[Modulation of alloreactivity using genetically modified T lymphocytes].
While effectively preventing graft-versus-host disease (GVHD), ex vivo T-lymphocyte depletion of the graft unfortunately increases graft rejection and reduces the graft-versus-leukemia (GVL) effect after allogeneic hematopoietic stem cell transplantation. The ex vivo transfer of the herpes-simplex thymidine-kinase (HS-tk) suicide gene into T-cells before their infusion with the hematopoietic stem cells, should allow for selective in vivo depletion of these T-cells with ganciclovir (GCV), if subsequent GVHD was to occur. We have demonstrated that retroviral-mediated transfer of HS-tk and Neomycine resistance genes in T-lymphocytes, followed by G418 selection, results in T-cells specifically inhibited by GCV with no bystander effect. In a phase I study, escalating amounts of HS-tk expressing T-cells are infused in conjunction with a T-cell depleted marrow graft to allogeneic HLA identical recipients. Toxicity, survival alloreactivity and GCV-sensitivity of the gene-modified cells are monitored.
Tiberghien
P
P
Laboratoire de Thérapeutique Immuno-moléculaire, Etablissement de Transfusion Sanguine de Franche-Comté, Besançon.
D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D005260:Female; D018014:Gene Transfer Techniques; D006084:Graft Rejection / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D018259:Herpesvirus 1, Human / Q000201:enzymology; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D013937:Thymidine Kinase / Q000235:genetics
D008565:Membrane Proteins; D013937:Thymidine Kinase