Graft-versus-leukemia effect after suicide-gene-mediated control of graft-versus-host disease.
Clinical data indicate that after allogeneic hematopoietic stem cell transplantation (HSCT) for hematological malignancies, the graft-versus-leukemia (GVL) effect is in large part mediated by the graft-versus-host reaction (GVHR), which also often leads to graft-versus-host disease (GVHD). Controlling alloreactivity to prevent GVHD while retaining GVL poses a true dilemma for the successful treatment of such malignancies. We reasoned that suicide gene therapy, which kills dividing cells expressing the thymidine kinase (TK) "suicide" gene using time-controlled administration of ganciclovir (GCV), might solve this dilemma. We have previously shown that after infusion of allogeneic TK T cells along with HSCT to an irradiated recipient, an early and short GCV treatment efficiently prevents GVHD by selectively eliminating alloreactive T cells while sparing nonalloreactive T cells, which can then contribute to immune reconstitution. Nevertheless, it remained to be established that this therapeutic strategy retained the desired GVL effect. Hypothesizing that a contained GVHR would be essential, we evaluated the GVL effect using different protocols of GCV administration. We were able to show that when the GCV treatment is initiated at, or close to, the time of grafting, GVHD is controlled but GVL is lost. In contrast, when the onset of GCV administration is delayed until day 6, a potent GVL effect is retained while GVHD is still controlled. These data emphasize that, by a time-optimized scheduling of the administration of GCV, this TK/GCV strategy can be tuned to efficiently treat malignant hemopathies.
Biologie et Thérapeutique des Pathologies Immunitaires CNRS/UPMC UMR 7087, Hôpital Pitié-Salpêtrière, 83 boulevard de l'Hôpital, F-75651 Paris Cedex 13, France.
Elena
E
Litvinova
Sébastien
S
Maury
Olivier
O
Boyer
Sylvie
S
Bruel
Laurent
L
Benard
Gilbert
G
Boisserie
David
D
Klatzmann
José L
JL
Cohen
D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005260:Female; D015774:Ganciclovir / Q000008:administration & dosage; D015316:Genetic Therapy / Q000379:methods*; D006086:Graft vs Host Disease / Q000517:prevention & control* / Q000628:therapy; D020544:Graft vs Leukemia Effect; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D007938:Leukemia / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D013601:T-Lymphocytes / Q000378:metabolism / Q000637:transplantation; D013937:Thymidine Kinase / Q000235:genetics*; D014161:Transduction, Genetic; D014184:Transplantation, Homologous
D016572:Cyclosporine; D013937:Thymidine Kinase; D015774:Ganciclovir