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Prepublished online as a Blood First Edition Paper on May 17, 2002; DOI 10.1182/blood-2002-01-0161.
Submitted January 17, 2002
Accepted April 16, 2002
Graft-versus-leukemia effect after suicide-gene-mediated control of graft-versus-host disease
ELENA LITVINOVA, SEBASTIEN MAURY, OLIVIER BOYER, SYLVIE BRUEL, LAURENT BENARD, GILBERT BOISSERIE, DAVID KLATZMANN*, and JOSE L COHEN
UMR7087, CNRS, Paris, France, France
Sevice d'anatomie pathologique, Hopital Pitie-Salpetriere, Paris, France, France
Service de radiotherapie, Hopital Pitie-Salpetriere, Paris, France, France
* Corresponding author; email: david.klatzmann{at}chups.jussieu.fr.
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 non-alloreactive 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.
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