Shi, J, Tricot, G, Szmania, S, Rosen, N, Garg, TK, Malaviarachchi, PA et al.. Infusion of haplo-identical killer immunoglobulin-like receptor ligand mismatched NK cells for relapsed myeloma in the setting of autologous stem cell transplantation. Br J Haematol 143: 641-653

Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
British Journal of Haematology (Impact Factor: 4.71). 11/2008; 143(5):641-53. DOI: 10.1111/j.1365-2141.2008.07340.x
Source: PubMed


Killer immunoglobulin-like receptor (KIR)-ligand mismatched natural killer (NK) cells play a key role in achieving durable remission after haplo-identical transplantation for acute myeloid leukaemia. We investigated the feasibility of transfusing haplo-identical, T-cell depleted, KIR-ligand mismatched NK cells, after conditioning therapy with melphalan and fludarabine, to patients with advanced multiple myeloma (MM) followed by delayed rescue with autologous stem cells. No graft-versus-host disease or failure of autologous stem cells to engraft was observed. There was significant variation in the number of allo-reactive NK cells transfused. However, all NK products containing allo-reactive NK cells killed the NK cell target K562, the MM cell line U266, and recipient MM cells when available. Post NK cell infusion there was a rise in endogenous interleukin-15 accompanied by increasing donor chimaerism. Donor chimaerism was eventually lost, which correlated with the emergence of potent host anti-donor responses indicating that the immunosuppressive properties of the conditioning regimen require further optimization. Further, blocking of inhibitory KIR-ligands with anti-human leucocyte antigen antibody substantially enhanced killing of MM cells thus highlighting the potential for modulating NK/MM cell interaction. Encouragingly, 50% of patients achieved (near) complete remission. These data set the stage for future studies of KIR-ligand mismatched NK cell therapy in the autologous setting.

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    • "Preclinical and clinical studies have shown that if infused in large numbers, NK cells can be used to eliminate malignant cells [7]. Both autologous and allogeneic NK cells are able to effectively eliminate cancer cells in vitro [8] [9]. Furthermore, it has been shown that interleukin (IL)-2eactivated NK cells from patients are effective against autologous cancer cells in vivo in a mouse model [10]. "
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    ABSTRACT: Natural killer (NK) cell-based immunotherapy is a promising treatment for a variety of malignancies. However, generating sufficient cell numbers for therapy remains a challenge. To achieve this, optimization of protocols is required. Mature NK cells were expanded from peripheral blood mononuclear cells PBMCs in the presence of anti-CD3 monoclonal antibody and interleukin-2. Additionally, NK-cell progenitors were generated from CD34(+) hematopoietic stem cells or different T/NK-cell progenitor populations. Generated NK cells were extensively phenotyped, and functionality was determined by means of cytotoxicity assay. Addition of ascorbic acid (AA) resulted in more proliferation of NK cells without influencing NK-cell functionality. In more detail, PBMC-derived NK cells expanded 2362-fold (median, range: 90-31,351) in the presence of AA and were capable of killing tumor cells under normoxia and hypoxia. Moreover, hematopoietic stem cell-derived progenitors appeared to mature faster in the presence of AA, which was also observed in the NK-cell differentiation from early T/NK-cell progenitors. Mature NK cells proliferate faster in the presence of phospho-L-AA, resulting in higher cell numbers with accurate functional capacity, which is required for adoptive immunotherapy. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.
    Cytotherapy 03/2015; 17(5). DOI:10.1016/j.jcyt.2015.01.004 · 3.29 Impact Factor
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    • "Complete remission or near complete remission in 50% of patients. [104] "
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    ABSTRACT: Abstract Natural Killer (NK) cells are innate immune effectors that are primarily involved in immunosurveillance to spontaneously eliminate malignantly transformed and virally infected cells without prior sensitization. NK cells trigger targeted attack through release of cytotoxic granules, and secrete various cytokines and chemokines to promote subsequent adaptive immune responses. NK cells selectively attack target cells with diminished major histocompatibility complex (MHC) class I expression. This “Missing-self” recognition by NK cells at first puzzled researchers in the early 1990s, and the mystery was solved with the discovery of germ line encoded killer immunoglobulin receptors that recognize MHC-I molecules. This review summarizes the biology of NK cells detailing the phenotypes, receptors and functions; interactions of NK cells with dendritic cells (DCs), macrophages and T cells. Further we discuss the various strategies to modulate NK cell activity and the practice of NK cells in cancer immunotherapy employing NK cell lines, autologous, allogeneic and genetically engineered cell populations. Keywords NK cells; Cancer; Immunotherapy; Adoptive cell transfer
    Cancer Letters 12/2014; 357(2). DOI:10.1016/j.canlet.2014.12.020 · 5.62 Impact Factor
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    • "Despite these advanced therapeutic options, median survival remains around 4–5 years in adults (29) and the development of better treatments is essential. Interestingly, evidence is accumulating that NK cells may play a prominent role in immune responses toward MM and can also contribute to graft-versus-myeloma responses in haploidentical HSCT (30), It is becoming clear that NK cells can elicit potent allogeneic and autologous responses to myeloma cells in vitro and in patients (30, 31). Given the importance of NK cells in immune responses toward MM, combination therapies that enhance NK cell functions are showing promise in treating this deadly disease, as will become evident in the following discussion. "
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    ABSTRACT: Natural killer (NK) cells are critical innate immune lymphocytes capable of destroying virally infected or cancerous cells through targeted cytotoxicity and further assisting in the immune response by releasing inflammatory cytokines. NK cells are thought to contribute to the process of tumor killing by certain therapeutic monoclonal antibodies (mAb) by directing antibody-dependent cellular cytotoxicity (ADCC) through FcγRIIIA (CD16). Numerous therapeutic mAb have been developed that target distinct cancer-specific cell markers and may direct NK cell-mediated ADCC. Recent therapeutic approaches have combined some of these cancer-specific mAb with additional strategies to optimize NK cell cytotoxicity. These include agonistic mAb targeting NK cell activating receptors and mAbs blocking NK cell inhibitory receptors to enhance NK cell functions. Furthermore, several drugs that can potentiate NK cell cytotoxicity through other mechanisms are being used in combination with therapeutic mAb. In this review, we examine the mechanisms employed by several promising agents used in combination therapies that enhance natural or Ab-dependent cytotoxicity of cancer cells by NK cells, with a focus on treatments for leukemia and multiple myeloma.
    Frontiers in Immunology 12/2013; 4:481. DOI:10.3389/fimmu.2013.00481
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