scholarly journals Natural Killer Cells and Current Applications of Chimeric Antigen Receptor-Modified NK-92 Cells in Tumor Immunotherapy

2019 ◽  
Vol 20 (2) ◽  
pp. 317 ◽  
Author(s):  
Jianguang Zhang ◽  
Huifang Zheng ◽  
Yong Diao
Keyword(s):  
Natural Killer ◽  
Cell Lines ◽  
Chimeric Antigen Receptor ◽  
Cell Biology ◽  
Nk Cell ◽  
Antigen Receptor ◽  
Tumor Immunotherapy ◽  
Innate Immune ◽  
Antitumor Effects ◽  
Infected Cells

Natural killer (NK) cells are innate immune cells that can be activated rapidly to target abnormal and virus-infected cells without prior sensitization. With significant advancements in cell biology technologies, many NK cell lines have been established. Among these cell lines, NK-92 cells are not only the most widely used but have also been approved for clinical applications. Additionally, chimeric antigen receptor-modified NK-92 cells (CAR-NK-92 cells) have shown strong antitumor effects. In this review, we summarize established human NK cell lines and their biological characteristics, and highlight the applications of NK-92 cells and CAR-NK-92 cells in tumor immunotherapy.

Engineering chimeric antigen receptor-natural killer cells for cancer immunotherapy

Immunotherapy ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 653-664 ◽  
Author(s):  
Yu Zhao ◽  
Xiaorong Zhou
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Chimeric Antigen Receptor ◽  
Nk Cell ◽  
Structural Characteristics ◽  
Antigen Receptor ◽  
Adoptive Cell Transfer ◽  
Antitumor Effects ◽  
Treatment Regimens ◽  
Existing Problems

Adoptive cell transfer has attracted considerable attention as a treatment for cancer. The success of chimeric antigen receptor (CAR)-engineered T (CAR-T) cells for the treatment of haematologic tumors has demonstrated the potential of CAR. In this review, we describe the current CAR-engineered natural killer (CAR-NK) cell construction strategies, including the design principles and structural characteristics of the extracellular, transmembrane and intracellular regions of the CAR structure. In addition, we review different cellular carriers used to develop CAR-NK cells, highlighting existing problems and challenges. We further discuss possible ways to optimize CAR from the perspective of the tumor microenvironment to harness the strength of CAR-NK cells and provided rationales to combine CAR-NK cells with other treatment regimens to enhance antitumor effects.

scholarly journals DAP12-Based Activating Chimeric Antigen Receptor for NK Cell Tumor Immunotherapy

2015 ◽  
Vol 194 (7) ◽  
pp. 3201-3212 ◽  
Author(s):  
Katrin Töpfer ◽  
Marc Cartellieri ◽  
Susanne Michen ◽  
Ralf Wiedemuth ◽  
Nadja Müller ◽  
...  
Keyword(s):  
Chimeric Antigen Receptor ◽  
Nk Cell ◽  
Antigen Receptor ◽  
Tumor Immunotherapy ◽  
Cell Tumor

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.

scholarly journals Inhibition of Human Natural Killer Cell Activity by Influenza Virions and Hemagglutinin

2010 ◽  
Vol 84 (9) ◽  
pp. 4148-4157 ◽  
Author(s):  
Huawei Mao ◽  
Wenwei Tu ◽  
Yinping Liu ◽  
Gang Qin ◽  
Jian Zheng ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Cell Activity ◽  
Immune Defense ◽  
Innate Immune ◽  
Human Natural Killer Cell ◽  
Viral Pathogen ◽  
Infected Cells

ABSTRACT Natural killer (NK) cells keep viral infections under control at the early phase by directly killing infected cells. Influenza is an acute contagious respiratory viral disease transmitted from host-to-host in the first few days of infection. The evasion of host innate immune defenses including NK cells is important for its success as a viral pathogen of humans and animals. NK cells encounter influenza virus within the microenvironment of infected cells. It therefore is important to investigate the direct effects of influenza virus on NK cell activity. Recently we demonstrated that influenza virus directly infects human NK cells and induces cell apoptosis to counter their function (H. Mao, W. Tu, G. Qin, H. K. W. Law, S. F. Sia, P.-L. Chan, Y. Liu, K.-T. Lam, J. Zheng, M. Peiris, and Y.-L. Lau, J. Virol. 83:9215-9222, 2009). Here, we further demonstrated that both the intact influenza virion and free hemagglutinin protein inhibited the cytotoxicity of fresh and interleukin-2 (IL-2)-activated primary human NK cells. Hemagglutinin bound and internalized into NK cells via the sialic acids. This interaction did not decrease NKp46 expression but caused the downregulation of the ζ chain through the lysosomal pathway, which caused the decrease of NK cell cytotoxicity mediated by NKp46 and NKp30. The underlying dysregulation of the signaling pathway involved ζ chain downregulation, leading to decreased Syk and ERK activation and granule exocytosis upon target cell stimulation, finally causing reduced cytotoxicity. These findings suggest that influenza virus developed a novel strategy to evade NK cell innate immune defense that is likely to facilitate viral transmission and also contribute to virus pathogenesis.

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 CIS checkpoint deletion enhances the fitness of cord blood derived natural killer cells transduced with a chimeric antigen receptor

2020 ◽  
Author(s):  
May Daher ◽  
Rafet Basar ◽  
Elif Gokdemir ◽  
Natalia Baran ◽  
Nadima Uprety ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Chimeric Antigen Receptor ◽  
Nk Cell ◽  
Aerobic Glycolysis ◽  
Protein A ◽  
Antigen Receptor ◽  
Negative Regulator ◽  
Combined Strategy ◽  
Anti Tumor Activity

AbstractImmune checkpoint therapy has produced remarkable improvements in the outcome for certain cancers. To broaden the clinical impact of checkpoint targeting, we devised a strategy that couples targeting of the cytokine-inducible SH2-containing (CIS) protein, a key negative regulator of interleukin (IL)-15 signaling, with chimeric antigen receptor (CAR) engineering of natural killer (NK) cells. This combined strategy boosted NK cell effector function through enhancing the Akt/mTORC1 axis and c-MYC signaling, resulting in increased aerobic glycolysis. When tested in a lymphoma mouse model, this combined approach improved NK cell anti-tumor activity more than either alteration alone, eradicating lymphoma xenografts without signs of any measurable toxicity. We conclude that combining CIS checkpoint deletion with CAR engineering promotes the metabolic fitness of NK cells in an otherwise suppressive tumor microenvironment. This approach, together with the prolonged survival afforded by CAR modification, represents a promising milestone in the development of the next generation of NK cells for cancer immunotherapy.

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