Mycobacterium bovis bacillus Calmette-Guérin (BCG) has become the predominant conservative treatment for nonmuscle invasive bladder cancer. Its mechanism of action continues to be defined but has been shown to involve a T helper type 1 (Th1) immunomodulatory response. While BCG treatment is the current standard of care, a significant proportion of patients fails or do not tolerate treatment. Therefore, many efforts have been made to identify other intravesical and immunomodulating therapeutics to use alone or in conjunction with BCG. This paper reviews the progress of basic science and clinical experience with several immunotherapeutic agents including IFN-α, IL-2, IL-12, and IL-10. 1. Introduction With more than 73,000 estimated cases diagnosed in 2012, bladder cancer is the fifth most common malignancy in the United States, responsible for more than 14,000 deaths per year [1]. Urothelial carcinoma accounts for 90% of bladder tumors, of which approximately 70% are confined to layers above the muscularis propria—the so-called nonmuscle invasive bladder cancer (NMIBC). These tumors (previously termed “superficial bladder tumors”) include stages Ta, T1, and Tis, occurring in 70%, 20%, and 10% of NMIBC cases, respectively [2]. Standard primary treatment for NMIBC is transurethral resection (TUR); however, recurrence rates for TUR alone can be as high as 70% with up to 30% progressing to muscle invasive disease requiring cystectomy [3]. High rates of recurrence and progression have prompted investigation into a myriad of treatments attempting to decrease the burden of this disease. Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the most well known and studied of these adjunctive treatments. Since its first description in 1976 by Morales et al. [4], intravesical BCG has become the standard therapy for NMIBC, superior to any other single chemotherapeutic agent for reducing recurrence and preventing progression. Typical complete response rates are 55–65% for papillary tumors and 70–75% for carcinoma in situ (CIS), which inversely indicates that 30–45% of patients will be BCG failures [5–7]. Of the complete responders, up to 50% will have a recurrence [8]. Furthermore, side effects range from cystitis and irritative voiding symptoms to much more uncommon life-threatening BCG sepsis. Up to 20% of patients are BCG intolerant due to these side effects [9]. Understanding of BCG, both its mechanisms (which remain incompletely characterized) and its obvious limitations, is critical to improving the efficacy of therapy. The initial step after BCG instillation
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