Treatment of patients with advanced cancer with the natural killer cell line NK-92
TL;DR: Despite the allogeneic nature of NK-92, development of human leukocyte antigen antibodies in these patients with cancer appears to be rare and some encouraging responses were seen in patients with advanced lung cancer.
About: This article is published in Cytotherapy.The article was published on 2013-12-01. It has received 381 citations till now. The article focuses on the topics: NK-92 & Natural killer cell.
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TL;DR: Diverse approaches encompass the development of large-scale NK cell–expansion protocols for adoptive transfer, the establishment of a microenvironment favorable toNK cell activity, the redirection of NK cell activity against tumor cells and the release of inhibitory signals that limit NK cell function.
Abstract: Alteration in the expression of cell-surface proteins is a common consequence of malignant transformation. Natural killer (NK) cells use an array of germline-encoded activating and inhibitory receptors that scan for altered protein-expression patterns, but tumor evasion of detection by the immune system is now recognized as one of the hallmarks of cancer. NK cells display rapid and potent immunity to metastasis or hematological cancers, and major efforts are now being undertaken to fully exploit NK cell anti-tumor properties in the clinic. Diverse approaches encompass the development of large-scale NK cell-expansion protocols for adoptive transfer, the establishment of a microenvironment favorable to NK cell activity, the redirection of NK cell activity against tumor cells and the release of inhibitory signals that limit NK cell function. In this Review we detail recent advances in NK cell-based immunotherapies and discuss the advantages and limitations of these strategies.
803 citations
TL;DR: Recent advances made in the understanding of how NK cells develop, mature, and their potential translational use in the clinic are summarized.
Abstract: Natural killer cells are the predominant innate lymphocyte subsets that mediate anti-tumor and anti-viral responses, and therefore possess promising clinical utilization. NK cells do not express polymorphic clonotypic receptors and utilize inhibitory receptors (KIR and Ly49) to develop, mature, and recognize ‘self’ from ‘non-self’. The essential roles of common gamma cytokines such as IL-2, IL-7, and IL-15 in the commitment and development of NK cells are well-established. However, the critical functions of proinflammatory cytokines IL-12, IL-18, IL-27, and IL-35 in the transcriptional-priming of NK cells are only starting to emerge. Recent studies have highlighted multiple shared characteristics between NK cells the adaptive immune lymphocytes. NK cells utilize unique signaling pathways that offer exclusive ways to genetically manipulate to improve their effector functions. Here, we summarize the recent advances made in the understanding of how NK cells develop, mature, and their potential translational use in the clinic.
610 citations
Cites background from "Treatment of patients with advanced..."
...Interestingly, the use of a clonal cell line derived from a human NK cell leukemia, known as NK-92, has been genetically modified to express fully functional CARs and these cells have shown great promise with regards to their safety and efficacy in recent clinical trials (327, 330, 331)....
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TL;DR: This Review analyses the different sources of T cells and technological approaches to produce optimal allogeneic chimeric antigen receptor T cells with limited potential for graft-versus-host disease and increased persistence and describes the different technological approaches.
Abstract: Autologous chimeric antigen receptor (CAR) T cells have changed the therapeutic landscape in haematological malignancies. Nevertheless, the use of allogeneic CAR T cells from donors has many potential advantages over autologous approaches, such as the immediate availability of cryopreserved batches for patient treatment, possible standardization of the CAR-T cell product, time for multiple cell modifications, redosing or combination of CAR T cells directed against different targets, and decreased cost using an industrialized process. However, allogeneic CAR T cells may cause life-threatening graft-versus-host disease and may be rapidly eliminated by the host immune system. The development of next-generation allogeneic CAR T cells to address these issues is an active area of research. In this Review, we analyse the different sources of T cells for optimal allogeneic CAR-T cell therapy and describe the different technological approaches, mainly based on gene editing, to produce allogeneic CAR T cells with limited potential for graft-versus-host disease. These improved allogeneic CAR-T cell products will pave the way for further breakthroughs in the treatment of cancer. The use of allogeneic chimeric antigen receptor T cells from donors has many potential advantages over autologous approaches, such as immediate availability, standardization and the possibility of redosing or combination. This Review analyses the different sources of T cells and technological approaches to produce optimal allogeneic chimeric antigen receptor T cells with limited potential for graft-versus-host disease and increased persistence.
506 citations
TL;DR: This review focuses on recent advances in NK cell engineering, particularly on preclinical evidence suggesting that NK cells may be as effective as T cells in recognizing and killing targets after genetic modification.
312 citations
Cites background or result from "Treatment of patients with advanced..."
...NK-92 cells lack almost all inhibitory KIRs except KIR2DL4.(60,61) The lack of KIRs on NK-92 cells may, at least in part, account for their marked in vitro activity against a broad spectrum of tumor targets....
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...Promising in vitro results have led to early-phase administration of NK-92 cells to over 40 human subjects with advanced cancers.(61,108) However, despite the safety of repeated infusions of NK-92 cells, efficacy remains limited; therefore, a number of groups are exploring the use of CAR modification to enhance the antitumor activity of these cells....
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...Although several NK cell lines exist (NKG, YT, NK-YS, HANK-1, YTS cells, and NKL cells),(80,107) the most widely studied by far is NK-92, a human NK-like cell line originally established from a patient with non-Hodgkin’s Lymphoma (NHL).(60,61) NK-92 cells lack almost all inhibitory KIRs except KIR2DL4....
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...Although several NK cell lines exist (NKG, YT, NK-YS, HANK-1, YTS cells, and NKL cells),80,107 the most widely studied by far is NK-92, a human NK-like cell line originally established from a patient with non-Hodgkin’s Lymphoma (NHL).60,61 NK-92 cells lack almost all inhibitory KIRs except KIR2DL4....
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TL;DR: Only NK-92 cells can easily be genetically manipulated to recognize specific tumor antigens or to augment monoclonal antibody activity through antibody-dependent cellular cytotoxicity, and is the only cell line product that has been infused into patients with advanced cancer with clinical benefit and minimal side effects.
Abstract: Natural killer cells are potent cytotoxic effector cells for cancer therapy and potentially for severe viral infections. However, there are technical challenges to obtain sufficient numbers of functionally active NK cells form a patient’s blood since they represent only 10% of the lymphocytes. Especially, cancer patients are known to have dysfunctional NK cells. The alternative is to obtain cells from a healthy donor, which requires depletion of the allogeneic T-cells. Establishing cell lines from donor blood NK cells have not been successful, in contrast to blood NK cells obtained from patients with a clonal NK cell lymphoma. Those cells can be expanded in culture in the presence of IL-2. However, except for the NK-92 cell line none of the other six known cell lines has consistent and reproducibly high anti-tumor cytotoxicity, nor can they be easily genetically manipulated to recognize specific tumor antigens or to augment monoclonal antibody activity through ADCC. NK-92 is also the only cell line product that has been widely given to patients with advanced cancer with demonstrated efficiency and minimal side effects.
309 citations
Cites background from "Treatment of patients with advanced..."
...The initial trials in Chicago and Frankfurt enrolled patients with renal cell and lung cancer and other solid tumors (22, 23)....
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...Those phase I studies also confirmed that even with cell numbers as high as 10 billion cells/m2, infusions are safe with no severe unexpected side effects (22, 23)....
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...NK-92 cells have undergone extensive preclinical development (18–21) and have completed phase I trials in cancer patients [(22, 23), clinical trials NCT00900809 and NCT00990717]....
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References
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TL;DR: The revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions, and a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included.
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TL;DR: It is shown that donor-versus-recipient natural killer (NK)–cell alloreactivity could eliminate leukemia relapse and graft rejection and protect patients against GVHD in human transplants and in mice, the pretransplant infusion of alloreactive NK cells obviated the need for high-intensity conditioning and reduced GV HD.
Abstract: T cells that accompany allogeneic hematopoietic grafts for treating leukemia enhance engraftment and mediate the graft-versus-leukemia effect. Unfortunately, alloreactive T cells also cause graft-versus-host disease (GVHD). T cell depletion prevents GVHD but increases the risk of graft rejection and leukemic relapse. In human transplants, we show that donor-versus-recipient natural killer (NK)-cell alloreactivity could eliminate leukemia relapse and graft rejection and protect patients against GVHD. In mice, the pretransplant infusion of alloreactive NK cells obviated the need for high-intensity conditioning and reduced GVHD. NK cell alloreactivity may thus provide a powerful tool for enhancing the efficacy and safety of allogeneic hematopoietic transplantation.
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TL;DR: The results explain the efficacy of allogeneic bone marrow transplantation in eradicating leukemia, provide evidence for a role of the immune system in controlling human cancers, and suggest future directions to improve leukemia therapy.
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TL;DR: NK cells are now recognized to express a repertoire of activating and inhibitory receptors that is calibrated to ensure self-tolerance while allowing efficacy against assaults such as viral infection and tumor development.
Abstract: Natural killer (NK) cells were originally defined as effector lymphocytes of innate immunity endowed with constitutive cytolytic functions. More recently, a more nuanced view of NK cells has emerged. NK cells are now recognized to express a repertoire of activating and inhibitory receptors that is calibrated to ensure self-tolerance while allowing efficacy against assaults such as viral infection and tumor development. Moreover, NK cells do not react in an invariant manner but rather adapt to their environment. Finally, recent studies have unveiled that NK cells can also mount a form of antigen-specific immunologic memory. NK cells thus exert sophisticated biological functions that are attributes of both innate and adaptive immunity, blurring the functional borders between these two arms of the immune response.
2,280 citations
TL;DR: Donor lymphocyte transfusions exert strong effects against myeloid forms of leukemia and induce durable remissions in CML.
2,014 citations