The term gene therapy describes a new type of medicine mediated by the transfer of genes into somatic cells. Knowledge of viruses and how they introduce their genetic material into cells has allowed for development of virus-derived "vectors" that can infect cells and thereby introduce a selected gene(s). Through advances in molecular biology we can achieve high-level expression of the transferred genes (or transgene) in almost any type of mammalian cell. The transgene can direct synthesis of an intracellular, cell surface, or secreted protein(s) that complements a genetic defect or that provides for a desired phenotype. Alternatively, the transferred genetic material may mitigate expression of genes encoding unwanted or mutated proteins through "gene interference" or gene complementation. Conceivably, transfer and expression of appropriate genes could be used to correct for genetic deficiencies or allow for expression of a desired characteristic(s) by vector-infected (or transduced) cells. Although we have yet to realize the application of this technology in clinical practice, gene therapy arguably has tremendous potential for altering our approach to the treatment of a variety of genetic and acquired diseases, including cancer.

Chronic lymphocytic leukemia (CLL) has several features that make it amenable to gene therapy. Like many other forms of cancer, CLL results from genetic changes that affect the turnover and survival of normal B-cells, allowing for accumulation of cells descending from one clone of differentiated B-cells. Knowledge of the genes encoding proteins that contribute to the resistance of leukemia cells to programmed cell death, or apoptosis, has allowed for development of strategies with which to interfere with expression or function of anti-apoptotic genes. In addition, the genetic alterations and clonal distribution of unique immunoglobulin gene rearrangements in this B-cell malignancy may encode "altered-self" proteins that potentially could be recognized by the patient's immune system. Since large numbers of leukemia cells can be harvested via a relatively simple procedure (e.g., leukapheresis), strategies involving ex vivo gene transfer into neoplastic cells are highly feasible. This allows for in vitro evaluation of gene transfer and expression prior to reinfusion of vector-modified leukemia cells. Also, it allows for development of clinical trials that evaluate the safety and clinical response to defined numbers of transduced neoplastic cells. Relatively simple blood tests then can be used to monitor expression of the transgene(s) by the neoplastic cells in vivo, leukemia cell number, or changes in bystander cells following gene transfer. Finally, normal host cells that infiltrate

From: Contemporary Hematology Chronic Lymphocytic Leukemia: Molecular Genetics, Biology, Diagnosis, and Management Edited by: G. B. Faguet © Humana Press Inc., Totowa, NJ 329

the tumor are found in the blood, making such cells accessible for isolation and analysis. Thus, CLL has several features that could facilitate development of novel gene therapy approaches.

Gene therapy trials in patients with CLL are under way. Methods have been identified for effecting high-level transgene expression in CLL using virus vectors. Studies have identified means with which to alter the leukemia cell through gene transfer so as to elicit immune effector mechanisms that can contribute to leukemia cell clearance. As of August of 2002, five active clinical trials of gene therapy in CLL had been reported to the Office of Biotechnology Activities of the National Institutes of Health. These include protocols studying the effect of transducing immunomodulator genes, such as CD40 ligand (CD154) and/or interleukin-2 (IL-2), the capacity for cell marking with genes encoding neomycin phosphotransferase in the context of hematopoietic stem cell transplantation, and intramuscular injection of plasmid DNA using tumor idiotype vaccination (1). This chapter discusses the current status of gene therapy applied to CLL, recent publications, and future strategies in this field.

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