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1.
Urol Clin North Am ; 47(1): 83-91, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31757303

RESUMO

After Bacillus Calmette-Guerin (BCG) failure, there is likely a 6- to 24-month window whereby salvage intravesical therapy might allow for preservation of the bladder without disease worsening. Combination intravesical, salvage therapy for nonmuscle invasive bladder cancer represents a promising avenue for treatment in patients unfit or unwilling to undergo cystectomy. BCG with concomitant immune stimulating agents or immune checkpoint inhibitors, combination chemotherapy regimens, such as gemcitabine and docetaxol, and novel agents currently in clinical trials provide hope for a bladder-sparing alternative for patients after BCG failure.


Assuntos
Vacina BCG/administração & dosagem , Desoxicitidina/análogos & derivados , Docetaxel/administração & dosagem , Terapia de Salvação/métodos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Adjuvantes Imunológicos , Administração Intravesical , Antimetabólitos Antineoplásicos/administração & dosagem , Antineoplásicos/administração & dosagem , Desoxicitidina/administração & dosagem , Quimioterapia Combinada , Humanos , Invasividade Neoplásica , Resultado do Tratamento , Neoplasias da Bexiga Urinária/patologia
2.
Urol Clin North Am ; 47(1): 1-4, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31757292

RESUMO

High-risk non-muscle invasive bladder cancer is marked by frequent disease recurrences and risk of stage progression, contributing to high surveillance, treatment-related costs, and patient anxiety. Although the mainstay of high-risk non-muscle invasive bladder cancer clinical management remains transurethral resection followed by intravesical bacillus Calmette-Guérin (BCG), patients who develop BCG-unresponsive disease have few salvage options outside of a radical cystectomy with pelvic lymphadenectomy. This article provides a historical context relevant to the development of the BCG-unresponsive definition, an overview of current clinical trial expectations, and an introduction to this issue of Urologic Clinics.


Assuntos
Vacina BCG/administração & dosagem , Terapia de Salvação/métodos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Adjuvantes Imunológicos/administração & dosagem , Administração Intravesical , Progressão da Doença , Humanos , Invasividade Neoplásica , Neoplasias da Bexiga Urinária/patologia
3.
Urol Clin North Am ; 47(1): 119-128, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31757295

RESUMO

Bacillus Calmette-Guerin (BCG)-refractory high-grade non-muscle-invasive bladder cancer remains a challenging problem. Radical cystectomy is standard of care, but carries significant morbidity. Therefore, there is a need for effective treatments. Previous salvage intravesical therapies have had disappointing results with long-term follow-up; however, a wide array of novel agents is currently under investigation. These include novel combinations of existing intravesical agents, novel modes of delivery such as hyperthermia, viral mediated therapies, and immunotherapy. We review the need for novel treatment with existing agents and their long-term results, and discuss novel intravesical therapies and the data currently available on these therapies.


Assuntos
Antineoplásicos/administração & dosagem , Vacina BCG/administração & dosagem , Terapia de Salvação/métodos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Adjuvantes Imunológicos/administração & dosagem , Administração Intravesical , Quimioterapia Combinada , Humanos , Invasividade Neoplásica , Resultado do Tratamento , Neoplasias da Bexiga Urinária/patologia
4.
Urol Clin North Am ; 47(1): 15-21, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31757296

RESUMO

Disease progression and recurrence are common among patients on Bacillus Calmette-Guérin (BCG) therapy, and options for bladder-preserving subsequent therapy remain limited. Ongoing efforts to develop better second-line bladder-sparing therapies rely on clinical trials of patients deemed to have failed management with BCG. This article describes historical definitions of BCG failure, as well as recent efforts to better delineate and refine the clinical criteria for identifying individual patients who will not benefit from further intravesical BCG therapy. It also reviews guidance from the most recent expert consensus panels and professional association guidelines regarding which patients should not receive additional BCG therapy.


Assuntos
Vacina BCG/administração & dosagem , Seleção de Pacientes , Terapia de Salvação/métodos , Neoplasias da Bexiga Urinária/terapia , Adjuvantes Imunológicos/administração & dosagem , Administração Intravesical , Progressão da Doença , Humanos , Invasividade Neoplásica , Falha de Tratamento , Neoplasias da Bexiga Urinária/patologia
5.
Urol Clin North Am ; 47(1): 23-33, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31757297

RESUMO

Despite the 40-year reign of bacillus Calmette-Guérin (BCG) as the most effective immunotherapy in urologic cancers, a lack of clinical tools to predict treatment response has hampered progress in the field. Acting as an immunostimulatory agent against a multitude of phenotypically diverse non-muscle-invasive bladder cancers, response to BCG likely depends on both tumor characteristics as well as host factors. With a deeper understanding of the tumor biology as well as the mechanism of action underpinning immunotherapy, newer and more effective clinical tools are being constructed to improve patient selection.


Assuntos
Vacina BCG/administração & dosagem , Imunoterapia/métodos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Adjuvantes Imunológicos/administração & dosagem , Administração Intravesical , Humanos , Resultado do Tratamento , Neoplasias da Bexiga Urinária/patologia
6.
Urol Clin North Am ; 47(1): 35-46, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31757298

RESUMO

Non-muscle-invasive bladder cancer (NMIBC) is heterogeneous, but current diagnostic and treatment strategies rely primarily on clinical parameters, lacking individualization to tumor and host genetics and biology. The heterogeneity of NMIBCs is derived from mutations, mutation signatures, chromosomal loss, and disruption of molecular pathways, which ultimately affects tumor progression, recurrence, and responsiveness to intravesical and systemic chemotherapy. Although research is still underway, advances in sequencing technology, insight into differential bacillus Calmette-Guérin responses, and new investigational treatment targets will soon offer clinicians new, precision-based tools to risk stratify and determine treatment regimens for future patients with bladder cancer.


Assuntos
Vacina BCG/administração & dosagem , Biomarcadores Tumorais/genética , DNA de Neoplasias/genética , Genômica/métodos , Imunoterapia/métodos , Mutação , Neoplasias da Bexiga Urinária/genética , Adjuvantes Imunológicos/administração & dosagem , Administração Intravesical , Biomarcadores Tumorais/metabolismo , Análise Mutacional de DNA , Progressão da Doença , Humanos , Invasividade Neoplásica , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia
7.
Urol Clin North Am ; 47(1): 47-54, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31757299

RESUMO

Despite therapy with intravesical Bacillus Calmette-Guérin, roughly 50% of patients with high-risk non-muscle-invasive bladder cancer will recur. Although cystectomy is the oncologic gold standard in BCG unresponsive disease, salvage intravesical therapies are valuable treatment options that aim to preserve quality of life while decreasing the risk of cancer recurrence and progression. Single-agent intravesical chemotherapy has been a mainstay salvage treatment and foundational to future trials of combination therapy. Treatment with Bacillus Calmette-Guérin derivative therapies has shown promise with response rates comparable with those of single agent chemotherapy and may warrant further investigation in the continued climate of Bacillus Calmette-Guérin shortages.


Assuntos
Vacina BCG/administração & dosagem , Desoxicitidina/análogos & derivados , Terapia de Salvação/métodos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Adjuvantes Imunológicos/administração & dosagem , Administração Intravesical , Antimetabólitos Antineoplásicos/administração & dosagem , Desoxicitidina/administração & dosagem , Progressão da Doença , Humanos , Invasividade Neoplásica , Resultado do Tratamento , Neoplasias da Bexiga Urinária/patologia
8.
Urol Clin North Am ; 47(1): 5-13, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31757300

RESUMO

The best predictors of response to intravesical immunotherapy are tumor grade and stage, tumor recurrence pattern, nomograms, panels of urinary cytokines, and fluorescent in situ hybridization patterns of urine cytology examinations. Future investigations on predictors of Bacillus Calmette-Guérin efficacy are needed to better select those patients who will really benefit from a conservative treatment. Hardly any of the proposed nomograms were designed to precisely predict the outcome of Bacillus Calmette-Guérin immunotherapy. A new nomogram for NMIBC recurrence and progression based on all non-muscle-invasive bladder cancer subgroups would include factors already proven in cancer prognosis and prediction.


Assuntos
Vacina BCG/administração & dosagem , Imunoterapia/métodos , Terapia de Salvação/métodos , Neoplasias da Bexiga Urinária/terapia , Adjuvantes Imunológicos/administração & dosagem , Administração Intravesical , Progressão da Doença , Humanos , Invasividade Neoplásica , Nomogramas , Resultado do Tratamento , Neoplasias da Bexiga Urinária/patologia
9.
Medicine (Baltimore) ; 98(33): e16771, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415377

RESUMO

The cell wall skeleton of Bacillus Calmette-Guérin (BCG-CWS) is a bioactive component that is a strong immune adjuvant for cancer immunotherapy. BCG-CWS activates the innate immune system through various pattern recognition receptors and is expected to elicit antigen-specific cellular immune responses when co-administered with tumor antigens. To determine the recommended dose (RD) of BCG-CWS based on its safety profile, we conducted a phase I dose-escalation study of BCG-CWS in combination with WT1 peptide for patients with advanced cancer.The primary endpoint was the proportion of treatment-related adverse events (AEs) at each BCG-CWS dose. The secondary endpoints were immune responses and clinical effects. A BCG-CWS dose of 50, 100, or 200 µg/body was administered intradermally on days 0, 7, 21, and 42, followed by 2 mg of WT1 peptide on the next day. For the escalation of a dose level, 3 + 3 design was used.Study subjects were 18 patients with advanced WT1-expressing cancers refractory to standard anti-cancer therapies (7 melanoma, 5 colorectal, 4 hepatobiliary, 1 ovarian, and 1 lung). Dose-limiting toxicity occurred in the form of local skin reactions in 2 patients at a dose of 200 µg although no serious treatment-related systemic AEs were observed. Neutrophils and monocytes transiently increased in response to BCG-CWS. Some patients demonstrated the induction of the CD4 T cell subset and its differentiation from the naïve to memory phenotype, resulting in a tumor response.The RD of BCG-CWS was determined to be 100 µg/body. This dose was well tolerated and showed promising clinical effects with the induction of an appropriate immune response.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Vacina BCG/uso terapêutico , Esqueleto da Parede Celular/uso terapêutico , Mycobacterium bovis , Adjuvantes Imunológicos/administração & dosagem , Adulto , Idoso , Vacina BCG/administração & dosagem , Contagem de Linfócito CD4 , Esqueleto da Parede Celular/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Feminino , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Melanoma/tratamento farmacológico , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Resultado do Tratamento
10.
Expert Opin Investig Drugs ; 28(9): 757-770, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31412742

RESUMO

Introduction: The current first line therapy for high grade (HG) non-muscle invasive bladder cancer (NMIBC) is intravesical Bacillus Calmette-Guerin (BCG). Patients who recur or progress despite BCG are recommended to undergo radical cystectomy or participate in clinical trials. There is an urgent need for alternative therapies in the BCG-unresponsive NMIBC realm. Areas covered: We queried clinicaltrials.gov and pubmed.gov for current and recently completed early clinical trials pertaining to investigational agents used for the treatment of BCG-unresponsive NMIBC. These included intravesical chemotherapy, immunotherapy, vaccines, gene therapy, viruses, and agents used with novel drug delivery methods. In this article, we discuss the treatment guidelines for non-muscle invasive bladder cancer and therapeutic approaches under investigation in clinical trials. Expert opinion: The FDA is currently allowing single-arm studies as a pathway for approval in BCG-refractory patients with CIS. Although many agents are currently undergoing testing, none have been approved since Valrubicin. Hopefully, we will identify therapies sufficiently effective and durable to achieve FDA approval. Other considerations in this realm include the use of biomarkers in NMIBC to identify patients who will most likely respond to specific interventions. In addition, as systemic agents such as checkpoint inhibitors, are studied further, a multidisciplinary approach may be needed to treat this subset of patients.


Assuntos
Antineoplásicos/farmacologia , Drogas em Investigação/farmacologia , Neoplasias da Bexiga Urinária/terapia , Animais , Antineoplásicos/administração & dosagem , Vacina BCG/administração & dosagem , Biomarcadores Tumorais/metabolismo , Cistectomia/métodos , Sistemas de Liberação de Medicamentos , Drogas em Investigação/administração & dosagem , Humanos , Imunoterapia/métodos , Invasividade Neoplásica , Recidiva Local de Neoplasia , Neoplasias da Bexiga Urinária/patologia
11.
J Urol ; 202(6): 1111-1119, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31042108

RESUMO

PURPOSE: Due to the high rate of recurrence and progression in patients with high risk nonmuscle invasive bladder cancer, there is an important unmet need to identify new therapies. This is particularly true for patients with recurrence after optimal intravesical bacillus Calmette-Guérin therapy, who are classified as having bacillus Calmette-Guérin unresponsive disease. MATERIALS AND METHODS: The PubMed® database was searched for publications related to immunotherapy for the treatment of patients with nonmuscle invasive bladder cancer who have recurrent or progressive disease despite receiving intravesical bacillus Calmette-Guérin therapy. Relevant congress abstracts were identified through searches of individual congress websites. Relevant planned and ongoing studies were identified via ClinicalTrials.gov or associated web searches. RESULTS: We provide a summary of the currently available immunotherapy options for patients with bacillus Calmette-Guérin unresponsive nonmuscle invasive bladder cancer, and discuss planned and ongoing research of potential targeted agents and immunotherapy based combination regimens. CONCLUSIONS: There is a clear biological and clinical rationale for the continued evaluation of immune based therapies in the setting of bacillus Calmette-Guérin unresponsive nonmuscle invasive bladder cancer. Data from early phase trials with novel immunotherapies targeting multiple immune related pathways have emerged, which support additional studies to assess the benefits of immune checkpoint inhibitors and other immunotherapy based regimens for patients with bacillus Calmette-Guérin unresponsive nonmuscle invasive bladder cancer.


Assuntos
Vacina BCG/administração & dosagem , Imunoterapia/tendências , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/terapia , Administração Intravesical , Progressão da Doença , Humanos , Invasividade Neoplásica
14.
Nat Commun ; 10(1): 874, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30787276

RESUMO

Recent evidence suggests that certain vaccines, including Bacillus-Calmette Guérin (BCG), can induce changes in the innate immune system with non-specific memory characteristics, termed 'trained immunity'. Here we present the results of a randomised, controlled phase 1 clinical trial in 20 healthy male and female volunteers to evaluate the induction of immunity and protective efficacy of the anti-tuberculosis BCG vaccine against a controlled human malaria infection. After malaria challenge infection, BCG vaccinated volunteers present with earlier and more severe clinical adverse events, and have significantly earlier expression of NK cell activation markers and a trend towards earlier phenotypic monocyte activation. Furthermore, parasitemia in BCG vaccinated volunteers is inversely correlated with increased phenotypic NK cell and monocyte activation. The combined data demonstrate that BCG vaccination alters the clinical and immunological response to malaria, and form an impetus to further explore its potential in strategies for clinical malaria vaccine development.


Assuntos
Vacina BCG/imunologia , Imunidade Inata/imunologia , Memória Imunológica/imunologia , Células Matadoras Naturais/imunologia , Malária Falciparum/imunologia , Malária Falciparum/prevenção & controle , Adolescente , Adulto , Animais , Anopheles/parasitologia , Antígeno B7-2/metabolismo , Vacina BCG/administração & dosagem , Proteína C-Reativa/metabolismo , Citocinas/sangue , Feminino , Proteínas Ligadas por GPI/metabolismo , Granzimas/sangue , Antígenos HLA-DR/metabolismo , Humanos , Interferon gama/sangue , Ativação Linfocitária/imunologia , Masculino , Parasitemia/prevenção & controle , Plasmodium falciparum/imunologia , Receptores de IgG/metabolismo , Vacinação , Adulto Jovem
15.
Ann Vasc Surg ; 59: 310.e7-310.e11, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30802589

RESUMO

BACKGROUND: Intravesical instillation of Bacillus Calmette-Guérin (BCG) is an effective and widely used treatment for patients with in situ bladder cancer. Major complications are quite uncommon, but a systemic dissemination of the attenuated strain of Mycobacterium bovis is possible. Few cases of aortic rupture caused by M bovis infection are described in literature. METHODS: A 70-year-old male, treated 3 months before with BCG instillation, presented to the emergency department because of a ruptured abdominal aortic aneurysm. The patient was hemodynamically stable, with a "hostile" abdomen. Therefore, an Endologix AFX endograft was deployed. During the postoperative period, his blood inflammatory markers increased, suspicious of a graft infection. Single-photon emission computed tomography (CT)/CT scan showed aortic increased uptake. Antibiotic therapy was continued, but after some days, the patient presented with hematemesis, and the CT scan showed an aortoenteric fistula. In emergency, the infected graft and aneurysm were removed, enteric fistula was closed, and an axillobifemoral bypass was performed. The patient died 25 days after endovascular aneurysm repair explantation. RESULTS: Despite the high suspicion of mycotic aortic aneurysm and graft infection by M bovis, there is no proof of this theory because of the absence of any positive culture test. M bovis is a slow-growing bacteria, and specific culture tests are required to identify it; indeed, all our blood and intraoperative samples were positive to other bacteria, probably the contaminant ones. CONCLUSIONS: Mycotic aneurysm is an extremely rare complication of intravesical BCG therapy, but it must be taken into consideration in patients with rapidly growing aortic aneurysms or rupture of a normal aorta, who have been previously submitted to this kind of instillation.


Assuntos
Aneurisma Infectado/microbiologia , Antineoplásicos/efeitos adversos , Aneurisma da Aorta Abdominal/microbiologia , Ruptura Aórtica/microbiologia , Vacina BCG/efeitos adversos , Mycobacterium bovis/patogenicidade , Neoplasias da Bexiga Urinária/tratamento farmacológico , Administração Intravesical , Idoso , Aneurisma Infectado/diagnóstico por imagem , Aneurisma Infectado/cirurgia , Antibacterianos/uso terapêutico , Antineoplásicos/administração & dosagem , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/cirurgia , Ruptura Aórtica/diagnóstico por imagem , Ruptura Aórtica/cirurgia , Aortografia/métodos , Vacina BCG/administração & dosagem , Angiografia por Tomografia Computadorizada , Evolução Fatal , Humanos , Masculino , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Resultado do Tratamento
16.
Pediatrics ; 143(2)2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30674610

RESUMO

BACKGROUND: The intestinal microbiome in early infancy affects immunologic development and thus may affect vaccine memory, though few prospective studies have examined such associations. We examined the association of Bifidobacterium levels in early infancy with memory responses to early vaccination measured at 2 years of age. METHODS: In this prospective observational study, we examined the association of Bifidobacterium abundance in the stool of healthy infants at 6 to 15 weeks of age, near the time of vaccination, with T-cell and antibody responses measured at 6 weeks, 15 weeks, and 2 years of age. Infants were vaccinated with Bacillus Calmette-Guérin (BCG) (at birth), oral polio virus (at birth and at 6, 10, and 14 weeks), tetanus toxoid (TT) (at 6, 10, and 14 weeks), and hepatitis B virus (at 6, 10, and 14 weeks). Fecal Bifidobacterium was measured at 6, 11, and 15 weeks. Bifidobacterium species and subspecies were measured at 6 weeks. RESULTS: Mean Bifidobacterium abundance in early infancy was positively associated with the CD4 T-cell responses to BCG, TT, and hepatitis B virus at 15 weeks, with CD4 responses to BCG and TT at 2 years, and with plasma TT-specific immunoglobulin G and stool polio-specific immunoglobulin A at 2 years. Similar associations were seen for the predominant subspecies, Bifidobacterium longum subspecies infantis. CONCLUSIONS: Bifidobacterium abundance in early infancy may increase protective efficacy of vaccines by enhancing immunologic memory. This hypothesis could be tested in clinical trials of interventions to optimize Bifidobacterium abundance in appropriate populations.


Assuntos
Vacina BCG/administração & dosagem , Infecções por Bifidobacteriales/diagnóstico , Infecções por Bifidobacteriales/prevenção & controle , Bifidobacterium/efeitos dos fármacos , Vacinação/métodos , Infecções por Bifidobacteriales/epidemiologia , Bifidobacterium/fisiologia , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Prospectivos , Resultado do Tratamento , Vacinação/tendências
17.
PLoS One ; 14(1): e0209196, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30608942

RESUMO

Intravesical therapy using Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the most established cancer immunotherapy for bladder cancer. However, its underlying mechanisms are unknown. Mycolic acid (MA), the most abundant lipid of the BCG cell wall, is suspected to be one of the essential active components of this immunogenicity. Here, we developed cationic liposomes incorporating three subclasses (α, keto, and methoxy) of MA purified separately from BCG, using the dendron-bearing lipid D22. The cationic liposomes using D22 were efficiently taken up by the murine bladder cancer cell line MB49 in vitro, but the non-cationic liposomes were not. Lip-kMA, a cationic liposome containing keto-MA, presented strong antitumor activity in two murine syngeneic graft models using the murine bladder cancer cell lines MB49 and MBT-2 in comparison to both Lip-aMA and Lip-mMA, which contained α-MA and methoxy-MA, respectively. Interestingly, Lip-kMA(D12), which was made of D12 instead of D22, did not exhibit antitumor activity in the murine syngeneic graft model using MB49 cells, although it was successfully taken up by MB49 cells in vitro. Histologically, compared to the number of infiltrating CD4 lymphocytes, the number of CD8 lymphocytes was higher in the tumors treated with Lip-kMA. Antitumor effects of Lip-kMA were not observed in nude mice, whereas weak but significant effects were observed in beige mice with natural killer activity deficiency. Thus, a cationized liposome containing keto-MA derived from BCG induced in vivo antitumor immunity. These findings will provide new insights into lipid immunogenicity and the underlying mechanisms of BCG immunotherapy.


Assuntos
Vacina BCG/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Ácidos Micólicos/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/imunologia , Animais , Vacina BCG/administração & dosagem , Vacina BCG/química , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/química , Linhagem Celular Tumoral , Feminino , Humanos , Imunoterapia , Cetoácidos/administração & dosagem , Cetoácidos/isolamento & purificação , Cetoácidos/uso terapêutico , Lipossomos/administração & dosagem , Lipossomos/química , Lipossomos/ultraestrutura , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Nus , Estrutura Molecular , Ácidos Micólicos/administração & dosagem , Ácidos Micólicos/isolamento & purificação , Tamanho da Partícula , Neoplasias da Bexiga Urinária/patologia
18.
Enferm. infecc. microbiol. clín. (Ed. impr.) ; 36(10): 648-656, dic. 2018. tab, graf, mapas
Artigo em Espanhol | IBECS | ID: ibc-176931

RESUMO

La vacunación con BCG (bacilo Calmette-Guérin) está incluida en el calendario de inmunización al nacimiento en países con alta incidencia de tuberculosis, con una cobertura global cercana al 90%. BCG tiene casi cien años de antigüedad y está basada en una cepa atenuada de Mycobacterium bovis, proporcionando protección contra las formas diseminadas de la enfermedad pero confiriendo una protección muy limitada contra las formas pulmonares de tuberculosis, responsables de su transmisión. Diferentes vacunas profilácticas contra la tuberculosis se encuentran hoy en desarrollo clínico para reemplazar a BCG o para mejorar la protección en individuos ya vacunados con BCG. MTBVAC es la primera y única vacuna candidata basada en una cepa de Mycobacterium tuberculosis atenuada en evaluación clínica. Los planes de desarrollo clínico del MTBVAC se dirigen en primer lugar a la prevención de la tuberculosis en recién nacidos, para reemplazar a BCG, y en segundo lugar en adolescentes y adultos


BCG (Bacille Calmette-Guérin) vaccination is included in the immunization schedule for tuberculosis endemic countries with a global coverage at birth close to 90% worldwide. BCG was attenuated from Mycobacterium bovis almost a century ago, and provides a strong protection against disseminated forms of the disease, though very limited against pulmonary forms of tuberculosis, responsible for transmission. Novel prophylactic tuberculosis vaccines are in clinical development either to replace BCG or to improve its protection against respiratory forms of the disease. There are limitations understanding the immunological responses involved and the precise type of long-lived immunity that new vaccines need to induce. MTBVAC is the first and only tuberculosis vaccine candidate based on live-attenuated Mycobacterium tuberculosis in clinical evaluation. MTBVAC clinical development plans to target tuberculosis prevention in newborns, as a BCG replacement strategy, and as secondary objective to be tested in adolescents and adults previous vaccinated with BCG


Assuntos
Humanos , Recém-Nascido , Adolescente , Adulto , Tuberculose/epidemiologia , Tuberculose/prevenção & controle , Vacina BCG/administração & dosagem , Vacina BCG/história
19.
Front Immunol ; 9: 2869, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30564249

RESUMO

Epidemiological studies regarding many successful vaccines suggest that vaccination may lead to a reduction in child mortality and morbidity worldwide, on a grander scale than is attributable to protection against the specific target diseases of these vaccines. These non-specific effects (NSEs) of the Bacille Calmette-Guérin (BCG) vaccine, for instance, implicate adaptive and innate immune mechanisms, with recent evidence suggesting that trained immunity might be a key instrument at play. Collectively referring to the memory-like characteristics of innate immune cells, trained immunity stems from epigenetic reprogramming that these innate immune cells undergo following exposure to a primary stimulus like BCG. The epigenetic changes subsequently regulate cytokine production and cell metabolism and in turn, epigenetic changes are regulated by these effects. Novel -omics technologies, combined with in vitro models for trained immunity and other immunological techniques, identify the biological pathways within innate cells that enable training by BCG. Future research should aim to identify biomarkers for vaccine heterologous effects, such that they can be applied to epidemiological studies. Linking biological mechanisms to the reduction in all-cause mortality observed in epidemiological studies will strengthen the evidence in favor of vaccine NSEs. The universal acceptance of these NSEs would demand a re-evaluation of current vaccination policies, such as the childhood vaccination recommendations by the World Health Organization, in order to produce the maximum impact on childhood mortality.


Assuntos
Vacina BCG/imunologia , Imunidade Heteróloga , Memória Imunológica , Mycobacterium bovis/imunologia , Tuberculose/prevenção & controle , Vacina BCG/administração & dosagem , Epigênese Genética/imunologia , Humanos , Imunidade Celular , Imunidade Inata , Vacinação/métodos , Vacinação/normas , Organização Mundial da Saúde
20.
Front Immunol ; 9: 2875, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30581437

RESUMO

The Human Respiratory Syncytial Virus (hRSV) and the Human Metapneumovirus (hMPV) are two pneumoviruses that are leading agents causing acute lower respiratory tract infections (ALRTIs) affecting young infants, the elderly, and immunocompromised patients worldwide. Since these pathogens were first discovered, many approaches for the licensing of safe and effective vaccines have been explored being unsuccessful to date. We have previously described that immunization with recombinant strains of Mycobacterium bovis Bacillus Calmette-Guérin (rBCG) expressing the hRSV nucleoprotein (rBCG-N) or the hMPV phosphoprotein (rBCG-P) induced immune protection against each respective virus. These vaccines efficiently promoted viral clearance without significant lung damage, mainly through the induction of a T helper 1 cellular immunity. Here we show that upon viral challenge, rBCG-immunized mice developed a protective humoral immunity, characterized by production of antibodies specific for most hRSV and hMPV proteins. Further, isotype switching from IgG1 to IgG2a was observed in mice immunized with rBCG vaccines and correlated with an increased viral clearance, as compared to unimmunized animals. Finally, sera obtained from animals immunized with rBCG vaccines and infected with their respective viruses exhibited virus neutralizing capacity and protected naïve mice from viral replication and pulmonary disease. These results support the notion that the use of rBCG strains could be considered as an effective vaccination approach against other respiratory viruses with similar biology as hRSV and hMPV.


Assuntos
Vacina BCG/imunologia , Imunidade Humoral , Mycobacterium bovis/imunologia , Infecções Respiratórias/prevenção & controle , Animais , Vacina BCG/administração & dosagem , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Metapneumovirus/genética , Metapneumovirus/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Nucleoproteínas/administração & dosagem , Nucleoproteínas/genética , Nucleoproteínas/imunologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Vírus Sincicial Respiratório Humano/genética , Vírus Sincicial Respiratório Humano/imunologia , Infecções Respiratórias/imunologia , Infecções Respiratórias/virologia , Células Th1/imunologia , Células Th1/metabolismo , Vacinação/métodos , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia , Proteínas Virais/administração & dosagem , Proteínas Virais/genética , Proteínas Virais/imunologia , Replicação Viral/imunologia
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