Genetically engineered T-cells expressing a ganciclovir-sensitive HSV-tk suicide gene for the prevention of GvHD.

Abstract : In vitro and in vivo preclinical studies and phase I/II clinical trials have demonstrated that the retroviral-mediated transfer of the suicide gene HSV-thymidine kinase into donor T-cells prior to infusion (ie, a 2-week ex vivo process including activation, retroviral transduction and selection of transduced cells), at the time of T-cell-depleted hematopoietic stem cell transplantation (HSCT) or as donor lymphocyte infusion after relapse, allows for the efficient control of donor T-cell alloreactivity. These donor suicide gene-modified T-cells (SGMTCs) can provide beneficial anti-leukemic, antiviral and immune reconstitution-facilitating effects to the recipient of an allogeneic HSCT. However, if the infused SGMTCs lead to GvHD, a severe complication of HSCT, these cells can be specifically depleted in vivo by the administration of the prodrug ganciclovir (GCV), without any associated immunosuppression. Limitations to this approach include a gene transfer-induced decrease in alloreactivity and antiviral reactivity, the immunogenicity of SGMTCs, and the development of GCV-resistant SGMTCs. However, major improvements that can prevent these limitations, such as introducing CD3/CD28 costimulation and immunomagnetic selection, have been applied to this approach, but further improvements are still required. The efficacy of suicide gene therapy as a safety control system allows the development of this strategy for gene therapy or immunotherapy approaches.
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Article dans une revue
Current Opinion in Investigational Drugs, Thomson Reuters (Professional), 2010, 11 (5), pp.559-70
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http://www.hal.inserm.fr/inserm-00508040
Contributeur : Philippe Saas <>
Soumis le : lundi 2 août 2010 - 14:49:54
Dernière modification le : jeudi 15 février 2018 - 08:48:14

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  • HAL Id : inserm-00508040, version 1
  • PUBMED : 20419602

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Laurent Mailly, Céline Leboeuf, Pierre Tiberghien, Thomas Baumert, Eric Robinet. Genetically engineered T-cells expressing a ganciclovir-sensitive HSV-tk suicide gene for the prevention of GvHD.. Current Opinion in Investigational Drugs, Thomson Reuters (Professional), 2010, 11 (5), pp.559-70. 〈inserm-00508040〉

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