Targetable Gene Delivery Vectors
Adenoviral vectors, which have targeting ligands for tumor cells on the capsid, no natural tropism, and carry a therapeutic payload should be constructed soon and tested in pre-clinical models. Nevertheless, there are still important considerations for th
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TARGETABLE GENE DELIVERY VECTORS Paul L. Hallenbeck and Susan C. Stevenson Genetic Therapy Inc., A Novartis Company
1. CANCER THERAPY: TARGETING The Holy Grail of cancer therapy, and a host of many therapies for major diseases, is to elicit a desired and selective biological effect on a specific cell type(s). In essence, cancer therapy is targeting. The key aspect of this therapy is in achieving a high rate of killing of cancer cells vs. normal cells. Accomplishing this has been extremely difficult for many reasons including the wide array of cell types involved, the systemic dissemination of cancer cells due to metastases, and the narrow biological differences between normal and cancer cells. While tremendous progress has been made in targeting, much still needs to be done, as current cancer therapies are clearly inadequate.
1.1. Conventional Therapy In the past surgeons have tried to physically remove the tumor surgically without harming normal tissue. Even complete removal of a primary tumor does not ensure survival since earlier metastases to unknown sites in the body are left undetected. There is also some research, which even suggests that surgical intervention may enhance the growth of distant metastases due to removal of tumor cells producing angiogenesis inhibitors (O’Reilly et al., 1994). Finally, in many cases the tumor grows back at the original site after surgical removal. Radiation aims to selectively destroy the most rapidly proliferating cells at the expense of the others. However, tumor cells can escape radiation therapy either by becoming resistant or by being in a non-dividing state during treatment. In addition, radiation is not always selective in that many normal cells are actively dividing and killed by the treatment. (Gastrointestinal cells, hair follicles, etc). Like radiation, chemotherapy is not completely selective and thus destroys many normal cells, and does not kill all tumor cells due to drug resistance and/or division state of the cell.
1.2. Immunotherapy Immunotherapy is essentially the induction of the immune system to selectively expand a subset of cells and/or antibodies, which can target tumor cells. A variety of Cancer Gene Therapy: Past Achievements and Future Challenges, edited by Habib Kluwer Academic/Plenum Publishers, New York, 2000.
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P. L. Hallenbeck and S. C. Stevenson
approaches are currently in preclinical and clinical studies to attempt to boost the number and specificity of T cells, which will track and destroy tumor cells (For review see Rosenberg, 1998). One approach, the use of monoclonal antibodies specific for tumor cells, was thought to be the great promise for cancer therapy approximately 20 years ago. However, most antibodies were generated in mice and elicited immune responses in humans, which effectively eliminated the therapeutic antibodies. However, they are now again showing great promise, as methods have been developed to humanize these antibodies. Of significant note are the clinical studies utilizing a humanized form of a monoclonal anti
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