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Encouraging Results for Gene Therapy in CLL

Encouraging Results for Gene Therapy in CLL

NEW ORLEANS—Encouraging 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 Hematology (ASH).

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.

Transgene Expression

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 infusion.

 
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