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Repeated Intravesical Instillations of an Adenoviral Vector in Patients With Locally Advanced Bladder Cancer: A Phase I Study of p53 Gene Therapy

Lance C. Pagliaro, Afsaneh Keyhani, Dallas Williams, Denise Woods, Baoshun Liu, Paul Perrotte, Joel W. Slaton, James A. Merritt, H. Barton Grossman, Colin P. Dinney

From the Department of Genitourinary Medical Oncology and the Department of Urology, The University of Texas M. D. Anderson Cancer Center; and Introgen Therapeutics, Inc, Houston, TX.

Address reprint requests to Lance C. Pagliaro, MD, Department of Genitourinary Medical Oncology, Box 427, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009; email: lpagliar{at}mdanderson.org.

Purpose: We investigated the feasibility, safety, and biologic activity of adenovirus-mediated p53 gene transfer in patients with locally advanced bladder cancer.

Patients and Methods: Patients with measurable, locally advanced transitional-cell carcinoma of the bladder who were not candidates for cystectomy were eligible. On a 28-day cycle, intravesical instillations of INGN 201 (Ad5CMV-p53) were administered on days 1 and 4 at three dose levels (10¹⁰ particles to 10¹² particles) or on either 4 or 8 consecutive days at a single dose level (10¹² particles).

Results: Thirteen patients received a total of 22 courses without dose-limiting toxicity. Specific transgene expression was detected by reverse transcriptase polymerase chain reaction in bladder biopsy tissue from two of seven assessable patients. There were no changes in p53, p21^waf1/cip1, or bax protein levels in bladder epithelium evident from immunohistochemical analysis of 11 assessable patients. Outpatient administration of multiple courses was feasible and well tolerated. A patient with advanced superficial bladder cancer showed evidence of tumor response.

Conclusion: Intravesical instillation of Ad5CMV-p53 is safe, feasible, and biologically active when administered in multiple doses to patients with bladder cancer. Observations from this study indicate that this treatment has an antitumor effect in superficial transitional-cell carcinoma. Improvements in the efficiency of gene transfer and the levels of gene expression are required to develop more effective gene therapy for bladder cancer.

Supported, in part, by grant nos. CA76233 and CA91846, and in part by core grant no. CA16672 from the National Cancer Institute, Bethesda, MD.

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