NEW ORLEANSEncouraging results have emerged for a gene therapy
approach that stimulates a T cell response in chronic lymphocytic
leukemia (CLL). William G. Wierda, MD, of the Human Gene Therapy
Program at the University of San Diego School of Medicine, presented
the results at the 41st annual meeting of the American Society of
Infusion of autologous adenovirus-vector-transduced CLL B cells was
well tolerated and appeared to have significant biologic activity. In
this treatment, the leukemia B cells of patients with CLL were
transduced to express recombinant CD154 (CD40-ligand) using
high-titer replication-defective adenovirus vector (Ad-CD154).
Unlike CLL B cells transfected with control adenovirus vectors,
Ad-CD154-infected CLL B cells become highly effective stimulators of
autologous T cells in mixed lymphocyte reactions and can even induce
autologous T cells to generate CLL-specific cytotoxic T lymphocytes n
vitro, Dr. Wierda explained.
The treatment was administered to 11 patients, aged 37 to 80, by a
single intravenous infusion in a dose-escalating protocol. The
objectives were to identify dose-limiting toxicity, identify maximum
tolerated dose, and assess host response to the transduced cells.
Refinement of the technique after the earlier pilot trial has
resulted in the ability to transduce about 50% of the cells for
infusion, Dr. Wierda said.
After infusion of the cells, the investigators measured transgene
expression in the peripheral blood and observed phenotypic changes in
the bystander leukemia cell population by flow cytometry, most
notably increases in FAS (CD9) and induction of the expression of
costimulatory molecules. Dr. Wierda speculated that, based on
laboratory studies, transgene expression could persist for about 1
week after infusion.
Measurable increases in plasma concentrations of interferon-gamma,
interleukin-6, and interleukin-12 were detected within 2 days of
infusion. Increases of 200% to 400% in absolute T-cell counts and
increases in leukemia-specific T cells were observed in most subjects
within several weeks, and most patients experienced an average 40%
reduction in absolute lymphocyte count.
Clinically, decreases in lymph node size corresponded with these
changes, the average reduction being 70% within 1 to 4 weeks of
treatment, Dr. Wierda said.
The therapy was safe, with no dose-limiting toxicity demonstrated.
The most common side effects were flu-like symptoms. Laboratory
abnormalities included decreases in platelet counts, a slight
prolongation of prothrombin time, and a slight elevation in
transaminase levels. All toxicities resolved within 7 to 10 days of