THE FUTURE OF GENE THERAPY IN THE TREATMENT OF UROLOGIC MALIGNANCIES

With significant media fanfare, human gene therapy technologies have emerged as new research approaches to cancer therapeutics. Expectations have exceeded the natural pace of any new treatment for cancer. Currently, it takes on average 8 to 10 years to receive FDA approval for an active antineoplastic drug. The field of clinical cancer gene therapy is less than 7 years old, and thus efficacy data are only now starting to be generated for concepts that went into clinical trial testing in 1994–1995. Efficacy data from phase II trials are forthcoming in 1998–1999, however, as more clinical trials are conducted and completed. More than 140 clinical protocols of human gene therapy have gained approval worldwide since the treatment of the first patient with gene therapy in 1990. 51 In 60 early studies reviewed by Roth and Cristiano, major tumor responses (defined as either complete regressions or partial regressions) were reported in 15 of 237 evaluable patients. 39 Twelve United States clinical trials of therapeutic gene transfer in the treatment of urologic malignancies are underway, and more are under active development or pending regulatory agency approval. Although the public expectations for cancer gene therapy research cannot yet be justified by disease-free survival data, enthusiasm is partly warranted by the expanding potential of gene therapy research to identify new approaches to the treatment of urologic cancers. The ability to engineer the DNA molecule's code to make any therapeutic protein of interest means that virtually any treatment concept could be tested if it is ethical, clinically appropriate, and safe to treat urologic cancers in a clinical trial. 41 This promise strongly fuels the optimism that gene therapy applied to urologic cancers ultimately will become a part of clinical practice. Gene therapy research applied to cancer has gained prominence in the entire field of human gene therapy since the first human gene therapy clinical trials in 1989–1990. Enthusiasm for gene therapy research for cancer is notable when compared with gene therapy for other diseases, where the correction of an inherited mutant gene is specifically identified and no disease resistance mechanism is known after gene replacement in experimental models. Several reasons explain this, particularly with respect to genitourinary cancers. First, the need for more effective systemic cancer treatments than conventional chemotherapy for metastatic bladder, kidney, Wilms' tumors, and prostate cancer demands new lines of therapeutic research such as gene therapy. Second, of the many human diseases potentially treatable with recombinant DNA, in cancer the ethics of human gene therapy clinical trials are least complicated for patients with metastatic disease. The United States regulatory agencies supervising human gene therapy research, the FDA and the National Institutes of Health (NIH) Recombinant Advisory Committee (RAC), have ruled that cancer is an ethically compelling disease for evaluating completely untested technologies of human gene transfer in early clinical trials. A further highly practical issue has influenced the intense interest in cancer gene therapy. Human tumor cells can be easily manipulated ex vivo, or rebiopsied after treatment in vivo, whereas many affected tissues (e.g., lung, liver) from individuals with other inherited genetic diseases such as cystic fibrosis often cannot. Ex vivo manipulation often is much easier and more controlled than in vivo manipulation and has been more acceptable to the regulatory review committees for studying effects of recombinant DNA in early clinical trials. 31 Furthermore, viral vector based human gene transfer in cancer cells often has proved to be more efficient in percentage of treated cells transduced than in corresponding normal organ tissues.