Th1 Cytokine-Secreting Recombinant Bacillus Calmette-Guérin: Prospective Use in Immunotherapy of Bladder Cancer

Abstract

1.1 Clinical use of BCG in bladder cancer treatment Urothelial carcinoma of the bladder is the second most common urologic neoplasm after prostate carcinoma in the United States, with an estimated 70,530 new cases and 14,680 deaths in 2010 (Jemal et al., 2010). Global prevalence of bladder cancer is estimated at >1 million and is steadily increasing. At the time of diagnosis, 20-25% of cases are muscle invasive (stage T2 or higher) and are typically treated with surgical resection (radical cystectomy) (Williams et al., 2010). The remainders are nonmuscle invasive bladder cancer (NMIBC) including tumors confined to the epithelial mucosa (Ta), tumors invading the lamina propria (T1), and carcinoma in situ (Tis). Transurethral resection of bladder tumor (TURBT) is the primary treatment for Ta and T1 lesions. Intravesical therapy is used as adjuvant treatment to prevent recurrence and progression of the disese after TURBT and is also the treatment of choice for carcinoma in situ. Intravesical administration of bacillus Calmette-Guerin (BCG), a live attenuated strain of Mycobacterium bovis widely used as a vaccine against tuberculosis, is currently the most common therapy employed for NMIBC. Since its advent in 1976 (Morales et al., 1976), BCG has been extensively used to reduce recurrence and progression of NMIBC in an attempt to preserve the bladder. BCG therapy results in 50-60% effectiveness against small residual tumors and a 70-75% complete response rate for carcinoma in situ. Adjuvant intravesical therapy was noted by the 2007 American Urological Association (AUA) panel to reduce recurrences by 24% and treatment with BCG was recommended by the panel. Unfortunately, a high percentage of patients fail initial BCG therapy and 40-50% of BCG responders develop recurrent tumors within the first 5 years (Williams et al., 2010). In addition, up to 90% of patients experience some sort of side effects including, although rare, life-threatening complications such as sepsis. According to the AUA’s 2007 clinical practice guidelines, BCG therapy should be initiated two to three weeks following TURBT with a classic course consisting of six weekly intravesical installations. Lyophilized powder BCG (81 mg corresponding to 1-5 X 108 colony-forming units of viable mycobacteria) is reconstituted in 50 ml of saline and administered via urethral catheter into an empty bladder with a dwell time of 2 hours. Maintenance BCG is more effective in decreasing recurrence as compared to induction therapy alone. Multiple meta-analyses support BCG maintenance and it is now firmly established in clinical practice. The European Association of Urology (EAU) and the AUA