Genetically engineered T-cells expressing a ganciclovir-sensitive HSV-tk suicide gene for the prevention of GvHD.
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.
Mailly
Laurent
L
INSERM U748, Institut de Virologie, 3 rue Koeberlé, 67000 Strasbourg, France. e.robinet@unistra.fr
Leboeuf
Céline
C
Tiberghien
Pierre
P
Baumert
Thomas
T
Robinet
Eric
E
D000818:Animals; D002986:Clinical Trials as Topic; D015774:Ganciclovir / Q000494:pharmacology*; D018014:Gene Transfer Techniques; D041722:Genes, Transgenic, Suicide; D005822:Genetic Vectors; D006086:Graft vs Host Disease / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation; D018259:Herpesvirus 1, Human / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D013937:Thymidine Kinase / Q000235:genetics*
D013937:Thymidine Kinase; D015774:Ganciclovir