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Prepublished online as a Blood First Edition Paper on August 22, 2002; DOI 10.1182/blood-2002-07-2142.
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Blood, 15 January 2003, Vol. 101, No. 2, pp. 476-484
GENE THERAPY
CD28 costimulation and immunoaffinity-based selection efficiently
generate primary gene-modified T cells for adoptive immunotherapy
Carolina Berger,
C. Anthony Blau,
Tim Clackson,
Stanley R. Riddell, and
Shelly Heimfeld
From the Fred Hutchinson Cancer Research Center, and
the Division of Hematology and the Department of Medicine, University
of Washington, Seattle; and ARIAD Gene Therapeutics, Cambridge, MA.
The introduction of an inducible suicide gene has been proposed as
a strategy to exploit the antitumor reactivity of donor T cells after
allogeneic hematopoietic stem cell transplantation but permit control
of graft-versus-host disease. However, there are several obstacles to
this approach that may impair the ability of T cells to function and
survive in vivo. These include the requirement for in vitro activation
or long-term culture to introduce the transgene and obtain therapeutic
cell numbers, the toxicity of drug selection to enrich transduced
cells, and the immunogenicity of the transgene-encoded products. Here
we have developed a transduction and selection strategy for generating
large numbers of polyclonal T cells transduced with a retroviral vector
encoding the human low-affinity nerve growth factor receptor (LNGFR)
for selection and a Fas-based suicide construct (LV'VFas). Ligation of
CD28 in conjunction with a T-cell receptor signal permitted efficient transduction, substantially promoted T-cell growth, and contributed to
the generation of gene-modified T cells that retained clonal diversity,
functional properties, and a homing receptor profile similar to
untransduced peripheral blood lymphocytes. Microbeads conjugated
directly to antibody specific to LNGFR significantly improved the
immunomagnetic selection of LV'VFas-modified T cells and assisted in
scaling of the selection procedure to therapeutic cell numbers. Thus,
these studies identified a strategy that requires only a brief ex vivo
culture and does not use drug selection to obtain large numbers of
functional gene-modified polyclonal T cells that can be used for
adoptive immunotherapy.
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