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Colorectal cancer (CRC) is a major cause of cancer-related deaths globally. While treatment advancements have improved survival rates, primarily through targeted therapies based on KRAS, NRAS, and BRAF mutations, personalized treatment strategies for CRC remain limited. Immunotherapy, mainly immune checkpoint blockade, has shown efficacy in various cancers but is effective in only a small subset of patients with CRC with deficient mismatch repair (dMMR) proteins or high microsatellite instability (MSI). Recent research has challenged the notion that CRC is immunologically inert, revealing subsets with high immunogenicity and diverse lymphocytic infiltration. Identifying precise biomarkers beyond dMMR and MSI is crucial to expanding immunotherapy benefits. Hence, exploration has extended to various biomarker sources, such as the tumor microenvironment, genomic markers, and gut microbiota. Recent studies have introduced a novel classification system, consensus molecular subtypes, that aids in identifying patients with CRC with an immunogenic profile. These findings underscore the necessity of moving beyond single biomarkers and toward a comprehensive understanding of the immunological landscape in CRC, facilitating the development of more effective, personalized therapies.
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Neoplasias Colorretais , Imunoterapia , Humanos , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/terapia , Neoplasias Colorretais/genética , Imunoterapia/métodos , Biomarcadores Tumorais/genética , Microambiente Tumoral/imunologia , Instabilidade de MicrossatélitesRESUMO
Immune checkpoint blockade (ICB) agents are prominent immunotherapies for the treatment of advanced melanoma. However, they fail to promote any durable clinical benefit in a large cohort of patients. This study assessed clinical and molecular predictors of ICB response and survival in advanced melanoma. A retrospective analysis was performed on 210 patients treated with PD-1 or CTLA-4 inhibitors at Barretos Cancer Hospital, Brazil. PD-L1 expression was assessed by immunohistochemistry using formalin-fixed paraffin-embedded tumor tissues collected prior to ICB therapy. Patients were divided into responders (complete and partial response and stable disease for more than 6 months) and non-responders (stable disease for less than 6 months and progressive disease). Among them, about 82% underwent anti-PD-1 immunotherapy, and 60.5% progressed after the ICB treatment. Patients that received ICB as first-line therapy showed higher response rates than previously treated patients. Higher response rates were further associated with superficial spreading melanomas and positive PD-L1 expression (>1%). Likewise, PD-L1 positive expression and BRAF V600 mutations were associated with a higher overall survival after ICB therapy. Since ICBs are expensive therapies, evaluation of PD-L1 tumor expression in melanoma patients should be routinely assessed to select patients that are most likely to respond.
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The complete regression of clear cell renal cell carcinoma (ccRCC) obtained pre-clinically with anti-carbonic anhydrase IX (CAIX) G36 chimeric antigen receptor (CAR) T cells in doses equivalent to â 108 CAR T cells/kg renewed the potential of this target to treat ccRCC and other tumors in hypoxia. The immune checkpoint blockade (ICB) brought durable clinical responses in advanced ccRCC and other tumors. Here, we tested CD8α/4-1BB compared to CD28-based anti-CAIX CAR peripheral blood mononuclear cells (PBMCs) releasing anti-programmed cell death ligand-1 (PD-L1) IgG4 for human ccRCC treatment in vitro and in an orthotopic NSG mice model in vivo. Using a â 107 CAR PBMCs cells/kg dose, anti-CAIX CD28 CAR T cells releasing anti-PD-L1 IgG highly decrease both tumor volume and weight in vivo, avoiding the occurrence of metastasis. This antitumoral superiority of CD28-based CAR PBMCs cells compared to 4-1BB occurred under ICB via PD-L1. Furthermore, the T cell exhaustion status in peripheral CD4 T cells, additionally to CD8, was critical for CAR T cells efficiency. The lack of hepatotoxicity and nephrotoxicity upon the administration of a 107 CAR PMBCs cells/kg dose is the basis for carrying out clinical trials using anti-CAIX CD28 CAR PBMCs cells releasing anti-PD-L1 antibodies or anti-CAIX 4-1BB CAR T cells, offering exciting new prospects for the treatment of refractory ccRCC and hypoxic tumors.
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Antígeno B7-H1 , Anidrase Carbônica IX , Carcinoma de Células Renais , Neoplasias Renais , Receptores de Antígenos Quiméricos , Animais , Anticorpos/imunologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígenos CD28 , Anidrase Carbônica IX/imunologia , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/terapia , Inibidores de Checkpoint Imunológico , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Leucócitos Mononucleares/patologia , Camundongos , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologiaRESUMO
BACKGROUND: Immune checkpoint inhibitors may be associated with multiple immune-related toxicities. Cardiovascular adverse effects are underreported in clinical trials. METHODS: We conducted a systematic review and meta-analysis to evaluate cardiovascular adverse effects incidence among patients with solid tumors receiving immune checkpoint inhibitors in randomized clinical trials and the relative risk of presenting these effects compared to placebo or best supportive care. The search was conducted through MEDLINE, Embase, and Scopus databases from January 1st, 2010 until July 1st, 2020. Outcomes were reported following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. RESULTS: 57 randomized clinical trials including 12,118 patients were included. All grade CV AEs incidence rate was 8.32% (95% CI = 6.35%-10.53%). When only grade 3-5 CV AEs were considered, ICIs were significantly associated with increased risk than placebo or BSC (RR = 1.36; 95% CI = 1.06-1.73; p = 0.01). CONCLUSION: This meta-analysis corroborates the hypothesis of increased CV risk related to immune checkpoint inhibitors.
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The Epstein-Barr Virus (EBV) is a gammaherpesvirus involved in the etiopathogenesis of a variety of human cancers, mostly of lymphoid and epithelial origin. The EBV infection participates in both cell transformation and tumor progression, also playing an important role in subverting immune responses against cancers. The homeostasis of the immune system is tightly regulated by inhibitory mechanisms affecting key immune effectors, such as T lymphocytes and NK cells. Collectively known as immune checkpoints, these mechanisms rely on a set of cellular receptors and ligands. These molecules may be candidate targets for immune checkpoints blockade-an emergent and promising modality of immunotherapy already proven to be valuable for a variety of human cancers. The EBV was lately suspected to interfere with the expression of immune checkpoint molecules, notably PD-1 and its ligands, found to be overexpressed in cases of Hodgkin lymphoma, nasopharyngeal, and gastric adenocarcinomas associated with the viral infection. Even though there is compelling evidence showing that the EBV interferes with other immune checkpoint regulators (e.g., CTLA-4, LAG-3, TIM-3, and VISTA), the published data are still scarce. Herein, we discuss the current state of the knowledge on how the EBV interferes with the activity of immune checkpoints regulators, as well as its implications considering the immune checkpoints blockade for clinical management of the EBV-associated malignancies, notably lymphomas.
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Infecções por Vírus Epstein-Barr , Transtornos Linfoproliferativos , Neoplasias Gástricas , Herpesvirus Humano 4 , Humanos , Inibidores de Checkpoint Imunológico , Ligantes , Transtornos Linfoproliferativos/complicaçõesRESUMO
Background: Combination therapy with lenvatinib plus programmed death-1 (PD-1) immune checkpoint blockades (ICBs) is under investigation in many solid tumors, including thyroid cancer. Lenvatinib is known to reduce angiogenesis and may overturn the immunosuppressive effects of vascular endothelial growth factor in the tumor microenvironment. Previous studies investigating the effects of VEGF receptor inhibition on the immune response were performed in rapidly growing tumor models where immune equilibrium is not established before treatment. We hypothesize that physiologically relevant preclinical models are necessary to define mechanisms of resistance to immune-targeted combination therapies. Methods: We utilized the TPO-CreER/BrafV600E/wt/Trp53Δex2-10/Δex2-10 inducible transgenic model of advanced thyroid cancer to investigate lenvatinib treatment in the context of an anti-PD-1 ICB. Following tumor establishment, 3.5 months postinduction, mice were treated with high- (10 mg/kg) or low-dose (2 mg/kg) lenvatinib, anti-PD-1, or combination of lenvatinib with anti-PD-1. Tumor volume and lung metastases were assessed in each group. Immune infiltrate was characterized by flow cytometry and immunohistochemistry, and TCRß sequencing was performed to further investigate the T cell response. Results: Both low- and high-dose lenvatinib reduced tumor volume, while anti-PD-1 had no effect, alone or in combination. Although both low- and high-dose lenvatinib reduced vascular density, low-dose lenvatinib was superior in controlling tumor size. Lung metastases and survival were not improved with therapy despite the effects of lenvatinib on primary tumor size. Low-dose lenvatinib treatment led to a subtle reduction in the dominant Ly6G+CD11b+ myeloid cell population and was associated with increased CD4+ T cell infiltrate and enrichment in 4-1BB+ and granzyme B+ CD4+ T cells and FoxP3+ regulatory T cells. Polyclonal T cell expansion was evident in the majority of mice, suggesting that a tumor-specific T cell response was generated. Conclusions: The effects of lenvatinib on the immune response were most pronounced in mice treated with low-dose lenvatinib, suggesting that dose should be considered in clinical application. While the immune-modulating potential of lenvatinib is encouraging, alterations in the immune milieu and T cell activation status were insufficient to sustain durable tumor regression, even with added anti-PD-1. Additional studies are necessary to develop more effective combination approaches in low-mutation burden tumors, such as thyroid cancer.
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Resistência a Medicamentos , Inibidores de Checkpoint Imunológico , Compostos de Fenilureia/administração & dosagem , Quinolinas/administração & dosagem , Neoplasias da Glândula Tireoide/patologia , Fator A de Crescimento do Endotélio Vascular/administração & dosagem , Animais , Antineoplásicos/uso terapêutico , Quimioterapia Combinada , Humanos , Camundongos , Modelos Animais , Neoplasias da Glândula Tireoide/induzido quimicamenteRESUMO
Immunotherapy has improved patient survival in many types of cancer, but for prostate cancer, initial results with immunotherapy have been disappointing. Prostate cancer is considered an immunologically excluded or cold tumor, unable to generate an effective T-cell response against cancer cells. However, a small but significant percentage of patients do respond to immunotherapy, suggesting that some specific molecular subtypes of this tumor may have a better response to checkpoint inhibitors. Recent findings suggest that, in addition to their function as cancer genes, somatic mutations of PTEN, TP53, RB1, CDK12, and DNA repair, or specific activation of regulatory pathways, such as ETS or MYC, may also facilitate immune evasion of the host response against cancer. This review presents an update of recent discoveries about the role that the common somatic mutations can play in changing the tumor microenvironment and immune response against prostate cancer. We describe how detailed molecular genetic analyses of the tumor microenvironment of prostate cancer using mouse models and human tumors are providing new insights into the cell types and pathways mediating immune responses. These analyses are helping researchers to design drug combinations that are more likely to target the molecular and immunological pathways that underlie treatment failure.
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Imunoterapia , Neoplasias da Próstata/genética , Microambiente Tumoral/imunologia , Animais , Ensaios Clínicos como Assunto , Genes Neoplásicos , Humanos , Masculino , Mutação , Neoplasias Experimentais/imunologia , Neoplasias da Próstata/imunologia , Análise de Célula Única , Análise Espacial , Microambiente Tumoral/genéticaRESUMO
As a very promising immunotherapy, PD-1/PD-L1 blockade has revolutionized the treatment of a variety of tumor types, resulting in significant clinical efficacy and lasting responses. However, these therapies do not work for a large proportion of patients initially, which is called primary resistance. And more frustrating is that most patients eventually develop acquired resistance after an initial response to PD-1/PD-L1 blockade. The mechanisms that lead to primary and acquired resistance to PD-1/PD-L1 inhibition have remained largely unclear. Recently, the gut microbiome has emerged as a potential regulator for PD-1/PD-L1 blockade. This review elaborates on the current understanding of the mechanisms in terms of PD-1 related signaling pathways and necessary factors. Moreover, this review discusses new strategies to increase the efficacy of immunotherapy from the perspectives of immune markers and gut microbiome.
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Resistencia a Medicamentos Antineoplásicos/fisiologia , Microbioma Gastrointestinal/fisiologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Neoplasias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Biomarcadores , Resistencia a Medicamentos Antineoplásicos/imunologia , Humanos , Interferon gama/uso terapêutico , Depleção Linfocítica , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais , Linfócitos T Reguladores/imunologia , Microambiente Tumoral/imunologiaRESUMO
Immune checkpoint blockers improve the overall survival of a limited number of patients among different cancers. Identifying pathways that influence the immunological and clinical response to treatment is critical to improve the therapeutic efficacy and predict clinical responses. Recently, a key role has been assigned to innate immune mechanisms in checkpoint blockade-driven anti-tumor responses. However, inflammatory pathways can both improve and impair anti-tumor immunity. In this review, we discuss how different inflammatory pathways, particularly inflammasome activation, can influence the clinical outcome of immune checkpoint blockers. Inflammasome activation may reinforce anti-tumor immunity by boosting CD8+ T cell priming as well as by enhancing T helper type 17 (Th17) responses. In particular, we focus on the modulation of the cation channel transmembrane protein 176B (TMEM176B) and the ectonucleotidase CD39 as potential targets to unleash inflammasome activation leading to reinforced anti-tumor immunity and improved efficacy of immune checkpoint blockers. Future studies should be aimed at investigating the mechanisms and cell subsets involved in inflammasome-driven anti-tumor responses.
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Antineoplásicos Imunológicos/uso terapêutico , Apirase , Inflamassomos/imunologia , Proteínas de Membrana , Proteínas de Neoplasias , Neoplasias , Animais , Apirase/antagonistas & inibidores , Apirase/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Humanos , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/imunologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Células Th17/imunologia , Células Th17/patologiaRESUMO
BACKGROUND: The purpose of this study was to investigate whether combining pembrolizumab with palliative radiation therapy (RT) improves outcomes in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). PATIENTS AND METHODS: Eligible patients had HR+/human epidermal growth factor receptor 2-negative MBC; were candidates for RT to ≥ 1 bone, soft tissue, or lymph node lesion; and had ≥ 1 lesion outside the RT field. Patients received 200 mg pembrolizumab intravenously 2 to 7 days prior to RT and on day 1 of repeating 21-day cycles. RT was delivered to a previously unirradiated area in 5 treatments each of 4 Gy. The primary endpoint was objective response rate. The study used a 2-stage design: 8 women were enrolled into the first stage, and if at least 1 of 8 patients experienced an objective response, 19 more would be enrolled. Secondary endpoints included progression-free survival, overall survival, and safety. Exploratory endpoints included association of overall response rate with programmed death-ligand 1 status and tumor-infiltrating lymphocytes. RESULTS: Eight patients were enrolled in stage 1. The median age was 59 years, and the median prior lines of chemotherapy for metastatic disease was 2. There were no objective responses, and the study was closed to further accrual. The median progression-free survival was 1.4 months (95% confidence interval, 0.4-2.1 months), and the median overall survival was 2.9 months (95% confidence interval, 0.9-3.6 months). All-cause adverse events occurred in 87.5% of patients, including just 1 grade 3 event (elevation of aspartate aminotransferase). CONCLUSIONS: RT combined with pembrolizumab did not produce an objective response in patients with heavily pre-treated HR+ MBC. Future studies should consider alternative radiation dosing and fractionation in patients with less heavily pre-treated HR+ MBC.
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Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Neoplasias da Mama/terapia , Carcinoma Ductal de Mama/terapia , Quimiorradioterapia/métodos , Cuidados Paliativos/métodos , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Mama/patologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/mortalidade , Carcinoma Ductal de Mama/patologia , Quimiorradioterapia/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Intervalo Livre de Progressão , Receptor ErbB-2/análise , Receptores de Estrogênio/análise , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/análise , Receptores de Progesterona/metabolismo , Critérios de Avaliação de Resposta em Tumores SólidosRESUMO
Stat3 is constitutively activated in several tumor types and plays an essential role in maintaining their malignant phenotype and immunosupression. To take advantage of the promising antitumor activity of Stat3 targeting, it is vital to understand the mechanism by which Stat3 regulates both cell autonomous and non-autonomous processes. Here, we demonstrated that turning off Stat3 constitutive activation in different cancer cell types induces senescence, thus revealing their Stat3 addiction. Taking advantage of the senescence-associated secretory phenotype (SASP) induced by Stat3 silencing (SASP-siStat3), we designed an immunotherapy. The administration of SASP-siStat3 immunotherapy induced a strong inhibition of triple-negative breast cancer and melanoma growth associated with activation of CD4 + T and NK cells. Combining this immunotherapy with anti-PD-1 antibody resulted in survival improvement in mice bearing melanoma. The characterization of the SASP components revealed that type I IFN-related mediators, triggered by the activation of the cyclic GMP-AMP synthase DNA sensing pathway, are important for its immunosurveillance activity. Overall, our findings provided evidence that administration of SASP-siStat3 or low dose of Stat3-blocking agents would benefit patients with Stat3-addicted tumors to unleash an antitumor immune response and to improve the effectiveness of immune checkpoint inhibitors.
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Melanoma , Neoplasias de Mama Triplo Negativas , Animais , Senescência Celular , Humanos , Imunoterapia , Camundongos , Vício Oncogênico , Fator de Transcrição STAT3/genéticaAssuntos
Imunoterapia/métodos , Terapia de Alvo Molecular , Neoplasias/terapia , Animais , Humanos , Neoplasias/imunologia , FenótipoRESUMO
In the last few years, there has been a twist in cancer treatment toward immunotherapy thanks to the impressive results seen in advanced patients from several tumor pathologies. Cutaneous melanoma is a highly mutated and immunogenic tumor that has been a test field for the development of immunotherapy. However, there is still a way on the road to achieving complete and long-lasting responses in most patients. It is desirable that immunotherapeutic strategies induce diverse immune reactivity specific to tumor antigens, including the so-called neoantigens, as well as the blockade of immunosuppressive mechanisms. In this review, we will go through the role of promising monoclonal antibodies in cancer immunotherapy with immunomodulatory function, especially blocking of the inhibitory immune checkpoints CTLA-4 and PD-1, in combination with different immunotherapeutic strategies such as vaccines. We will discuss the rational basis for these combinatorial approaches as well as different schemes currently under study for cutaneous melanoma in the clinical trials arena. In this way, the combination of "push and release" immunomodulatory therapies can contribute to achieving a more robust and durable antitumor immune response in patients.
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The success of immunotherapies brings hope for the future of cancer treatment. Even so, we are faced with a new challenge, that of understanding which patients will respond initially and, possibly, develop resistance. The examination of the immune profile, especially approaches related to the immunoscore, may foretell which tumors will have a positive initial response. Ideally, the mutation load would also be analyzed, helping to reveal tumor associated antigens that are predictive of an effective cytolytic attack. However, the response may be hindered by changes induced in the tumor and its microenvironment during treatment, perhaps stemming from the therapy itself. To monitor such alterations, we suggest that minimally invasive approaches should be explored, such as the analysis of circulating tumor DNA. When testing new drugs, the data collected from each patient would initially represent an N of 1 clinical trial that could then be deposited in large databases and mined retrospectively for trends and correlations between genetic alterations and response to therapy. We expect that the investment in personalized approaches that couple molecular analysis during clinical trials will yield critical data that, in the future, may be used to predict the outcome of novel immunotherapies.
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Imunoterapia/tendências , Neoplasias/imunologia , Neoplasias/terapia , Ensaios Clínicos como Assunto , DNA/sangue , Genes cdc , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Medicina de Precisão , Microambiente TumoralRESUMO
Leprosy remains a health problem in several countries. Current management of patients with leprosy is complex and requires multidrug therapy. Nonetheless, antibiotic treatment is insufficient to prevent nerve disabilities and control Mycobacterium leprae. Successful infectious disease treatment demands an understanding of the host immune response against a pathogen. Immune-based therapy is an effective treatment option for malignancies and infectious diseases. A promising therapeutic approach to improve the clinical outcome of malignancies is the blockade of immune checkpoints. Immune checkpoints refer to a wide range of inhibitory or regulatory pathways that are critical for maintaining self-tolerance and modulating the immune response. Programmed cell-death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4, and lymphocyte-activation gene-3 are the most important immune checkpoint molecules. Several pathogens, including M. leprae, are supposed to utilize these mechanisms to evade the host immune response. Regulatory T cells and expression of co-inhibitory molecules on lymphocytes induce specific T-cell anergy/exhaustion, leading to disseminated and progressive disease. From this perspective, we outline how the co-inhibitory molecules PD-1, PD-L1, and Th1/Th17 versus Th2/Treg cells are balanced, how antigen-presenting cell maturation acts at different levels to inhibit T cells and modulate the development of leprosy, and how new interventions interfere with leprosy development.
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Leprosy remains a health problem in several countries. Current management of patients with leprosy is complex and requires multidrug therapy. Nonetheless, antibiotic treatment is insufficient to prevent nerve disabilities and control Mycobacterium leprae. Successful infectious disease treatment demands an understanding of the host immune response against a pathogen. Immune-based therapy is an effective treatment option for malignancies and infectious diseases. A promising therapeutic approach to improve the clinical outcome of malignancies is the blockade of immune checkpoints. Immune checkpoints refer to a wide range of inhibitory or regulatory pathways that are critical for maintaining self-tolerance and modulating the immune response. Programmed cell-death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4, and lymphocyte-activation gene-3 are the most important immune checkpoint molecules. Several pathogens, including M. leprae, are supposed to utilize these mechanisms to evade the host immune response. Regulatory T cells and expression of co-inhibitory molecules on lymphocytes induce specific T-cell anergy/exhaustion, leading to disseminated and progressive disease. From this perspective, we outline how the co-inhibitory molecules PD-1, PD-L1, and Th1/Th17 versus Th2/Treg cells are balanced, how antigen-presenting cell maturation acts at different levels to inhibit T cells and modulate the development of leprosy, and how new interventions interfere with leprosy development.
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Imunoterapia/métodos , Hanseníase/imunologia , Linfócitos T , Hanseníase/prevenção & controleRESUMO
Systemic therapy for metastatic urothelial carcinoma has seen minimal progress and no new approved therapies in the past 20 years. However, with the approval of the checkpoint inhibitor atezolizumab in May 2016, immunotherapy inserted itself into the standard clinical dogma. The emergence of systemic immunotherapies, heralded by drugs targeting immune checkpoint blockade, can provide durable remissions in a subset of patients with a favorable toxicity profile. With other similar agents showing promise in early-phase trials, more options may be on the way. Current and ongoing trials are investigating ways to increase response rates with rational combinations as well as to uncover predictive biomarkers to identify patients most likely to benefit. In this review, we present updated data regarding immunotherapeutic agents in clinical trials as well as ongoing studies investigating novel designs, intriguing combinations, and alternative immunotherapy strategies.