Date Published: June 20, 2012
Publisher: Hindawi Publishing Corporation
Author(s): Eric J. Askeland, Mark R. Newton, Michael A. O’Donnell, Yi Luo.
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.
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 . 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 . 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 .
Interferons (IFNs) are glycoproteins initially isolated in the 1950s and valued for their antiviral properties. Three types have been isolated, IFN-α (which is actually a family of interferons), IFN-β, and IFN-γ. IFN-α and IFN-β are grouped as “Type I” interferons, whereas IFN-γ is a “Type II” interferon. The Type I interferon receptor has 2 components, IFNAR-1 and IFNAR-2, which subsequently bind and phosphorylate Jak molecules initiating a cascade resulting in gene transcription . The IFN-α family is well known to stimulate natural killer (NK) cells, induce MHC class I response, and increase antibody recognition . They have antineoplastic properties by direct antiproliferative effects and complex immunomodulatory effects , both of which could be advantageous for bladder cancer treatment. Clinically available preparations include IFN-α2a (Roferon-A, Roche Laboratories, Nutley, NJ) and IFN-α2b (Intron-A, Schering Plough, Kenilworth, NJ), though to date most research involves IFN-α2b. There has been interest in IFN-α2b both alone and in combination with BCG, where a synergistic response has been described. Conceptually, combining BCG and IFN makes sense. BCG efficacy depends on the induction of a robust Th1 cytokine profile, and IFN-α2b has been shown to potentiate the Th1 immune response . However, despite theoretical promise, data after translation to clinical practice has been mixed.
The discovery and characterization of interleukin-2 (IL-2) was one of the most important breakthroughs in the field of immunology. Prior to its discovery, lymphocytes were thought to be terminally differentiated and incapable of proliferation [47, 48]. In 1975, it was discovered that the supernatant of murine splenic cell cultures could stimulate thymocytes, suggesting a native effector protein was responsible for this mitogenic activity [48, 49]. When initially examined independently by different investigators, this “effector protein” was given multiple working names including thymocyte-stimulating factor (TSF), thymocyte mitogenic factor (TMF), T cell growth factor (TCGF), costimulator, killer cell helper factor (KHF), and secondary cytotoxic T-cell-inducing factor (SCIF) . In 1979, it was recognized that these factors likely represented the same entity, and the nomenclature was standardized with the term “interleukin” (between leukocytes). Thus, the “effector protein” was named IL-2, differentiating it from the only other interleukin known at that time, IL-1 . Regardless of the nomenclature, this protein was recognized to promote proliferation of primary T cells in vitro, which revolutionized the experimental armamentarium in the field of immunology [47, 49, 51].
Interleukin-12 (IL-12) has been the focus of significant cancer research among cytokines as well. In 1987, it was discovered through in vitro experiments that there existed a factor which synergized with IL-2 in promoting a cytotoxic T lymphocyte (CTL) response . This factor was given the name cytotoxic lymphocyte maturation factor (CLMF) . Shortly thereafter a factor was discovered that induced IFN-γ production, enhanced T cell responses to mitogens, and augmented NK cell cytotoxicity . This factor was provisionally called natural killer cell stimulatory factor (NKSF) . It did not take long to discover that these factors represented the same entity, thus the nomenclature converged and this protein was termed IL-12 [91–95].
Unlike other cytokines previously discussed, interleukin-10 (IL-10) is distinct in that its primary effect is to promote a Th2 response and thus dampen the immunotherapeutic effects of BCG for the treatment of bladder cancer [54, 138, 139]. As a result, it may have therapeutic value not by its native function, but by abrogation of its native function. IL-10 was first characterized in 1989. It was initially termed cytokine synthesis inhibitory factor (CSIF), a rather fitting name, because it was found to inhibit the production of several cytokines produced by Th1 clones . The most important of these cytokines was IFN-γ, which was recognized as an important player in the Th1 response. As discussed previously, it is a key contributor in the immunotherapeutic effectiveness of BCG [140, 141]. Further studies showed that IL-10 prevented a delayed-type hypersensitivity (DTH) response to BCG and the neutralization or abrogation of IL-10 prolonged a response, thus further supporting its role in the Th1/2 response [138, 142]. Several human tumors, including melanoma, non-small-cell lung carcinoma, renal cell carcinoma, and bladder cancer, have been found to express elevated levels of IL-10 [143–147]. It is speculated that production of IL-10 by tumor cells may represent an “escape mechanism” whereby tumor cells avoid Th1-immune-mediated tumoricidal effects .
Bladder cancer is a disease that places significant social and financial burdens both on the patient and on society, costing nearly $4 billion annually in the U.S. BCG, which stimulates a robust immune response in most patients and has become the standard of care after surgical resection of nonmuscle invasive disease. However, despite treatment, a significant portion of patients still recur or are intolerant of BCG side effects. Multiple immunotherapies including IFN-α, IL-2, IL-12, and IL-10 have been investigated, either as adjuncts with BCG or as a solo replacement therapy. To date, there are a multitude of encouraging in vitro and murine studies; however, no clinical data has yet been reported, which is compelling enough to change the standard of care, yet many practitioners continue to use adjunctive immunotherapy based on basic science data and theoretical benefit. At our institution, for instance, BCG or BCG/IFN-α refractory disease is often treated with “quadruple therapy”—a combination of BCG, IFN-α, IL-2, and GM-CSF. The widespread use of immunotherapy for bladder cancer highlights the need for additional basic science and clinical research to further our understanding of tumor biology, human immunology, and the treatment of urothelial carcinoma.