Phase I study of intravesical vaccinia virus as a vector for gene therapy of bladder cancer

Purpose: Vaccinia virus is a DNA poxvirus previously used as a vaccine to e radicate 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 effici ent infection of the tumor cells and recombinant gene transfection. To dete rmine if vaccinia, when given intravesically, can effectively infect bladde r mucosa and tumor with acceptable toxicity, we performed a phase I trial o f intravesical vaccinia in patients with muscle invasive transitional cell carcinoma before radical cystectomy. Materials and Methods: After documenting immune competence and demonstratio n of a major reaction after revaccination, patients received 3 increasing d oses of intravesical Dryvax vaccinia virus (Wyeth-Ayerst Laboratories, Phil adelphia, Pennsylvania) that was provided by the Centers for Disease Contro l. Approximately 24 hours after the third dose, cystectomy was performed an d the tissue was examined microscopically. Results: There were 4 patients who were treated. The 3 patients who receive d the highest doses (100 x 10(6) plaque forming units) had significant muco sal and submucosal inflammatory infiltration by lymphocytes, eosinophils, a nd plasma cells into tumor and normal tissue. Dendritic cells were recruite d to the site after exposure to the vaccinia. Significant mucosal edema and vascular ectasia were seen. Tumor and normal urothelial cells showed evide nce of viral infection, including enlarged vacuolated cells with cytoplasmi c inclusions. There were no clinical or laboratory manifestations of vaccin ia related toxicity except mild dysuria. Of the 4 patients 3 survived and w ere 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 rep ort of direct delivery of live virus into the human bladder. The role of wi ld type vaccinia as immunotherapy for bladder cancer warrants further study . Furthermore, these data support the exploration of recombinant vaccinia a s a putative gene therapy vector for intravesical infection and transfectio n of bladder tumor cells with cytokine or other genes, an approach that our group pioneered and most recently studied in patients with superficial mel anoma.