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Prepublished online as a Blood First Edition Paper on October 3, 2002; DOI 10.1182/blood-2002-08-2351.
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Blood, 15 February 2003, Vol. 101, No. 4, pp. 1290-1298
GENE THERAPY
Immunologic potential of donor lymphocytes expressing a suicide
gene for early immune reconstitution after hematopoietic
T-cell-depleted stem cell transplantation
Sarah Marktel,
Zulma Magnani,
Fabio Ciceri,
Sabrina Cazzaniga,
Stanley R. Riddell,
Catia Traversari,
Claudio Bordignon, and
Chiara Bonini
From the Cancer Immunotherapy and Gene Therapy Program
and Bone Marrow Transplantation Unit, Istituto Scientifico H. S. Raffaele, Milan, Italy; Program in Immunology, Fred
Hutchinson Cancer Research Center, Seattle, WA; and Molmed S.p.A.,
Milan, Italy.
We have previously shown that the infusion of donor lymphocytes
expressing the herpes simplex virus thymidine kinase
(HSV-tk) gene is an efficient tool for controlling
graft-versus-host disease (GVHD) while preserving the
graft-versus-leukemia (GVL) effect. In addition to the GVL effect, the
administration of donor HSV-tk+ cells could have a clinical
impact in promoting immune reconstitution after T-cell-depleted stem
cell transplantation (SCT). To explore this hypothesis, we have
investigated whether in vitro polyclonal activation, retroviral
transduction, immunoselection, and expansion affect the immune
competence of donor T cells. We have observed that, after appropriate
in vitro manipulation, T cells specific for antigens relevant in the
context of SCT are preserved in terms of frequency, expression of
T-cell receptor, proliferation, cytokine secretion, and lytic activity.
A reduction in the frequency of allospecific T-cell precursors is
observed after prolonged T-cell culture, suggesting that cell
manipulation protocols involving a short culture time and high
transduction efficiency are needed. Finally, the long-term persistence
of HSV-tk+ cells was observed in a patient treated in the
GVL clinical trial, and a reversion of the phenotype of
HSV-tk+ cells from CD45RO+ to
CD45RA+ was documented more than 2 years after the
infusion. Based on all this evidence, we propose a clinical study of
preemptive infusions of donor HSV-tk+ T cells after SCT
from haploidentical donors to provide early immune reconstitution
against infection and potential immune protection against disease recurrence.
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