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Blood, 1 December 2001, Vol. 98, No. 12, pp. 3447-3455
TRANSPLANTATION
Engraftment of DLA-haploidentical marrow with ex vivo expanded,
retrovirally transduced cytotoxic T lymphocytes
George E. Georges,
Rainer Storb,
Benedetto Bruno,
Scott J. Brodie,
Jennifer D. Thompson,
Anna G. Taranova,
J. Maciej Zaucha,
Marie-Térèse Little,
Eustacia Zellmer,
Peter F. Moore,
Theodore Gooley,
George Sale,
Hans-Peter Kiem,
Brenda M. Sandmaier,
Russette
M. Lyons, and
Richard A. Nash
From the Clinical Research Division, Fred Hutchinson
Cancer Research Center; Departments of Medicine and Laboratory
Medicine, University of Washington, Seattle; Department of Veterinary
Pathology, University of California, Davis; and Genetic Therapy, a
Novartis company, Gaithersburg, MD.
Genetically modified donor T cells with an inducible "suicide"
gene have the potential to improve the safety and availability of
allogeneic hematopoietic stem cell transplantation by enhancing engraftment and permitting control of graft-versus-host disease (GVHD).
However, several clinical studies of gene-modified T cells have shown
limited to no in vivo function of the ex vivo expanded T cells. Using
the well-established dog model of allogeneic marrow transplantation,
the question was asked if retrovirally transduced, donor derived, ex
vivo expanded cytotoxic T lymphocytes (CTLs) that are recipient
specific could enhance engraftment of dog leukocyte antigen
(DLA)-haploidentical marrow following a single dose of 9.2 Gy total
body irradiation and no postgrafting immunosuppression. In this
setting, only 4 of 11 control recipients of DLA-haploidentical marrow
without added CTLs engrafted. CTLs did not enhance engraftment of
CD34+ selected peripheral blood stem cells. However,
recipient-specific CTLs enhanced engraftment of DLA-haploidentical
marrow in 9 of 11 evaluable recipients (P = .049). All
dogs that engrafted developed multiorgan GVHD. To facilitate in vivo
tracking, 8 dogs received CTLs transduced with a retroviral vector
encoding green fluorescent protein (GFP) and neomycin
phosphotransferase (neo). Recipients that engrafted had
sharp increases in the numbers of circulating GFP+ CTLs on
days +5 to +6 after transplantation. GFP+ CTLs isolated
from blood were capable of recipient-specific lysis. At necropsy, up to
7.1% of CD3+ cells in tissues were GFP+ and
polymerase chain reaction in situ hybridization for neo
showed infiltration of transduced CTLs in GVHD-affected organs. These results show that ex vivo expanded, transduced T cells maintained in
vivo function and enhanced marrow engraftment.
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