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1.
Eur Urol Focus ; 6(2): 280-283, 2020 03 15.
Article in English | MEDLINE | ID: mdl-30219710

ABSTRACT

Towards the development of vaccines against urinary tract infections (UTI), we determined the ability of intramuscular (i.m.) immunization to result in antigen-specific antibodies in urine. As a model antigen/vaccine, levels of total and vaccine-specific antibodies were determined in urine as a spin-out study of a phase 1 trial. Non-muscle-invasive bladder cancer (NMIBC) patients at different risks of progression, undergoing intravesical bacillus Calmette-Guérin (BCG) immunotherapy or not, received an adjuvanted recombinant protein vaccine that resulted in high titers of vaccine-specific serum immunoglobulin G (IgG) in all patients, regardless of the risk group. Vaccine-specific IgG and immunoglobulin A (IgA) were detected in urine of half of the patients at low risk of progression NMIBC and in all the intermediary/high- (int/high) risk patients. Vaccine-specific IgG titers were correlated to total urinary IgG levels, the latter being higher in the int/high-risk patients. In contrast, vaccine-specific IgA did not correlate to urinary IgA levels. Furthermore, vaccine-specific antibodies were transiently increased by intravesical BCG instillations. Altogether, our data show that a standard i.m. immunization can effectively induce antigen-specific antibodies in urine, which, upon selection of optimal vaccine targets, may provide protection against UTI. Vaccine-specific IgG titers were dependent on conditions affecting total urinary IgG levels, while production of vaccine-specific IgA in situ might independently contribute to protection against infections in the bladder. PATIENT SUMMARY: Towards the development of vaccines able to protect against urinary tract infections, we examined the potential of the intramuscular vaccination using a model antigen. We found two types of specific antibodies in the urine, which together may locally contribute to protection against infections, thus supporting the use of such a standard immunization route.


Subject(s)
Antigens, Neoplasm/administration & dosage , Antigens, Neoplasm/immunology , Immunization/methods , Immunoglobulin A/urine , Immunoglobulin G/urine , Neoplasm Proteins/administration & dosage , Neoplasm Proteins/immunology , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/immunology , Adjuvants, Immunologic/therapeutic use , BCG Vaccine/therapeutic use , Humans , Injections, Intramuscular , Urinary Bladder Neoplasms/drug therapy , Urinary Tract Infections/prevention & control
2.
J Clin Invest ; 127(8): 2916-2929, 2017 Aug 01.
Article in English | MEDLINE | ID: mdl-28650339

ABSTRACT

Non-muscle-invasive bladder cancer (NMIBC) is a highly recurrent tumor despite intravesical immunotherapy instillation with the bacillus Calmette-Guérin (BCG) vaccine. In a prospective longitudinal study, we took advantage of BCG instillations, which increase local immune infiltration, to characterize immune cell populations in the urine of patients with NMIBC as a surrogate for the bladder tumor microenvironment. We observed an infiltration of neutrophils, T cells, monocytic myeloid-derived suppressor cells (M-MDSCs), and group 2 innate lymphoid cells (ILC2). Notably, patients with a T cell-to-MDSC ratio of less than 1 showed dramatically lower recurrence-free survival than did patients with a ratio of greater than 1. Analysis of early and later time points indicated that this patient dichotomy existed prior to BCG treatment. ILC2 frequency was associated with detectable IL-13 in the urine and correlated with the level of recruited M-MDSCs, which highly expressed IL-13 receptor α1. In vitro, ILC2 were increased and potently expressed IL-13 in the presence of BCG or tumor cells. IL-13 induced the preferential recruitment and suppressive function of monocytes. Thus, the T cell-to-MDSC balance, associated with a skewing toward type 2 immunity, may predict bladder tumor recurrence and influence the mortality of patients with muscle-invasive cancer. Moreover, these results underline the ILC2/IL-13 axis as a targetable pathway to curtail the M-MDSC compartment and improve bladder cancer treatment.


Subject(s)
Neoplasm Recurrence, Local/immunology , Neoplasm Recurrence, Local/urine , Urinary Bladder Neoplasms/immunology , Urinary Bladder Neoplasms/urine , Administration, Intravesical , Aged , Aged, 80 and over , BCG Vaccine , Disease-Free Survival , Female , Humans , Immune System , Immunotherapy , Interleukin-13/metabolism , Longitudinal Studies , Lymphocytes/cytology , Male , Middle Aged , Monocytes/cytology , Neutrophils/cytology , Prospective Studies , T-Lymphocytes/cytology , Urinary Bladder Neoplasms/therapy
3.
Eur Urol ; 71(6): 854-857, 2017 06.
Article in English | MEDLINE | ID: mdl-28277277

ABSTRACT

Blockade of inhibitory receptors (IRs) overexpressed by T cells can activate antitumor immune responses, resulting in the most promising therapeutic approaches, particularly in bladder cancer, currently able to extend patient survival. Thanks to their ability to cross-present antigens to T cells, dendritic cells (DCs) are an immune cell population that plays a central role in the generation of effective antitumor T-cell responses. While IR function and expression have been investigated in T cells, very few data are available for DCs. Therefore, we analyzed whether DCs express IRs that can decrease their functions. To this end, we investigated several IRs (PD-1, CTLA-4, BTLA, TIM-3, and CD160) in circulating CD1c+ DCs, CD141+ DCs, and plasmacytoid DCs from healthy donors and patients with urothelial cancer (UCa). Different DC subsets expressed BTLA and TIM-3 but not other IRs. More importantly, BTLA and TIM-3 were significantly upregulated in DCs from blood of UCa patients. Locally, bladder tumor-infiltrating DCs also overexpressed BTLA and TIM-3 compared to DCs from paired nontumoral tissue. Finally, in vitro functional experiments showed that ligand-mediated engagement of BTLA and TIM-3 receptors significantly reduced the secretion of effector cytokines by DC subpopulations. Our findings demonstrate that UCa induces local and systemic overexpression of BTLA and TIM-3 by DCs that may result in their functional inhibition, highlighting these receptors as potential targets for UCa treatment. PATIENT SUMMARY: We investigated the expression and function of a panel of inhibitory receptors in dendritic cells (DCs), an immune cell subpopulation critical in initiation of protective immune responses, among patients with urothelial carcinoma. We found high expression of BTLA and TIM-3 by blood and tumor DCs, which could potentially mediate decreased DC function. The results suggest that BTLA and TIM-3 might be new targets for urothelial carcinoma treatment.


Subject(s)
Biomarkers, Tumor/analysis , Dendritic Cells/immunology , Hepatitis A Virus Cellular Receptor 2/analysis , Receptors, Immunologic/analysis , Urinary Bladder Neoplasms/immunology , Urothelium/immunology , Case-Control Studies , Dendritic Cells/pathology , Humans , Phenotype , Signal Transduction , Tumor Microenvironment , Up-Regulation , Urinary Bladder Neoplasms/pathology , Urothelium/pathology
4.
Clin Cancer Res ; 23(3): 717-725, 2017 Feb 01.
Article in English | MEDLINE | ID: mdl-27521445

ABSTRACT

PURPOSE: Treatments with cancer vaccines may be delivered as combination therapies for better efficacy. Addition of intravesical immunostimulation with bacteria promotes vaccine-specific T cells in the bladder and tumor-regression in murine bladder cancer models. Here, we determined whether an adjuvanted cancer vaccine can be safely administered with concomitant standard intravesical Bacillus-Calmette-Guérin (BCG) therapy and how vaccine-specific immune responses may be modulated in patients with non-muscle-invasive bladder cancer (NMIBC). EXPERIMENTAL DESIGN: In a nonrandomized phase I open-label exploratory study, 24 NMIBC patients, apportioned in three groups, received 5 injections of a subunit cancer vaccine (recMAGE-A3 protein+AS15) alone or in two combinations of intravesical BCG-instillations. Safety profiles were compared between the three treatment groups, considering single vaccine injections or BCG instillations and concomitant interventions. Immune responses in blood and urine were compared between treatment groups and upon BCG instillations. RESULTS: The mild adverse events (AE) experienced by all the patients were similar to AE previously reported for this vaccine and standard BCG treatment. AEs were not increased by the double interventions, suggesting that BCG did not exacerbate the AE caused by the MAGE-A3 vaccine and vice-versa. All patients seroconverted after MAGE-A3 vaccination. In half of the patients, vaccine-specific T cells were induced in blood, irrespective of BCG treatment. Interestingly, such T cells were only detected in urine upon BCG-induced T-cell infiltration. CONCLUSIONS: Cancer vaccines, including strong adjuvants, can be safely combined with intravesical BCG therapy. The increase of vaccine-specific T cells in the bladder upon BCG provides proof-of-principle evidence that cancer vaccines with local immunostimulation may be beneficial. Clin Cancer Res; 23(3); 717-25. ©2016 AACR.


Subject(s)
Antigens, Neoplasm/immunology , BCG Vaccine/therapeutic use , Cancer Vaccines/therapeutic use , Carcinoma, Transitional Cell/therapy , Immunotherapy/methods , Lymphocytes, Tumor-Infiltrating/drug effects , Neoplasm Proteins/immunology , Urinary Bladder Neoplasms/therapy , Adjuvants, Immunologic/administration & dosage , Administration, Intravesical , BCG Vaccine/administration & dosage , BCG Vaccine/adverse effects , Cancer Vaccines/administration & dosage , Cancer Vaccines/adverse effects , Carcinoma, Transitional Cell/immunology , Carcinoma, Transitional Cell/pathology , Carcinoma, Transitional Cell/surgery , Combined Modality Therapy , Cystectomy/methods , Cytokines/urine , Dose-Response Relationship, Immunologic , Humans , Immunization Schedule , Injections, Intramuscular , Lipid A/administration & dosage , Lipid A/analogs & derivatives , Oligodeoxyribonucleotides/administration & dosage , Plant Extracts/administration & dosage , Quillaja , Recombinant Proteins/immunology , Urinary Bladder Neoplasms/immunology , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/surgery
5.
Int J Mol Sci ; 17(7)2016 Jul 14.
Article in English | MEDLINE | ID: mdl-27428950

ABSTRACT

Bladder cancer is the second most common urological malignancy in the world. In 70% of cases it is initially diagnosed as non-muscle-invasive bladder cancer (NMIBC) and it is amenable to local treatments, with intravesical (IVES) Bacillus-Calmette-Guerin (BCG) immunotherapy being routinely used after transurethral resection of the lesion. However, this treatment is associated with significant side-effects and treatment failures, highlighting the necessity of novel strategies. One potent approach is the suicide-gene mediated therapy/prodrug combination, provided tumor-specificity can be ensured and anti-tumor immune responses induced. Using the mouse syngeneic orthotopic MB49-bladder tumor model, here we show that IVES human papillomavirus non-replicative pseudovirions (PsV) can pseudoinfect tumors with a ten-fold higher efficacy than normal bladders. In addition, PsV carrying the suicide-gene herpes-simplex virus thymidine kinase (PsV-TK) combined to Ganciclovir (GCV) led to immunogenic cell-death of tumor cells in vitro and to MB49-specific CD8 T-cells in vivo. This was associated with reduction in bladder-tumor growth and increased mice survival. Altogether, our data show that IVES PsV-TK/GCV may be a promising alternative or combinatory treatment for NMIBC.


Subject(s)
Ganciclovir/therapeutic use , Genetic Therapy , Papillomaviridae/genetics , Papillomaviridae/immunology , Thymidine Kinase/metabolism , Urinary Bladder Neoplasms/therapy , Animals , Antiviral Agents/therapeutic use , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Combined Modality Therapy , Female , Genetic Vectors , Humans , Mice , Mice, Inbred C57BL , Papillomaviridae/enzymology , Thymidine Kinase/genetics , Urinary Bladder Neoplasms/enzymology , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/immunology
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