Evolution and Clinical Significance of the T Cell Proliferative and Cytokine Response Directed Against the Fibronectin Binding Antigen 85 Complex of Bacillus Calmette-Guerin During Intravesical Treatment of Superficial Bladder Cancer (original) (raw)
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What Are the Immunologically Active Components of BCG in BCG Therapy of Superficial Bladder Cancer?
The Journal of Urology, 1999
The subcomponents of bacille Calmette-Gué rin (BCG) involved in the mechanism of action of intravesical BCG immunotherapy used for prophylaxis of superficial bladder cancer recurrences have been poorly investigated. We purified various BCG subcomponents and analyzed in vitro their ability to enhance a Th1 polarized immune response as well as to increase lymphocyte-mediated cytotoxicity against bladder tumors. Human peripheral blood mononuclear cells (PB-MCs) from healthy purified protein derivative-positive subjects were incubated for 7 days with whole BCG and various fractions (BCG cell wall, plasma membrane, cytosol, purified polysaccharides as glucan or arabinomannan, purified native proteins from BCG culture filtrate, recombinant 22 kDa protein, phosphate transporter PstS-2 and -3 proteins). IFN-␥, . IL-2 receptor blockage resulted in a clear reduction in the cytotoxic activity of stimulated PBMCs. Numerous BCG subcomponents thus provide positive stimuli for Th1 cell differentiation and enhance in vitro, non-MHC-restricted cytotoxicity against bladder tumor cells. Our findings provide the basis for the therapeutic use of several of these subfractions in experimental animal models bearing bladder tumors. Int.
Immunotherapy of superficial bladder cancer with BCG
World Journal of Urology, 1986
Bacillus Calmette-Gu6rin (BCG) has achieved an important role in the prophylaxis and treatment of superficial bladder cancer. It has been found effective in the prevention of recurrences after endoscopic surgery as well as in the treatment of residual tumors. The most dramatic responses have been consistently demonstrated in the treatment of carcinoma in situ. Recent experience suggests that prolongation of treatment beyond the 6 weeks advocated in early protocols, significantly increases the anti-tumor activity of BCG. The side effects of intravesical administration of the vaccine are, in the vast majority of patients, well-tolerated, minimal and self-limiting. No permanent functional or structural damage of the bladder has been observed. The effectiveness of BCG is primarily dependent on the strain used as well as the dose, duration and frequency of its administration.
Role of BCG in Treatment of Bladder Cancer
Aim: This review is written to describe the role of immunotherapy in cancer treatment. Annually, 13,000 deaths result from bladder cancer. Since the first report of intravesical use of BCG in 1976, investigators try to understand the working mechanism of BCG as an antitumour modality. Arbitrarily, BCG therapy consists of a single course of six weekly intravesical instillations. Bacillus Calmette-Guérin, an attenuated strain of Mycobacterium bovis, was developed by Calmette and Guérin with the intention to generate a vaccine against tuberculosis. Extension of BCG treatment (maintenance immunotherapy) is used to increase efficacy. Results of various experiments describe that after instillation in the bladder, BCG accumulates near the bladder wall and is internalised and processed by professional antigen-presenting cells (APCs) and (highgrade) tumour cells. Then BCG antigens are presented to CD4+ T cells. Then local synthesis of a particular set of cytokines or cell-mediated immune response. NK cells may be involved in tumour cell killing.
Clinical and Experimental Immunology, 1997
Few studies have analysed the antibody response during intravesical BCG immunotherapy for superficial bladder cancer. We have examined the evolution in serum antibody response against several heat shock proteins (hsp), including the recombinant mycobacterial hsp65 and the native protein P64 from BCG, GroEL from Escherichia coli (hsp60 family), recombinant mycobacterial hsp70 and the E. coli DnaK (hsp70 family), against purified protein derivative of tuberculin (PPD) and the AG85 complex of Mycobacterium bovis BCG, as well as against tetanus toxoid in 42 patients with a superficial bladder tumour, 28 treated with six intravesical BCG instillations and 14 patients used as controls. We also analysed the lymphoproliferative response of peripheral blood mononuclear cells against PPD in this population. Data of antibody responses at 6 weeks post BCG were available in all 28 patients, and at 4 month follow up in 17 patients. All patients who demonstrated a significant increase in IgG antibodies against PPD at 4 months follow up had a significant increase already at 6 weeks of follow up. In contrast, IgG antibodies against hsp increased significantly from 6 weeks to 4 months post-treatment. A significant increase in IgG antibodies against PPD, hsp65, P64, GroEL, and hsp70 at 4 months follow up was observed in 10/17, 8/17, 10/17, 4/17 and 8/17 patients. Native P64 protein elicited a higher antibody response than recombinant mycobacterial hsp65. No increase in antibody response was observed against Dnak from E. coli, against AG85 or tetanus toxoid after BCG therapy. An increase in IgG antibodies against P64 at 4 months follow up compared with pretreatment values was found to be a significant predictor of tumour recurrence (P < 0 . 01). Further studies with a larger number of patients are needed to confirm the value of the antibody response against P64 as a clinical independent prognostic factor.
Spectrum of Bacille Calmette‐Guerin (BCG) Infection after Intravesical BCG Immunotherapy
Clinical Infectious Diseases, 2003
In some patients, infection appears early (within 3 months after instillation) and is characterized by generalized symptoms, with pneumonitis and hepatitis. Late-presentation disease occurs 11 year after the first BCG treatment and usually involves focal infection of the genitourinary tract (the site at which bacteria were introduced) and/or other sites that are typical for reactivation of mycobacterial disease, such as the vertebral spine or the retroperitoneal tissues. Noncaseating granulomas are found in the majority of cases, whether early or late. Most patients respond to treatment with antituberculous drugs; in early-presentation disease, when features of hypersensitivity predominate, glucocorticosteroids are sometimes added. Late localized infection often requires surgical resection.
Cancer, 2010
BACKGROUND:Intravesical immunotherapy with Mycobacteriumbovis (M. bovis) bacillus Calmette-Guerin (BCG) is the current standard of care against superficial, high-grade transitional cell carcinoma (TCC) of the urinary bladder (carcinoma in situ and pathologic T1, grade 3 disease). However, individual patient outcome is barely predictable because of the lack of serum markers. Consequently, progression to muscle-invasive bladder cancer and critical delay of treatments (such as neoadjuvant combination chemotherapy and/or radical cystectomy) often occur. The objectives of this study were to identify a marker for measuring the BCG-induced immune response and to predict the outcomes and potential improvements of BCG immunotherapy.Intravesical immunotherapy with Mycobacteriumbovis (M. bovis) bacillus Calmette-Guerin (BCG) is the current standard of care against superficial, high-grade transitional cell carcinoma (TCC) of the urinary bladder (carcinoma in situ and pathologic T1, grade 3 disease). However, individual patient outcome is barely predictable because of the lack of serum markers. Consequently, progression to muscle-invasive bladder cancer and critical delay of treatments (such as neoadjuvant combination chemotherapy and/or radical cystectomy) often occur. The objectives of this study were to identify a marker for measuring the BCG-induced immune response and to predict the outcomes and potential improvements of BCG immunotherapy.METHODS:Because host immunoresponse mediates BCG activity, the authors screened a combinatorial random peptide library on the circulating pool of immunoglobulins (Igs) purified from an index patient after successful BCG immunotherapy to identify the corresponding target antigen(s).Because host immunoresponse mediates BCG activity, the authors screened a combinatorial random peptide library on the circulating pool of immunoglobulins (Igs) purified from an index patient after successful BCG immunotherapy to identify the corresponding target antigen(s).RESULTS:An immunogenic peptide motif was selected, isolated, and validated from M. bovis BCG heat-shock protein 65 (HSP-65) as a dominant epitope of the humoral response to treatment. Increasing IgA and IgG anti-HSP-65 titers specifically predicted a positive patient outcome in a cohort of patients with bladder cancer relative to several cohorts of control patients.An immunogenic peptide motif was selected, isolated, and validated from M. bovis BCG heat-shock protein 65 (HSP-65) as a dominant epitope of the humoral response to treatment. Increasing IgA and IgG anti-HSP-65 titers specifically predicted a positive patient outcome in a cohort of patients with bladder cancer relative to several cohorts of control patients.CONCLUSIONS:The current results indicated that antibody production against M. bovis BCG HSP-65 can serve as a serologic marker for the predictive outcome of BCG immunotherapy. Subsequent studies will determine the value of this candidate marker to modify BCG-based treatment for individual patients with bladder cancer. Cancer 2010. © 2009 American Cancer Society.The current results indicated that antibody production against M. bovis BCG HSP-65 can serve as a serologic marker for the predictive outcome of BCG immunotherapy. Subsequent studies will determine the value of this candidate marker to modify BCG-based treatment for individual patients with bladder cancer. Cancer 2010. © 2009 American Cancer Society.
Long-term BCG immune therapy of superficial bladder tumours
International urology and nephrology, 1992
Long-term local BCG treatment of superficial bladder tumours is described and the 5-year results are reviewed. Complications of major significance in the course of immune therapy did not occur, loss due to death was not recorded. PPD skin test failed to furnish extra information regarding the biologic behaviour of the tumour. Annual repeats of the therapy promise better results than one single 6-week course.