Changes in urinary cytokines and soluble intercellular adhesion molecule-1 (ICAM-1) in bladder cancer patients after Bacillus Calmette—Guérin (BCG) immunotherapy

Abstract

SUMMARY Intravesical immunotherapy for carcinoma in situ of the bladder is arguably the most effective form of tumour immunotherapy described to date. Following repeated instillations of BCG organisms into the bladder, large quantities of cytokines are detected in patients’ urine. This study concerns the production of IL‐1β, IL‐2, IL‐4, IL‐6, IL‐8, IL‐10, tumour necrosis factor‐alpha (TNF‐α), interferon‐gamma (IFN‐γ) and soluble ICAM‐1 (sICAM‐1) throughout the six weekly instillations which comprise a therapeutic course. Sequential instillations of BCG induced secretion of IL‐1β, IL‐2, IL‐6, IL‐8, IL‐10, TNF‐α, IFN‐γ and sICAM‐1 into urine. The responses were heterogeneous between patients and cytokines, but some general trends were evident. Although cytokine levels were initially low, their concentration increased with repeated instillation of BCG. Certain cytokines (e.g. IL‐6, IL‐8 and IL‐10) could be detected after the first instillation, whilst others (e.g. IL‐2 and IFN‐γ) were not detected until after the third or fourth instillation. Interestingly, IL‐4 was not detected, perhaps suggesting a differential effect on Th2‐like responses. Some patients produced particularly elevated or non‐detectable levels of cytokines, and a positive correlation was found between the production of various cytokines. The production of a particular cytokine did not correspond with lack of production of another species. Whether monitoring the production of cytokines following therapy may be of prognostic value will be determined in a larger series of patients. However, as these potent immunomodulators are thought t o be important for the 75% complete clinical response observed with BCG therapy, there remains the possibility that detection of the products of an activated immune system may correlate with eventual clinical outcome. This study is a necessary forerunner to full prognostic evaluation of such immunological data.

Mathematical model of tumor immunotherapy for bladder carcinoma identifies the limitations of the innate immune response

“…In particular, neutrophils and inflammatory monocytes are believed to be critical effector cells, capable of mediating the observed tumor immunity. [12][13][14][15][16] Specifically, innate cells have the capacity to degranulate in response to exposure to BCG, resulting in the bystander killing of tumor cells. 17 In support of this model, it has been demonstrated that BCG treatment induces surface expression of TRAIL on neutrophils, thus arming them with the capacity to induce tumor cell death.…”

BCG Immunotherapy for Bladder Carcinoma

“…Several cytokines have been implicated in this cell-mediated response, including interleukin (IL)-1, IL-2, IL-6, IL-8, IL-10, IL-12, tumor necrosis factor-, and IFN. 11 This has been demonstrated by analysis of urine following administration of BCG. IL-1, IL-6, and IL-8 are increased after the first BCG instillation 12,13 .…”

Role of neutrophils in BCG immunotherapy for bladder cancer

“…The presence of soluble TRAIL in the granule fraction is consistent with its rapid release into culture supernatants following stimulation with BCG and also the inability of actinomycin D and cycloheximide to inhibit TRAIL secretion. However, the findings that IFN treatment induces de novo synthesis of TRAIL [19] that accumulates in secretory vesicles [22], suggest that IFN present in the urine either during BCG therapy [29,30] or supplied exogenously [31] may augment the total amount of TRAIL released by PMN and contribute to the sustained secretion of TRAIL after preformed intracellular stores are expended.…”