BERKELEY, CA (UroToday.com) - Presently, despite immunotherapy with bacillus Calmette-Guérin (BCG) - which represents the gold standard adjuvant treatment of non-muscle invasive bladder cancer (NMIBC) - the optimal dose, schedule of instillations, and the ideal strain still remain undefined.
Only about one third of patients referred for adjuvant intravesical therapy are treated accordingly, illustrating great potential for bladder cancer treatment optimization. A major goal of immunotherapy is to generate a tumor-specific response that contributes to its eradication and subsequent immune-surveillance. Urothelial carcinomas have high rates of recurrence and progression, suggesting impaired ability to present their own antigens to T cells and a consequent resistance to the natural immune system. However, the use of an attenuated live microorganism can cause side effects as well as inconveniences and limitations in predicting response. Side effects, in different degrees of intensity, are present in more than 90% of patients treated with BCG - with urinary tract and systemic symptoms ranging from mild to moderate and even serious complications such as hemodynamic instability, persistent fever, allergic reactions compromising its use, as well death. Add to the side effects the failure rate of BCG (about 20% to 40%), which can occur at variable intervals of treatment. Although about 35% of these patients respond to a second cycle of BCG, the majority end up an alternative rescue therapy, currently entailing radical surgery and cystectomy, even in cases not proven muscle invasive.
Thus, alternative treatments using non-viable bacteria sub-fractions have been proposed with promising results, including “superantigens” (SAg). SAgs are proteins produced by microorganisms such as bacteria, mycoplasma, or viruses as a defense mechanism against the immune system. The SAg(s) are among the most potent (polyclonal) activators of T-cell proliferation and massive cytokine release via non-specific induction of pronounced expression of its receptors. Compared to a normal antigen-induced T-cell response where 0.001 to 0.0001% of the body’s T-cells are activated, these SAg(s) are capable of activating up to 20% of the body’s T-cells.
The Staphylococcus aureus enterotoxin B (SEB) is a kind of SAg with 30kDa and is therefore not able to diffuse through healthy tissue such as the intact urothelium, which theoretically points for the containment of possible side effects. SEB has been shown to trigger very potent and unique immune response. SEB experimentally activated lymphocytes are capable of inducing apoptosis in urothelial carcinoma cells. Although this immune response resembles that triggered by BCG, this is exceptional and underexplored in terms of its biological effects, and it deserves further studies.
Efforts to increase the effectiveness of treatment of urothelial carcinoma include, in addition to modifying current regimens, multiple attempts to introduce new promising agents for intravesical therapy, combined, or not, with established agents.
In conjunction with efforts to reduce its side effects, future potential means to optimize the effectiveness of BCG can be envisioned based on advances in knowledge of its mechanisms of action. An attractive mechanism aims to improve the cytokine cascade of the immune regulatory pathway based on T lymphocytes that can be obtained by associating BCG and SAg(s) such as SEB.
Importantly, our presented results foreshadow positive developments with urothelial carcinoma treatment, including:
- Greater antitumor efficacy with the introduction of SAg (SEB);
- Less potential for adverse effects of SEB compared to BCG;
- Direct relationship between therapeutic response and activation of angiogenesis pathways (VEGF, endostatin, MMP-9), proliferation (Ki-67, IGF-1) and apoptosis; there are important potential limitations to be overcome in the future.
In our targeted study, the efficacy of proposed intravesical immunotherapy correlated well with the expression of inhibitors and enhancers of angiogenesis and proliferative and apoptotic activities. This pioneering study proposes analysis of these phenomena in an integrated manner, and paves the way for their clinical application. In the future, the expression dynamics of the studied molecules might determine the clinical course and treatment response of patients with bladder carcinoma, and are possible targets for the development of new treatments.
Genetic engineering of SAg(s) has been used to develop therapeutic applications with improved antitumor effects and reduced toxicity. MHC class II-independent and tumor-specific synthetic proteins fusions have been successfully evaluated and may represent the future of SAg(s). Although current clinical trials have demonstrated the safety of the staphylococcal enterotoxins in humans, with promising results in treating cancer, specific clinical studies are needed - i.e. phase I study of the intravesical route.
Leonardo Oliveira Reis, MD, MSc, PhD* as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Urologic Oncology Division
School of Medical Sciences
University of Campinas