In vivo and ex vivo gene therapy strategies to treat tumors using adenovirus gene transfer vectors.
Gene Transfer Techniques
The adaptation of gene therapy strategies to treat tumors has broadened the potential armamentarium of anticancer strategies to include approaches for local control of tumor growth as well as to enhance systemic antitumor immunity to treat metastases. A major focus of the author and colleagues has been to use replication-deficient adenovirus vectors, both in vivo and ex vivo, to enhance local control of and systemic immunity against cancer. Several examples will be used to demonstrate these strategies. Using prodrugs, systemically administered drugs converted to toxic metabolites in the local tumor milieu, has proven to be a useful strategy for achieving high local concentrations of the toxic product while avoiding the systemic toxicity that limits the use of chemotherapy agents. Transfer of genes encoding cytosine deaminase (with 5-fluorocytosine) and carboxylesterase (CE) (with irinotecan) are two paradigms that have been used in our laboratory. The data demonstrate that using adenoviruses to deliver these genes to the tumor site leads to production of the active chemotherapeutic agent, which diffuses from the cell in which it was produced to suppress tumor growth and attain regional control in a single organ. Extensive experimental and clinical data now exist to support the concept that tumor growth is critically dependent on angiogenesis and that vascular endothelial growth factor (VEGF) appears to play a central role in the process of tumor neovascularization. Data generated in our laboratory have shown that adenovirus-mediated regional anti-VEGF therapy using a gene encoding a soluble form of flt-1 (one of the VEGF receptors) can be used for regional control of tumor growth. The critical dependence of many tumors on VEGF for neovascularization and dissemination predicts the general applicability of this strategy for treatment of many solid tumors. Another paradigm involves dendritic cells, potent antigen-presenting cells that play a critical role in the initiation of antitumor immune responses. Immunization of mice with dendritic cells genetically modified using an adenovirus vector transferring a gene encoding a tumor antigen confers potent protection against a lethal tumor challenge, as well as suppression of preestablished tumors, resulting in a significant survival advantage. One clinical scenario to which this approach is relevant is treating micrometastases present at the time of primary detection of many malignancies. A possible clinical strategy would be to modify dendritic cells from such patients using an adenovirus vector encoding the relevant tumor antigen, and then administering the genetically modified dendritic cells as adjuvant treatment following primary therapy.