PHASE I STUDY OF INTRAVESICAL VACCINIA VIRUS AS A VECTOR FOR GENE THERAPY OF BLADDER CANCER (2001)

No AccessJournal of UrologyCLINICAL UROLOGY: Original Articles1 Oct 2001PHASE I STUDY OF INTRAVESICAL VACCINIA VIRUS AS A VECTOR FOR GENE THERAPY OF BLADDER CANCER LEONARD G. GOMELLA, MICHAEL J. MASTRANGELO, PETER A. McCUE, HENRY C. MAGUIRE, S. GRANT MULHOLLAND, and EDMUND C. LATTIME LEONARD G. GOMELLALEONARD G. GOMELLA , MICHAEL J. MASTRANGELOMICHAEL J. MASTRANGELO , PETER A. McCUEPETER A. McCUE , HENRY C. MAGUIREHENRY C. MAGUIRE , S. GRANT MULHOLLANDS. GRANT MULHOLLAND , and EDMUND C. LATTIMEEDMUND C. LATTIME View All Author Informationhttps://doi.org/10.1016/S0022-5347(05)65755-2AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: Vaccinia virus is a DNA poxvirus previously used as a vaccine to eradicate smallpox. The virus has a high efficiency of infection, replicates in the cytoplasm without chromosomal integration and can transport a large amount of recombinant DNA without losing infectivity. Therefore, it is an excellent choice as a vector for gene delivery in vivo. Large quantities of vaccinia have been injected into dermal, subcutaneous and peripheral lymph node melanoma metastases without significant side effects, and with efficient infection of the tumor cells and recombinant gene transfection. To determine if vaccinia, when given intravesically, can effectively infect bladder mucosa and tumor with acceptable toxicity, we performed a phase I trial of intravesical vaccinia in patients with muscle invasive transitional cell carcinoma before radical cystectomy. Materials and Methods: After documenting immune competence and demonstration of a major reaction after revaccination, patients received 3 increasing doses of intravesical Dryvax vaccinia virus (Wyeth-Ayerst Laboratories, Philadelphia, Pennsylvania) that was provided by the Centers for Disease Control. Approximately 24 hours after the third dose, cystectomy was performed and the tissue was examined microscopically. Results: There were 4 patients who were treated. The 3 patients who received the highest doses (100 × 106 plaque forming units) had significant mucosal and submucosal inflammatory infiltration by lymphocytes, eosinophils, and plasma cells into tumor and normal tissue. Dendritic cells were recruited to the site after exposure to the vaccinia. Significant mucosal edema and vascular ectasia were seen. Tumor and normal urothelial cells showed evidence of viral infection, including enlarged vacuolated cells with cytoplasmic inclusions. There were no clinical or laboratory manifestations of vaccinia related toxicity except mild dysuria. Of the 4 patients 3 survived and were free of disease at 4-year followup. Conclusions: Our study demonstrates that vaccinia virus can be administered safely into the bladder with recruitment of lymphocytes and induction of a brisk local inflammatory response. To our knowledge, this is the first report of direct delivery of live virus into the human bladder. The role of wild type vaccinia as immunotherapy for bladder cancer warrants further study. Furthermore, these data support the exploration of recombinant vaccinia as a putative gene therapy vector for intravesical infection and transfection of bladder tumor cells with cytokine or other genes, an approach that our group pioneered and most recently studied in patients with superficial melanoma. References 1 : Principles of intravesical chemotherapy and immunotherapy. Urol Clin North Am1992; 19: 509. 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Crossref, Medline, Google Scholar From the Departments of Urology, Pathology and Medicine (Division of Medical Oncology), Jefferson Medical College and the Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania© 2001 by American Urological Association, Inc.FiguresReferencesRelatedDetailsCited byFang C, Tsai Y, Lin M, Wang M, Chen P, Chao C, Huang Y, Chang D and Shen C (2015) Inhibition of Human Bladder Cancer Growth by a Suicide Gene Delivered by JC Polyomavirus Virus-like Particles in a Mouse ModelJournal of Urology, VOL. 193, NO. 6, (2100-2106), Online publication date: 1-Jun-2015.FODOR I, TIMIRYASOVA T, DENES B, YOSHIDA J, RUCKLE H and LILLY M (2018) VACCINIA VIRUS MEDIATED p53 GENE THERAPY FOR BLADDER CANCER IN AN ORTHOTOPIC MURINE MODELJournal of Urology, VOL. 173, NO. 2, (604-609), Online publication date: 1-Feb-2005.SIEMENS D, CRIST S, AUSTIN J, TARTAGLIA J and RATLIFF T (2018) Comparison of Viral Vectors: Gene Transfer Efficiency and Tissue Specificity in a Bladder Cancer ModelJournal of Urology, VOL. 170, NO. 3, (979-984), Online publication date: 1-Sep-2003. Volume 166Issue 4October 2001Page: 1291-1295 Advertisement Copyright & Permissions© 2001 by American Urological Association, Inc.Keywordsadministration, intravesicalvacciniabladder neoplasmsgene therapyMetricsAuthor Information LEONARD G. GOMELLA More articles by this author MICHAEL J. MASTRANGELO More articles by this author PETER A. McCUE More articles by this author HENRY C. MAGUIRE More articles by this author S. GRANT MULHOLLAND More articles by this author EDMUND C. LATTIME More articles by this author Expand All Advertisement PDF downloadLoading ...