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    Retroviral transduction of human peripheral blood lymphocytes with Bcl-X(L) promotes in vitro lymphocyte survival in pro-apoptotic conditions.

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    Authors
    Eaton, David
    Gilham, David E
    O'Neill, Alison C
    Hawkins, Robert E
    Affiliation
    CRC Department of Medical Oncology, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK.
    Issue Date
    2002-04
    
    Metadata
    Show full item record
    Abstract
    The prolonged in vivo survival of genetically modified effector cells is crucial to the success of any (gene-modified) adoptive cellular immunotherapy approach. In cancer clinical trials to date, however, the detection of surviving circulating gene-modified T cells has required highly sensitive techniques. In vitro studies of T cell co-stimulation have shown that up-regulation of the anti-apoptosis gene Bcl-X(L) by ligation of CD28 promotes T cell survival, but not proliferation. Here we have investigated the ability to modulate resistance to apoptosis and improve cell survival by transducing human peripheral blood lymphocytes using a retroviral vector that expresses Bcl-X(L). We show that Jurkat cells transduced with Bcl-X(L) retrovirus were partially resistant to Fas (CD95) antibody-induced apoptosis. Subsequent in vitro assays with transduced primary human lymphocytes demonstrates that over-expression of Bcl-X(L) promotes the survival of lymphocytes cultured in the absence of interleukin-2. Activation-induced apoptosis with anti-CD3(epsilon) antibody, OKT3 is also modulated. Furthermore, Bcl-X(L) over-expression in human lymphocytes delays the onset of apoptosis induced by long-term co-culture with tumour cell lines. Despite this improved in vitro survival, in a preliminary experiment to assess safety, no signs of malignancy or autoimmunity were observed in NOD/SCID mice injected with Bcl-X(L) transduced lymphocytes. These results indicate that expression of Bcl-X(L) in lymphocyte therapy either alone or in conjunction with an additional therapeutic gene could enhance persistence of cells in vivo thereby potentially improving the clinical outcome of adoptive cellular therapy.
    Citation
    Retroviral transduction of human peripheral blood lymphocytes with Bcl-X(L) promotes in vitro lymphocyte survival in pro-apoptotic conditions. 2002, 9 (8):527-35 Gene Ther.
    Journal
    Gene Therapy
    URI
    http://hdl.handle.net/10541/83575
    DOI
    10.1038/sj.gt.3301685
    PubMed ID
    11948378
    Type
    Article
    Language
    en
    ISSN
    0969-7128
    ae974a485f413a2113503eed53cd6c53
    10.1038/sj.gt.3301685
    Scopus Count
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    All Paterson Institute for Cancer Research

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