Abstract
The live attenuated mycobacterial strain BCG, in use as vaccine against tuberculosis, is considered the gold standard for primary therapy of carcinoma in situ of the bladder. Despite its limitations, to date it has not been surpassed by any other treatment. Our group has developed a recombinant BCG strain expressing the detoxified S1 pertussis toxin (rBCG-S1PT) that proved more effective than wild type BCG (WT-BCG) in increasing survival time in an experimental mouse model of bladder cancer, due to the well-known adjuvant properties of pertussis toxin. Here, we investigated the capacity of rBCG-S1PT to stimulate human immune responses, in comparison to WT-BCG, using an in vitro stimulation assay based on human whole blood cells that allows for a comprehensive evaluation of leukocyte activation. Blood leukocytes stimulated with rBCG-S1PT produced increased levels of IL-6, IL-8, and IL-10 as compared to WT-BCG, but comparable levels of IL-1β, IL-2, IFN-γ, and TNF-α. Stimulation of blood cells with the recombinant BCG strain also enhanced the expression of CD25 and CD69 on human CD4+ T cells. PBMC stimulated with rBCG-S1PT induced higher cytotoxicity to MB49 bladder cancer cells than WT-BCG-stimulated PBMC. These results suggest that the rBCG-S1PT strain is able to activate an immune response in human leukocytes that is higher than that induced by WT-BCG for parameters linked to better prognosis in bladder cancer (regulation of immune and early inflammatory responses), while fully comparable to WT-BCG for classical inflammatory parameters. This establishes rBCG-S1PT as a new highly effective candidate as immunotherapeutic agent against bladder cancer.
Highlights
The Bacille-Calmette-Guérin (BCG) is a live anti-tuberculosis vaccine, which has been administered to more than 3 billion individuals worldwide over 80 years [1,2,3]
BCG and one non-vaccinated), in which we compared the ability of wild type BCG (WT-BCG) and recombinant BCG (rBCG)-S1PT to induce cytokine production by using a rapid and very efficient assay on whole blood, which assesses the global response of blood cells to exogenous stimuli [28]
We provide evidence that rBCG-S1PT is efficient in the activation of human CD4+ lymphocytes and of innate/inflammatory immune response, the latter being superior to that induced by WT-BCG, likely relying on the potent non-specific adjuvant capacity of the expressed detoxified S1PT [20]
Summary
The Bacille-Calmette-Guérin (BCG) is a live anti-tuberculosis vaccine, which has been administered to more than 3 billion individuals worldwide over 80 years [1,2,3]. BCG is used as immunotherapeutic treatment of non-muscle invasive bladder cancer (NMIBC). After over 40 years of use, BCG is still the gold standard for bladder cancer at early stage [4], by decreasing disease. Recombinant BCG Activates Human Immunity progression and the risk of recurrence [5]. As mechanism of anti-tumor activity, BCG instilled into the bladder induces a local inflammatory immune response with influx of granulocytes and mononuclear cells and a potent production of inflammatory and Th1 cytokines, resulting in the activation of a significant anti-tumor response [6, 7]. In an attempt to increase treatment efficacy, different strains of BCG have been used as immunotherapy, as yet without satisfactory results [10, 11]
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