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Thymidine kinase (TK) gene-transduced human lymphocytes can be highly
purified, remain fully functional, and are killed efficiently with
ganciclovir
NC Munshi, R Govindarajan, R Drake, LM Ding, R Iyer, R Saylors, J Kornbluth, S Marcus, Y Chiang, D Ennist, L Kwak, C Reynolds, G Tricot and B Barlogie
University of Arkansas for Medical Sciences, Little Rock 72205, USA.
A graft-versus-leukemia (GVL) effect has been considered a major factor
responsible for cures in patients with hematologic malignancies undergoing
allogeneic bone marrow transplantation; however, associated
graft-versus-host disease (GVHD) results in significant morbidity and
mortality. T-cell depletion reduces the incidence and severity of GVHD but
eliminates, at least partially, the GVL effect. Reinfusion of donor T
lymphocytes at relapse posttransplantation can induce a potent antitumor
response, but GVHD still occurs in the majority of patients. Prior
transduction of T lymphocytes with the suicide gene, the viral thymidine
kinase (TK), permits specific cell kill on administration of ganciclovir
(GCV). Therefore, infusion of TK-transduced T lymphocytes may induce GVL
effect and allow for their subsequent selective elimination in case GVHD
develops. To evaluate the efficacy and feasibility of this promising
approach, anti-CD3-stimulated primary human lymphocytes cultured in
interleukin-2 were TK-transduced by a retroviral vector carrying both TK
and neomycin-resistance genes. After selection in G418, more than 90% of
the cells contained the TK gene as shown by a semiquantitative polymerase
chain reaction. In addition, 1 to 5 days of GCV exposure, at clinically
achievable concentrations of 20 to 50 micromol/L, induced > or = 90%
killing of G418-selected cells without affecting nontransduced cells.
Correlation of the extent of T- cell kill and the proportion of
TK-gene-transduced cells is consistent with the absence of a bystander
effect. Transduced cells were CD3+ and either CD8+ or CD4+ and retained
functional properties of untransduced cells. In vivo administration of GCV
prevented tumor development after subcutaneous injection of TK-transduced
murine myeloma cells (MOPC-11), whereas such an effect was not observed on
injection of untransduced cells into the opposite flank. Our studies
provide critical information that (1) adequate numbers of TK-transduced
lymphocytes can be selected efficiently with > or = 90% purity, (2)
selected cells remain functional, (3) 24 hours of exposure to GCV at
clinically achievable concentration effects > or = 90% killing of
selected cells, and (4) GCV is effective in vivo in killing TK-transduced
cells. Based on these data, a clinical study has been initiated in patients
with multiple myeloma with persistent or relapsing disease after
T-cell-depleted allogeneic transplants.
Volume 89,
Issue 4,
pp. 1334-1340,
02/15/1997
Copyright © 1997 by The American Society of Hematology
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