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Prepublished online as a Blood First Edition Paper on May 17, 2002; DOI 10.1182/blood-2002-01-0161.
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Blood, 15 September 2002, Vol. 100, No. 6, pp. 2020-2025
GENE THERAPY
Graft-versus-leukemia effect after suicide-gene-mediated
control of graft-versus-host disease
Elena Litvinova,
Sébastien Maury,
Olivier Boyer,
Sylvie Bruel,
Laurent Benard,
Gilbert Boisserie,
David Klatzmann, and
José L. Cohen
From Biologie et Thérapeutique des Pathologies
Immunitaires CNRS/UPMC UMR 7087, the Service d'Anatomie Pathologique,
and the Service de Radiothérapie, Hôpital
Pitié-Salpêtrière, Paris, France.
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.
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