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    Potential limitations of the NSG humanized mouse as a model system to optimize engineered human T cell therapy for cancer.

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    Authors
    Alcantar-Orozco, Erik M
    Gornall, Hannah
    Baldan, Vania
    Hawkins, Robert E
    Gilham, David E
    Affiliation
    Clinical and Experimental Immunotherapy Group, Department of Medical Oncology, The Institute of Cancer Sciences, Manchester Academic Healthcare Science Centre, The University of Manchester , Manchester M20 4BX, United Kingdom .
    Issue Date
    2013-10
    
    Metadata
    Show full item record
    Abstract
    The genetic modification of peripheral blood lymphocytes using retroviral vectors to redirect T cells against tumor cells has been recently used as a means to generate large numbers of antigen-specific T cells for adoptive cell therapy protocols. However, commonly used retroviral vector-based genetic modification requires T cells to be driven into cell division; this potent mitogenic stimulus is associated with the development of an effector phenotype that may adversely impact upon the long-term engraftment potential and subsequent antitumor effects of T cells. To investigate whether the cytokines used during culture impact upon the engraftment potential of gene-modified T cells, a humanized model employing T cells engrafted with a MART-1-specific T cell receptor adoptively transferred into NOD/Shi-scid IL-2rγ(-/-) (NSG) immune-deficient mice bearing established melanoma tumors was used to compare the effects of the common γ chain cytokines IL-2, IL-7, and IL-15 upon gene-modified T cell activity. MART-1-specific T cells cultured in IL-7 and IL-15 demonstrated greater relative in vitro proliferation and viability of T cells compared with the extensively used IL-2. Moreover, the IL-15 culture prolonged the survival of animals bearing melanoma tumors after adoptive transfer. However, the combination of IL-7 and IL-15 produced T cells with improved engraftment potential compared with IL-15 alone; however, a high rate of xenogeneic graft-versus-host disease prevented the identification of a clear improvement in antitumor effect of these T cells. These results clearly demonstrate modulation of gene-modified T cell engraftment in the NSG mouse, which supports the future testing of the combination of IL-7 and IL-15 in adoptive cell therapy protocols; however, this improved engraftment is also associated with the long-term maintenance of xenoreactive T cells, which limits the ultimate usefulness of the NSG mouse model in this situation.
    Citation
    Potential limitations of the NSG humanized mouse as a model system to optimize engineered human T cell therapy for cancer. 2013, 24 (5):310-20 Hum Gene Ther Methods
    Journal
    Human Gene Therapy Methods
    URI
    http://hdl.handle.net/10541/324235
    DOI
    10.1089/hgtb.2013.022
    PubMed ID
    23931270
    Type
    Article
    Language
    en
    ISSN
    1946-6544
    ae974a485f413a2113503eed53cd6c53
    10.1089/hgtb.2013.022
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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