Pluripotent stem cell-derived natural killer cells for cancer therapy

Department of Medicine and Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA.
Translational research : the journal of laboratory and clinical medicine 09/2010; 156(3):147-54. DOI: 10.1016/j.trsl.2010.07.008
Source: PubMed


Human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) provide an accessible, genetically tractable, and homogenous starting cell population to efficiently study human blood cell development. These cell populations provide platforms to develop new cell-based therapies to treat both malignant and nonmalignant hematological diseases. Our group previously demonstrated the ability of hESC-derived hematopoietic precursors to produce functional natural killer (NK) cells as well as an explanation of the underlying mechanism responsible for the inefficient development of T and B cells from hESCs. hESCs and iPSCs, which can be engineered reliably in vitro, provide an important new model system to study human lymphocyte development and produce enhanced cell-based therapies with the potential to serve as a "universal" source of antitumor lymphocytes. This review will focus on the application of hESC-derived NK cells with currently used and novel therapeutics for clinical trials, barriers to translation, and future applications through genetic engineering approaches.

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Available from: Dan S Kaufman, Nov 17, 2014
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    • "As previously mentioned, human NK cells can be differentiated from CD34+ HSC under certain culture conditions (31, 35, 42). Currently, optimizing the generation of CD34+ HSC from hESC and iPSC remains a major challenge to rationally approach hESC- and iPSCs-based NK cell therapy (45–48). hESCs or iPSCs derived CD34+ cells are known to be enriched for hematopoietic progenitors defined by colony-forming cells, which could serve as a suitable source for cell therapy (47). "
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    ABSTRACT: Blurring the boundary between innate and adaptive immune system, natural killer (NK) cells are widely recognized as potent anti-leukemia mediators. Alloreactive donor NK cells have been shown to improve the outcome of allogeneic stem-cell transplantation for leukemia. In addition, in vivo transfer of NK cells may soon reveal an important therapeutic tool for leukemia, if tolerance to NK-mediated anti-leukemia effects is overcome. This will require, at a minimum, the ex vivo generation of a clinically safe NK cell product containing adequate numbers of NK cells with robust anti-leukemia potential. Ideally, ex vivo generated NK cells should also have similar anti-leukemia potential in different patients, and be easy to obtain for convenient clinical scale-up. Moreover, optimal clinical protocols for NK therapy in leukemia and other cancers are still lacking. These and other issues are being currently addressed by multiple research groups. This review will first describe current laboratory NK cell expansion and differentiation techniques by separately addressing different NK cell sources. Subsequently, it will address the mechanisms known to be responsible for NK cell alloreactivity, as well as their clinical impact in the hematopoietic stem cells transplantation setting. Finally, it will briefly provide insight on past NK-based clinical trials.
    Full-text · Article · Mar 2014 · Frontiers in Immunology
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    • "Several studies have also focused on generating NK cells because of their anti-tumor effects without the need for antigen matching or previous exposure [81, 82]. iPSC-mediated immunotherapy can prevent relapse and immune rejection, and decrease tumor burden [83]. In addition, Li et al. investigated the possibility of using PSCs to develop a cancer vaccine [84]. "
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    ABSTRACT: One aim of stem cell-based therapy is to utilize pluripotent stem cells (PSCs) as a supplementary source of cells to repair or replace tissues or organs that have ceased to function due to severe tissue damage. However, PSC-based therapy requires extensive research to ascertain if PSC derivatives are functional without the risk of tumorigenicity, and also do not engender severe immune rejection that threatens graft survival and function. Recently, the suitability of induced pluripotent stem cells applied for patient-tailored cell therapy has been questioned since the discovery of several genetic and epigenetic aberrations during the reprogramming process. Hence, it is crucial to understand the effect of these abnormalities on the immunogenicity and survival of PSC grafts. As induced PSC-based therapy represents a hallmark for the potential solution to prevent and arrest immune rejection, this review also summarizes several up-to-date key findings in the field.
    Full-text · Article · Oct 2013 · Current Stem Cell Research & Therapy
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    • "This approach could generate novel insights into NK cell turnover, differentiation, migratory behavior , in vivo killing of target cells, and other areas. Moreover, induced pluripotent stem cells have been used to generate hNK cells with antiviral activity against HIV (Knorr and Kaufman, 2010). NK cells derived from induced rhesus pluripotent stem cells (Liu et al., 2008) could be used to monitor in vivo NK cell development and differentiation. "
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    ABSTRACT: Human NK (hNK) cells play a key role in mediating host immune responses against various infectious diseases. For practical reasons, the majority of the data on hNK cells has been generated using peripheral blood lymphocytes. In contrast, our knowledge of NK cells in human tissues is limited, and not much is known about developmental pathways of hNK cell subpopulations in vivo. Although research in mice has elucidated a number of fundamental features of NK cell biology, mouse, and hNK cells significantly differ in their subpopulations, functions, and receptor repertoires. Thus, there is a need for a model that is more closely related to humans and yet allows experimental manipulations. Non-human primate models offer numerous opportunities for the study of NK cells, including the study of the role of NK cells after solid organ and stem cell transplantation, as well as in acute viral infection. Macaque NK cells can be depleted in vivo or adoptively transferred in an autologous system. All of these studies are either difficult or unethical to carry out in humans. Here we highlight recent advances in rhesus NK cell research and their parallels in humans. Using high-throughput transcriptional profiling, we demonstrate that the human CD56(bright) and CD56(dim) NK cell subsets have phenotypically and functionally analogous counterparts in rhesus macaques. Thus, the use of non-human primate models offers the potential to substantially advance hNK cell research.
    Full-text · Article · Feb 2013 · Frontiers in Immunology
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