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Purpose: Interleukin (IL)-2 and interferon-gamma are released during T helper 1 lymphocyte responses and IL-10 is released during T helper 2 lymphocyte responses. We have previously reported that a T helper 1 lymphocyte urinary cytokine profile is associated with a favorable prognosis after bacillus Calmette-Guerin (BCG) treatment. We evaluated the T helper 1/2 lymphocyte cytokine profiles during courses 1 and 2 of 6 weekly BCG instillations., Materials and Methods: Urinary interferon-gamma, IL-2 and IL-10 were measured by enzyme-linked immunosorbent assay after each of 6 weekly instillations of 150 mg. BCG, Pasteur strain, in 19 patients with superficial stages Ta and T1 bladder cancer, and carcinoma in situ. The 11 patients who did not respond to course 1 were re-treated according to the same schedule and reevaluated., Results: During course 1 interferon-gamma was higher than during course 2 (p <0.001), which was associated with nonrecurrence (p <0.001). In contrast, IL-2 cytokine was higher after course 2 (p <0.01), which was associated with a BCG response (p = 0.01). Interferon-gamma and IL-10 correlated during courses 1 and 2 (p = 0.04 and 0.0004, respectively). We distinguished groups 1-immediate T helper 1 lymphocyte profile consisting of responders to course 1 with high interferon-gamma, IL-2 and IL-10, 2-delayed T helper 1 lymphocyte profile consisting of responders to course 2 with early high IL-2 and 3-consisting of nonresponders to the 2 courses with low interferon-gamma, IL-2 and IL-10., Conclusions: A T helper 1 lymphocyte urinary cytokine profile was associated with a clinical response to BCG. A repeat BCG course induces a favorable immune response in a subset of patients, suggesting that maintenance therapy may be beneficial.

Objectives: To study the influence of adverse reactions on adherence to an immunotherapy maintenance schedule and the recurrence rate of bladder cancer. Bacille Calmette-Guérin immunotherapy has documented efficacy in the management of high-risk superficial bladder cancer. However, the optimal duration of intravesical bacille Calmette-Guérin therapy and the risk/benefit ratio of maintenance therapy are controversial., Methods: From April 1996 to April 2000, 72 patients with superficial bladder cancer were treated with Immucyst (six consecutive weekly instillations of 81 mg) and then received maintenance therapy consisting of three consecutive weekly instillations 3, 6, 12, 18, 24, 30, and 36 months later. Adverse reactions, studied during 518 instillations, were classified in four categories using a scale based on the World Health Organization recommendations, and their impact on the adherence to therapy was analyzed., Results: After an average follow-up of 24 months, a durable disease-free response was observed in 84.9% of the patients; 12.5% of patients had a relapse and 2.6% had disease progression. The response rate was similar in patients with and without adverse reactions. Only 14 patients (19%) received all the scheduled maintenance instillations. The dose was reduced in 41 patients (57%), and treatment was stopped in 28 patients (39%). In multivariate analysis, an adverse event score of 1.5 or greater during induction therapy was significantly associated with cessation or modification of maintenance therapy (P = 0.01)., Conclusions: The scale developed in this study to monitor the adverse reactions to bacille Calmette-Guérin and their impact on the adherence to maintenance therapy may be helpful for tailoring maintenance regimens or implementing protective measures (dose reduction or treatment postponement).

Objectives: To examine leukocyturia as a predictor of tumor recurrence and occurrence of adverse events after bacille Calmette-Guérin (BCG) immunotherapy. The use of BCG immunotherapy, a very major advance in the management of superficial bladder cancer, is limited by the frequency of adverse events. As yet, we have no way of predicting the efficacy and tolerability of BCG instillation in clinical practice. This problem is even more acute during BCG maintenance therapy., Methods: Adverse events in 72 patients who received 518 instillations were prospectively assessed using a four-class scale based on severity and duration. Urinary leukocytes were counted 3 days after each instillation, using the KOVA-Slide 10 method., Results: High leukocyturia during BCG treatment (cutoff value 1.65 x 10(5)/mL urine) correlated with recurrence-free status (P = 0.009). The degree of leukocyturia correlated with the severity/duration of adverse events (P <0.0001); the median leukocyturia values associated with class I, II, and III adverse events were 4 x 10(4)/mL, 1.5 x 10(5)/mL, and 3.5 x 10(5)/mL, respectively. No class IV events occurred. The cutoff point indicating treatment cessation for adverse events was leukocyturia of 8.6 x 10(4)/mL., Conclusions: These results suggest a link between adverse events and efficacy during BCG maintenance therapy. Leukocyturia appears to correlate with both efficacy and tolerability in this setting. Prospective randomized studies are required to evaluate leukocyturia as a basis on which to adapt the BCG instillation schedule to individual patient susceptibility.

A better knowledge of antitumour immunity and the mechanisms allowing the tumour to overcome the host's immune surveillance has led to progress in the understanding of the mechanisms of action of Bacille Calmette-Guérin (BCG), as the local intravesical immune response is intimately related to the interaction of three systems: the host (the patient), the BCG (mycobacteria) and the tumour. This interaction gives rise to a cascade of immunological events, some of which are essential to the protective action of BCG against relapse and tumour progression. The immune response to BCG is currently considered to comprise three phases. First of all, the BCG adheres to the urothelium and is then phagocytosed by antigen-presenting cells. This phase corresponds to early release of so-called inflammatory cytokines (IL1, IL6, IL8). These cytokines could be responsible for certain adverse effects, but could also participate in cytotoxic phenomena. The second phase consists of recognition of bacterial antigens by helper CD4 lymphocytes, which mainly release IL2 and IFNg (Th1 response). This cellular activation leads to the third phase: amplification of cytotoxic populations capable of killing tumour cells: CD8, gd lymphocytes, macrophages, NK, LAK, BAK cells. All these cells also produce cytokines, which participate in regulation of the immune response. The understanding of these mechanisms of action, urinary cytokine assays, a better definition of cytotoxic cells and their role, molecular analysis of the tumour and probably certain genetic characteristics of the host will allow the elaboration of more effective immunization protocols by defining an individualized therapeutic approach.

The better understanding of antitumour immunity has improved our knowledge concerning the mechanisms of action of BCG. There are three phases in the immune response to BCG: first of all, BCG adheres and is then phagocytosed by antigen-presenting cells, but also by urothelial cells. This phase corresponds to the early release of so-called inflammatory cytokines (IL-1, IL-6, IL-8). These cytokines may be responsible for certain adverse effects, but may also participate in the cytotoxic phenomenon. The second phase consists of recognition of bacterial antigens by CD4 lymphocytes, which release mainly IL-2 and IFN-gamma(TH1 response). This cell activation leads to the third phase, which consists of amplification of cytotoxic-populations: CD8, gamma delta lymphocytes, macrophages, NK, LAK, BAK. All these cells also release cytokines which then regulate the response. The identification of these modulations allows rationalization of BCG instillation protocols, but identification of the truly cytotoxic elements would allow the proposal of more effective immunization protocols.

Objective: To help define the optimal protocol of Bacille Calmette-Guérin (BCG) treatment for transitional cell carcinoma (TCC) of the bladder by examining cytokine production and antigen presentation to effector cells after instillations of BCG in patients with bladder TCC., Patients and Methods: Sixty-four urine samples from 11 patients were tested for the production of interferon gamma (IFN-gamma) using a modified commercial enzyme-linked immunosorbent assay (ELISA) kit. Urine was collected before and at intervals up to 24 h after the intravesical instillation of BCG. Immunohistological studies were also carried out using a two-step alkaline phosphatase technique to explore the expression of tumour-associated antigens (TAAs) (E7, 19A211, T138), major histocompatibility complex (MHC) molecules and lymphocyte subset infiltrates (CD3, CD4, CD8) in bladder biopsies before and 3 weeks after the completion of treatment in seven patients., Results: IFN-gamma was only detected 4, 6 and 8 h after instillation, with a maximum concentration at 6 h (2.9-34.7 IU/mL in 10 patients). During a 6-week course of BCG, IFN-gamma was barely detectable after the first two instillations, but gradually increased from the third instillation onwards. TAA and MHC II antigens, which were absent or faintly expressed on normal urothelial cells before treatment, were expressed strongly in five patients after treatment. The local recruitment of immunocompetent cells was detected in all patients., Conclusion: These results suggest that the local immune response after the intravesical instillation of BCG can be quantified using simple ELISA tests and could be useful in defining objective criteria for rationalizing treatment (dose and duration), and in determining the relation between the immune response and anti-tumour activity. There is evidence that antigen presentation is enhanced after BCG instillations, suggesting that a T cell-MHC restricted pathway might be involved in the anti-tumour response. This study supports the search for tumour-rejection antigens in bladder cancer.

Initial reports focused on purified protein derivative skin test reactivity and granuloma formation in patients treated with intravesical bacillus Calmette-Guérin. Then some investigators using immunohistochemical methods showed that some lymphocyte phenotypes where predominant in such infiltrates and that HLA DR antigens where strongly expressed following BCG therapy. Similar results where obtained in urine using flow cytometric analysis. Additionally some cytokines where found at significant levels in urine after BCG instillations. In this paper we reviewed these studies, we discussed the meaning of these results and the potential value for treatment monitoring.

In an attempt to appreciate urological practices concerning BCG instillations a study was performed with members of university urological centers. Questions concerned instillation modalities, persons performing instillations and criteria for survey. Main differences concerned doses (low doses versus high doses) and duration of treatment. These results suggest the need of development of new parameters for the rationalisation of this treatment.

Local immunotherapy with bacillus Calmette-Guérin (BCG) is an effective treatment to prevent recurrence and progression of superficial bladder cancer, but the antitumor mechanism of action of BCG remains unclear. There are some experimental and clinical data suggesting that BCG antigens are processed not only by immunocompetent cells but also by urothelial cells and tumor cells. The foreign antigen may be presented at the cell surface by major histocompatibility complex (MHC) class II molecules and recognized by CD4 cells. The cytotoxic effect could result from the direct activity of CD4 cells or from the cytotoxic effect of released cytokines and the activation of other cytotoxic cells [cytolytic T-lymphocytes CTLs; CD8 cells), macrophages, natural killer (NK) or lymphokine-activated killer (LAK) cells]. These mechanisms are also involved in tumor rejection, and the identification of some specific tumor rejection antigens presented to specific CTLs could provide new therapeutic approaches.

Local immunotherapy with BCG was first described by Zbar in an experimental model. The clinical use of BCG in human bladder carcinoma was proposed by Morales in 1976. Since then randomised studies have confirmed the value of BCG against recurrence and progression in superficial transitional cell carcinoma of the bladder (Lamm, Herr). However the optimal protocol has not been defined and the mode of action of BCG remains obscure. In this paper, the authors review the clinical results of BCG and its complications then focus on recent immunological data concerning its mode of action. Finally a practical protocol is proposed.