Gene transfer: Methods and applications

The concept of using gene transfer techniques to express a new gene in the somatic cells of a patient has stimulated considerable interest, speculation, and hyperbole. The inevitable backlash against promises that so far have not been fulfilled has led to much confusion about the aims and achievements of gene transfer and to a lurking suspicion that the entire field is simply a “South Sea bubble” waiting to burst. This chapter seeks to provide a balanced account of the current status of gene transfer as applied to leukemia and related disorders, and to review the accomplishments of the field as well as the impediments to progress. Most importantly, it will try to give an idea of the incremental way in which gene transfer technologies will supplement, long before they supplant, current therapeutic approaches to hematologic malignancies. There are two broad strategies of gene transfer applicable to the treatment of leukemia and lymphoma. First, the tumor cell itself can be genetically modified to “repair” its intrinsic molecular defect. Alternatively, a toxic gene can be introduced to destroy the tumor cell, or it can be transduced to express molecules that trigger an immune response against it. Second, the host’s T-cells can be redirected or their anti-tumor activity augmented, and they can be transduced with suicide genes to terminate potentially harmful immune reactions. The drug sensitivity of normal host tissues can be decreased by delivering genes encoding cytotoxic drug resistance to sensitive tissues, thereby increasing the therapeutic index of chemotherapy. Host cells may also be transduced with marker genes, not for any direct therapeutic benefit, but simply as a means to track their behavior and persistence.