Clinical Trial Summary For Suicide Gene Therapy Strategies

As of July 2002, there were 636 human gene therapy clinical trials that were either initiated or completed worldwide with an estimated patient enrollment of 5000 (83,84). A summary of the progression of patient enrollment is depicted in Fig. 5, and a breakdown of the trials by diseases in Fig. 6. Of these human clinical trials, approximately 505 have been or are being conducted in the United States with the next highest number of trials at 43 for the United Kingdom. Of these total human clinical trials, 403 are directed at cancer and 55 of these cancer trials are evaluating suicide gene therapy.

With respect to the vectors being used, Fig. 7 showns the distribution to date. The retrovirus remains the most commonly studied vector at approximately 34% of all trials. The adenovirus has advanced to a close second at 27% of all trials. The largest increase over the past 5 years has been in the strategy of nonviral gene delivery with approximately 23% of all trials focusing on this method. The distribution within nonviral trials is evenly split between lipid-mediated and naked plasmid-mediated gene transfer.

The ongoing or completed clinical trials for suicide gene therapy and cancer overall have provided a few important points for human gene therapy investigation. The first point is that retroviral, adenoviral, and DNA-mediated vectors are at present overall safe vehicles for gene transfer. Except for the

Infectious Diseases / HIV

Infectious Diseases / HIV

Figure 6 Distribution of human clinical trials by disease state.

Figure 6 Distribution of human clinical trials by disease state.

Figure 7 Distribution of vectors used in human clinical trials.

unfortunate death of a young man in 1999 who was enrolled in a gene therapy trial for congenital liver disease, there have been rare and limited side effects with the collection of vectors and genes under investigation (84,85). There have been no significant adverse events with nonviral or DNA-mediated gene transfer in human trials to date. The second important point is that gene transfer and expression in human cancer cells in vivo is possible with both viral and nonviral strategies. The last point is that tumor responses or reports of regression must be interpreted cautiously because the majority of trials remain in phase I or phase I/II and have limited controls for measuring outcomes. Fig. 8 depicts the breakdown of trials with respect to the phase.

At this early stage of human clinical trial investigation, the studies have focused on patients with advanced or incurable cancer. Although this patient population is a standard choice for establishing the safety of novel therapies, the greatest chance of eventual success with presently available suicide gene therapy strategies may be found in patients with less advanced disease. Another important potential for suicide gene therapy is in combination with immune therapies or standard therapy such as with surgery or radiation. As advancements in both preclinical development and clinical application

Figure 8 Distribution of human gene therapy trials by phase.

continue, suicide gene therapy should achieve a role in the treatment of cancer.

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