Future Directions

The completed clinical trials in brain tumor gene therapy have offered evidence for the safety of this modality but have suggested that its efficacy will continue to be limited by inefficient transduction, the biggest discrepancy between the experimental rodent studies and the clinical trials. Inefficient trans-duction will need to be addressed in the laboratory before any larger scale clinical trials are conducted.

The efficiency of transduction could be improved by modifying VPCs or by modifying the means by which they are delivered. Use of migratory VPCs, which have shown the ability to "track" even single tumor cells invading the surrounding normal brain (78), may allow better spatial distribution of VPCs throughout the tumor, particularly in distal areas that become foci of recurrence. The currently used manual injections of VPCs into multiple needle tracks are plagued by the limitations in volume that can be injected at any given time and the reflux that occurs along needle tracks. These problems might be addressed by using 3D neuronavigation techniques and automated slow-speed injection/infusion devices (79,80).

The dependence on the bystander effect and limitations of poor transduction could also be overcome by recruiting the immune response. Hoping that the use of a transgene encoding a secreted protein might overcome the difficulty obtaining extensive HSV-TK transduction, a phase I trial has been launched using a recombinant adenovirus expressing human interferon-^ (81).

It could well be that the next step in the development of brain tumor gene therapy will require a multimodal approach combining several of the ideas suggested above. Hopefully, continued gene therapy studies in the laboratory will lead to novel clinical trials capable of improving the outcome for patients diagnosed in the future with malignant gliomas.

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