To further enhance the antitumoral activity of NK-92 cells and expand the range of tumor entities suitable for NK-92–based therapies, here by transduction with a retroviral vector we have generated genetically modified NK-92 cells expressing a chimeric antigen receptor specific for the tumor-associated ErbB2 (HER2/neu) antigen, which is overexpressed by many tumors of epithelial origin. The chimeric antigen receptor consists of the ErbB2-specific scFv(FRP5) antibody fragment, a flexible hinge region derived from CD8, and transmembrane and intracellular regions of the CD3 ζ chain. Transduced NK-92-scFv(FRP5)-ζ cells express high levels of the fusion protein on the cell surface as determined by fluorescence-activated cell-scanning (FACS) analysis. In europium release assays, no difference in cytotoxic activity of NK-92 and NK-92-scFv(FRP5)-ζ cells toward ErbB2-negative targets was found. However, even at low effector-to-target ratios, NK-92-scFv(FRP5)-ζ cells specifically and efficiently lysed established and primary ErbB2-expressing tumor cells that were completely resistant to cytolytic activity of parental NK-92 cells. These results demonstrate that efficient retargeting of NK-92 cytotoxicity can be achieved and might allow the generation of potent cell-based therapeutics for the treatment of ErbB2-expressing malignancies.

β-Endorphin and natural killer cell cytolytic activity during prolonged exercise. Is there a connection?

1998 ◽  
Vol 275 (6) ◽  
pp. R1725-R1734 ◽  
Author(s):  
G. A. Gannon ◽  
S. G. Rhind ◽  
M. Suzui ◽  
J. Zamecnik ◽  
B. H. Sabiston ◽  
...  
Keyword(s):  
Natural Killer Cell ◽  
Natural Killer ◽  
Nk Cell ◽  
Block Design ◽  
Killer Cell ◽  
Cytolytic Activity ◽  
Opioid Antagonist ◽  
Moderate Intensity ◽  
Moderate Intensity Exercise ◽  
Cell Counts

This study was designed to test whether a single 50-mg dose of the opioid antagonist naltrexone hydrochloride, ingested 60 min before 2 h of moderate-intensity exercise (i.e., 65% peak O2consumption), influenced the exercise-induced augmentation of peripheral blood natural killer cell cytolytic activity (NKCA). Ten healthy male subjects were tested on four occasions separated by intervals of at least 14 days. A rested-state control trial was followed by three double-blind exercise trials [placebo (P), naltrexone (N), and indomethacin] arranged according to a random block design. The indomethacin exercise trial is discussed elsewhere (S. G. Rhind, G. A. Gannon, P. N. Shek, and R. J. Shepherd. Med. Sci. Sports Exerc. 30: S20, 1998). For both the P and N trials, plasma levels of β-endorphin were increased ( P < 0.05) at 90 and 120 min of exercise but returned to resting (preexercise) levels 2 h postexercise. CD3−CD16+CD56+NK cell counts and NKCA were significantly ( P < 0.05) elevated at each 30-min interval of exercise compared with correspondingly timed resting control values. However, there were no differences in NK cell counts or NKCA between P and N trials at any time point during the two trials. Changes in NKCA reflected mainly changes in NK cell count ( r = 0.72; P < 0.001). The results do not support the hypothesis that the enhancement of NKCA during prolonged submaximal aerobic exercise is mediated by β-endorphin.

Ligands for natural killer cell–activating receptors are expressed upon the maturation of normal myelomonocytic cells but at low levels in acute myeloid leukemias

Blood ◽  
2005 ◽  
Vol 105 (9) ◽  
pp. 3615-3622 ◽  
Author(s):  
Pegah Nowbakht ◽  
Mihai-Constantin S. Ionescu ◽  
Andreas Rohner ◽  
Christian P. Kalberer ◽  
Emmanuel Rossy ◽  
...  
Keyword(s):  
Cell Surface ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Interferon Γ ◽  
Cytolytic Activity ◽  
Human Leukemia ◽  
Increased Sensitivity ◽  
Low Levels ◽  
Acute Myeloid

AbstractNatural killer (NK) cell–mediated cytolytic activity against tumors requires the engagement of activating NK receptors by the tumor-associated ligands. Here, we have studied the role of NKG2D and natural cytotoxicity receptors (NCRs) in the recognition of human leukemia. To detect as-yet-unknown cell-surface molecules recognized by NCRs, we developed soluble forms of NKp30, NKp44, and NKp46 as staining reagents binding the putative cognate ligands. Analysis of UL16-binding protein-1 (ULBP1), ULBP2, and ULBP3 ligands for NKG2D and of potential ligands for NKp30, NKp44, and NKp46 in healthy hematopoietic cells demonstrated the ligand-negative phenotype of bone marrow–derived CD34+ progenitor cells and the acquisition of cell-surface ligands during the course of myeloid differentiation. In acute myeloid leukemia (AML), leukemic blasts from approximately 80% of patients expressed very low levels of ULBPs and NCR-specific ligands. Treatment with differentiation-promoting myeloid growth factors, together with interferon-γ, upregulated cell-surface levels of ULBP1 and putative NCR ligands on AML blasts, conferring an increased sensitivity to NK cell–mediated lysis. We conclude that the ligand-negative/low phenotype in AML is a consequence of cell maturation arrest on malignant transformation and that defective expression of ligands for the activating NKG2D and NCR receptors may compromise leukemia recognition by NK cells.

scholarly journals p46, a Novel Natural Killer Cell–specific Surface Molecule That Mediates Cell Activation

1997 ◽  
Vol 186 (7) ◽  
pp. 1129-1136 ◽  
Author(s):  
Simona Sivori ◽  
Massimo Vitale ◽  
Luigia Morelli ◽  
Lorenza Sanseverino ◽  
Raffaella Augugliaro ◽  
...  
Keyword(s):  
Specific Surface ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell ◽  
Cytolytic Activity ◽  
Surface Molecule ◽  
Limited Information ◽  
Cell Clones

Limited information is available on the surface molecules that are involved in natural killer (NK) cell triggering. In this study, we selected the BAB281 monoclonal antibody (mAb) on the basis of its ability to trigger NK-mediated target cell lysis. BAB281 identified a novel NK cell–specific surface molecule of 46 kD (p46) that is expressed by all resting or activated NK cells. Importantly, unlike the NK cell antigens identified so far, the expression of p46 was strictly confined to NK cells. Upon mAb-mediated cross-linking, p46 molecules induced strong cell triggering leading to [Ca2+]i increases, lymphokine production, and cytolytic activity both in resting NK cells and NK cell clones. The p46-mediated induction of Ca2+ increases or triggering of cytolytic activity was downregulated by the simultaneous engagement of inhibitory receptors including p58, p70, and CD94/NKG2A. Both the unique cellular distribution and functional capability of p46 molecules suggest a possible role in the mechanisms of non-major histocompatibility complex–restricted cytolysis mediated by human NK cells.

scholarly journals Selective Cytotoxicity of Single and Dual Anti-CD19 and Anti-CD138 Chimeric Antigen Receptor-Natural Killer Cells against Hematologic Malignancies

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Sudjit Luanpitpong ◽  
Jirarat Poohadsuan ◽  
Phatchanat Klaihmon ◽  
Surapol Issaragrisil
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Chimeric Antigen Receptor ◽  
Nk Cell ◽  
Antigen Receptor ◽  
Antigen Expression ◽  
In Vivo Studies ◽  
Selective Cytotoxicity

Natural killer (NK) cells are part of the first line of defense that rapidly respond to malignant transformed cells. Chimeric antigen receptor- (CAR-) engineered NK cells, although are still at the preliminary stage, have been shown to be alternative to CAR-T cells, mainly due to the absence of graft-versus-host disease and safer clinical profile. Allogeneic human NK cell line NK-92 cells, equipped by CAR, are being developed for clinical applications. Herein, we designed third-generation CARs, optimized the production protocol, and generated CAR-NK-92 cells, targeting CD19 and/or CD138 antigens that employ CD28, 4-1BB, and CD3ζ signaling, with >80% CAR expression, designated as CD19-NK-92, CD138-NK-92, and dual-NK-92 cells. The generated CAR-NK-92 cells displayed high and selective cytotoxicity toward various corresponding leukemia, lymphoma, and multiple myeloma cell lines in vitro. Multitargeting approach using a mixture of CD19-NK-92 and CD138-NK-92 cells was also evaluated at various ratios to test the idea of personalized formulation to match the patients’ antigen expression profile. Our data indicate that increasing the ratio of CD19-NK-92 to CD138-NK-92 could improve NK cytotoxicity in leukemia cells with a relatively higher expression of CD19 over CD138, supporting the personalized proof of concept. This information represents the basis for further in vivo studies and future progress to clinical trials.

scholarly journals Response of human natural killer (NK) cells to NK cell stimulatory factor (NKSF): cytolytic activity and proliferation of NK cells are differentially regulated by NKSF.

1992 ◽  
Vol 175 (3) ◽  
pp. 779-788 ◽  
Author(s):  
M J Robertson ◽  
R J Soiffer ◽  
S F Wolf ◽  
T J Manley ◽  
C Donahue ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Human Peripheral Blood ◽  
Killer Cell ◽  
Interleukin 2 ◽  
Cytolytic Activity ◽  
Stimulatory Factor

Natural killer cell stimulatory factor (NKSF) is a 70-kD heterodimeric cytokine that was initially isolated from conditioned medium of human B lymphoblastoid cell lines. The effects of recombinant NKSF on the function of human peripheral blood NK cells were examined. NKSF directly augmented the cytolytic activity of freshly isolated NK cells. Both CD56dim and CD56bright NK cells demonstrated enhanced cytotoxicity after brief exposure to NKSF. In contrast, highly purified T lymphocytes did not exhibit major histocompatibility complex-unrestricted cytotoxicity after short-term culture with NKSF. Like interleukin 2 (IL-2), NKSF augmented the lysis of NK-sensitive, NK-resistant, and antibody-coated targets. Both NKSF and IL-2 induced marked upregulation of several NK cell adhesion molecules known to participate in cytolysis, including CD2, CD11a, and CD54. However, NKSF activates NK cells through a pathway distinct from that of IL-2, since the presence of anti-IL-2 receptor (anti-IL-2R) antibodies or IL-4 did not inhibit the effects of NKSF. NKSF by itself induced very little proliferation of resting NK cells. NK cells preactivated in vitro with IL-2 demonstrated enhanced proliferation to NKSF, but the degree of proliferation was always inferior to that induced by IL-2 alone. Moreover, NKSF strongly inhibited IL-2-induced proliferation of either resting or preactivated NK cells. This inhibition was not the result of decreased IL-2R expression, because NKSF-activated NK cells expressed higher levels of both IL-2Rs p75 and p55. Furthermore, NKSF did not inhibit the proliferation of mitogen-activated T cells, indicating a selective effect on NK cell proliferation. Human NK cells expanded in vivo by prolonged continuous infusions of IL-2 remained fully responsive to NKSF. Picomolar concentrations of NKSF were as effective as nanomolar concentrations of IL-2 in augmenting the cytolytic activity of NK cells expanded in vivo by IL-2. NKSF may play an important role in the regulation of human NK cell function, and its possible use as a therapeutic cytokine deserves further investigation.

Sign in / Sign up

Export Citation Format

Share Document