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1.
Biomed Pharmacother ; 148: 112768, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35247717

RESUMO

Pulmonary fibrosis induced by silica particles is defined as silicosis, which is an incurable disease. The pathogenesis of silicosis is not completely clear, but it's certain that immune system dysfunction is closely related to it. Immune checkpoint inhibitors (ICIs) are emerging immunotherapeutic agents that mainly target adaptive immune cells, and there is abundant evidence that ICIs are of great value in cancer treatment. However, whether these attractive agents can be implemented in silicosis treatment is unclear. In this study, we explored the efficacy of small molecule inhibitors targeted PD-1/PD-L1 and CTLA-4 on silica-induced pulmonary fibrosis in mice. ICIs were injected intraperitoneally into mice that received silica instillation twice a week. The mice were sacrificed 7 and 28 days after the injection. The lungs, spleen, hilar lymph nodes, thymus, and peripheral blood of mice were collected and subjected to histological examination, flow cytometry analysis, and mRNA and protein quantification. Our results demonstrated that silica exposure caused damage to multiple immune organs in mice, leading to an imbalance in systemic immune homeostasis. Specifically, proportions and subtypes of T and B cells were significantly altered, and the expressions of PD-1, PD-L1 and CTLA-4 were abnormal on these cells. Both PD-1/PD-L1 and CTLA-4 inhibitor administration modulated silica-induced immune system disruption, however, only PD-1/PD-L1 signaling inhibition showed significant amelioration of silicosis. Our findings confirmed for the first time the potential value of ICIs for the treatment of silica-induced pulmonary fibrosis, and this may provide new ideas for the treatment of other fibrosis-related diseases.


Assuntos
Inibidores de Checkpoint Imunológico/farmacologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Dióxido de Silício/efeitos adversos , Animais , Subpopulações de Linfócitos B/efeitos dos fármacos , Antígeno B7-H1/efeitos dos fármacos , Antígeno CTLA-4/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Insuficiência de Múltiplos Órgãos/induzido quimicamente , Insuficiência de Múltiplos Órgãos/patologia , Receptor de Morte Celular Programada 1/efeitos dos fármacos , RNA Mensageiro , Subpopulações de Linfócitos T/efeitos dos fármacos
2.
Rheumatology (Oxford) ; 61(3): 1233-1242, 2022 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-34009274

RESUMO

OBJECTIVE: Treatment with CTLA-4Ig blocks T-cell activation and is clinically effective in RA. However, it is unknown if specific CD4+ T-cell subsets in blood at baseline predict remission after CTLA-4Ig, or other biological treatments with different modes of action, and how treatment affects CD4+ T cells in patients with untreated early RA (eRA). METHODS: This study included 60 patients with untreated eRA from a larger randomized trial. They were treated with methotrexate combined with CTLA-4Ig (abatacept, n = 17), anti-IL6 receptor (tocilizumab, n = 21) or anti-TNF (certolizumab-pegol, n = 22). Disease activity was assessed by clinical disease activity index (CDAI), DAS28, swollen joint counts, tender joint counts, CRP and ESR. The primary outcome was CDAI remission (CDAI ≤ 2.8) at week 24. Proportions of 12 CD4+ T-cell subsets were measured by flow cytometry at baseline and after 4, 12 and 24 weeks of treatment. RESULTS: In patients treated with CTLA-4Ig, the proportions of PD-1+TFh and CTLA-4+ conventional CD4+ T cells at baseline predicted CDAI remission at week 24. CD4+ T-cell subset proportions could not predict remission after treatment with anti-IL6R or anti-TNF. The percentage of regulatory T cells (Tregs) expressing CTLA-4 decreased in all treatment arms by 24 weeks, but only CTLA-4Ig treatment significantly reduced the proportions of Tregs and PD-1+T follicular helper (TFh) cells. CONCLUSION: These findings indicate that circulating proportions PD-1+TFh and CTLA-4+ conventional CD4+ T cells at baseline may serve as predictive biomarkers for remission in early RA after CTLA-4Ig treatment.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Linfócitos T CD4-Positivos/efeitos dos fármacos , Antígeno CTLA-4/efeitos dos fármacos , Receptor de Morte Celular Programada 1/sangue , Abatacepte/uso terapêutico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Artrite Reumatoide/imunologia , Biomarcadores/sangue , Linfócitos T CD4-Positivos/imunologia , Antígeno CTLA-4/imunologia , Certolizumab Pegol/uso terapêutico , Quimioterapia Combinada , Humanos , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/imunologia , Adulto Jovem
3.
Dtsch Med Wochenschr ; 146(17): 1119-1128, 2021 09.
Artigo em Alemão | MEDLINE | ID: mdl-34448188

RESUMO

Immunotherapy with checkpoint inhibitors - monoclonal antibodies targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA4) or the programmed death-1 receptor (PD-1) and its ligand PD-L1 - is now standard of care in the treatment of patients with various tumor types. Therefore, the management of immune-related adverse events (irAEs) has become part of clinical routine.Immune-related adverse events can involve any organ or tissue. They can occur very early within days or weeks after initiation of treatment but can also occur months into treatment and after termination of treatment. Newest data suggest that irAEs can occur until 2 years after stopping therapy.Immune-related adverse events are graded according to Common Terminology Criteria for Adverse Events (CTCAE). Treatment ranges from local or symptomatic treatment, systemic application of corticosteroids to other immunosuppressive agents according to severity.The following article seeks to give a general approach to the management of patients receiving immunotherapy and experiencing irAEs including prevention, diagnostics and treatment.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Antígeno CTLA-4/efeitos dos fármacos , Imunoterapia/efeitos adversos , Neoplasias/terapia , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Humanos , Padrão de Cuidado
4.
J Cell Physiol ; 236(8): 5495-5511, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33452716

RESUMO

Programmed cell death protein-1/programmed cell death-ligand 1 and cytotoxic T-lymphocyte antigen-4 are two immune checkpoint inhibitors (ICIs), exhibiting significant antitumor effects on multiple types of cancers in clinical practice. However, only some patients respond to ICI agents, which limits their widespread application. Recent findings revealed that the gut microbiota is relevant to host health through the modulation of host physical and immune functions. Therefore, the modulation of gut microbiota to achieve the desired taxa may be a potential strategy to improve the efficacy of immunotherapies. In this review, we classified the relative microbes according to their taxonomic information and aimed to clarify their modulatory functions and potent effects on ICI immunotherapy by focusing on recent trials investigating the relationships between the gut microbiota and ICIs.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/efeitos dos fármacos , Antígeno CTLA-4/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Neoplasias/tratamento farmacológico , Antígeno B7-H1/metabolismo , Antígeno CTLA-4/imunologia , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Imunoterapia/métodos
5.
Cell Rep Med ; 1(9): 100163, 2020 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-33377134

RESUMO

Combination immunotherapy with antibodies directed against PD-1 and CTLA-4 shows improved clinical benefit across cancer indications compared to single agents, albeit with increased toxicity. Leveraging the observation that PD-1 and CTLA-4 are co-expressed by tumor-infiltrating lymphocytes, an investigational PD-1 x CTLA-4 bispecific DART molecule, MGD019, is engineered to maximize checkpoint blockade in the tumor microenvironment via enhanced CTLA-4 blockade in a PD-1-binding-dependent manner. In vitro, MGD019 mediates the combinatorial blockade of PD-1 and CTLA-4, confirming dual inhibition via a single molecule. MGD019 is well tolerated in non-human primates, with evidence of both PD-1 and CTLA-4 blockade, including increases in Ki67+CD8 and ICOS+CD4 T cells, respectively. In the ongoing MGD019 first-in-human study enrolling patients with advanced solid tumors (NCT03761017), an analysis undertaken following the dose escalation phase revealed acceptable safety, pharmacodynamic evidence of combinatorial blockade, and objective responses in multiple tumor types typically unresponsive to checkpoint inhibitor therapy.


Assuntos
Anticorpos/uso terapêutico , Antígeno CTLA-4/imunologia , Imunoterapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Antígeno CTLA-4/efeitos dos fármacos , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Receptor de Morte Celular Programada 1/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
6.
Theranostics ; 10(4): 1910-1922, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32042344

RESUMO

Tumor normalization strategies aim to improve tumor blood vessel functionality (i.e., perfusion) by reducing the hyper-permeability of tumor vessels or restoring compressed vessels. Despite progress in strategies to normalize the tumor microenvironment (TME), their combinatorial antitumor effects with nanomedicine and immunotherapy remain unexplored. Methods: Here, we re-purposed the TGF-ß inhibitor tranilast, an approved anti-fibrotic and antihistamine drug, and combined it with Doxil nanomedicine to normalize the TME, increase perfusion and oxygenation, and enhance anti-tumor immunity. Specifically, we employed two triple-negative breast cancer (TNBC) mouse models to primarily evaluate the therapeutic and normalization effects of tranilast combined with doxorubicin and Doxil. We demonstrated the optimized normalization effects of tranilast combined with Doxil and extended our analysis to investigate the effect of TME normalization to the efficacy of immune checkpoint inhibitors. Results: Combination of tranilast with Doxil caused a pronounced reduction in extracellular matrix components and an increase in the intratumoral vessel diameter and pericyte coverage, indicators of TME normalization. These modifications resulted in a significant increase in tumor perfusion and oxygenation and enhanced treatment efficacy as indicated by the notable reduction in tumor size. Tranilast further normalized the immune TME by restoring the infiltration of T cells and increasing the fraction of T cells that migrate away from immunosuppressive cancer-associated fibroblasts. Furthermore, we found that combining tranilast with Doxil nanomedicine, significantly improved immunostimulatory M1 macrophage content in the tumorigenic tissue and improved the efficacy of the immune checkpoint blocking antibodies anti-PD-1/anti-CTLA-4. Conclusion: Combinatorial treatment of tranilast with Doxil optimizes TME normalization, improves immunostimulation and enhances the efficacy of immunotherapy.


Assuntos
Imunoterapia/métodos , Fator de Crescimento Transformador beta/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas , Microambiente Tumoral/efeitos dos fármacos , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antígeno CTLA-4/efeitos dos fármacos , Quimioterapia do Câncer por Perfusão Regional/métodos , Modelos Animais de Doenças , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacologia , Combinação de Medicamentos , Matriz Extracelular/efeitos dos fármacos , Feminino , Imunização/métodos , Camundongos , Nanomedicina/métodos , Nanopartículas/uso terapêutico , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/farmacologia , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/imunologia , ortoaminobenzoatos/administração & dosagem , ortoaminobenzoatos/farmacologia
7.
Clin Pharmacokinet ; 59(3): 287-296, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31701469

RESUMO

Cancer immunotherapy is based on checkpoint inhibitors (CPIs) that significantly improve the clinical outcome of several malignant diseases. These inhibitors are monoclonal antibodies (mAbs) directed at cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), or programmed death-ligand 1 (PD-L1), sharing most of the clinical pharmacokinetic characteristics of mAb targeted therapies, all of which differ from those of cytotoxics and small molecules. Establishing the labeled dose of mAbs, and particularly of the CPIs, represents a true challenge. This review therefore examines the main criteria used for dose selection, along with their limits. The relationships between CPI pharmacokinetic parameters and treatment outcome (efficacy and/or toxicity) differ somewhat among the various drugs, but general features can be identified. Nevertheless, the interpretation of these relationships remains quite controversial. A first interpretation asserts that inter-individual pharmacokinetic variability in clearance has an impact on outcome and should be taken into consideration for dosing individualization. The second considers that higher clearance values observed in some patients result from characteristics associated with poor predictive factors of efficacy. Finally, the schedule, and particularly its frequency of administration, merits rethinking.


Assuntos
Anticorpos Monoclonais/farmacocinética , Antineoplásicos Imunológicos/farmacocinética , Inibidores de Checkpoint Imunológico/farmacocinética , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/efeitos dos fármacos , Antígeno B7-H1/imunologia , Variação Biológica da População , Antígeno CTLA-4/efeitos dos fármacos , Antígeno CTLA-4/imunologia , Esquema de Medicação , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Farmacogenética , Farmacologia Clínica , Valor Preditivo dos Testes , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Receptor de Morte Celular Programada 1/imunologia , Resultado do Tratamento
8.
Biomed J ; 42(5): 299-306, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31783990

RESUMO

The 2018 Nobel Prize in Physiology or Medicine was awarded to Tasuku Honjo and James Allison for their discoveries in cancer immunology. Professor Honjo was awarded due to his discovery of the programmed death molecule-1 (PD-1) on T cells. Professor Allison discovered another important immunosuppressive molecule: cytotoxic T-lymphocyte antigen-4 (CTLA-4). Suppression of T cell activation by PD-1 and/or CTLA-4 is considered one of the major escape mechanisms of cancer cells. Inhibition of these molecules by immune checkpoint inhibitors can successfully activate the immune system to fight cancer. Checkpoint inhibitors have brought about a major breakthrough in cancer immunotherapy, reviving the hope of curing patients with end-stage cancer, including a wide variety of cancer types. In metastatic malignant melanoma, the previous long-term survival of only 5% can now be extended to 50% with anti-PD-1 plus anti-CTLA-4 combined treatment in the latest report. More checkpoint molecules such as lymphocyte-activation gene 3 and T cell immunoglobulin and mucin domain 3 are under investigation. The achievement of Drs. Honjo and Allison in cancer immunotherapy has encouraged research into other immune-pathological diseases.


Assuntos
Imunoterapia , Ativação Linfocitária/imunologia , Neoplasias/terapia , Prêmio Nobel , Distinções e Prêmios , Antígeno CTLA-4/efeitos dos fármacos , Antígeno CTLA-4/imunologia , Humanos , Fatores Imunológicos/imunologia , Ativação Linfocitária/efeitos dos fármacos , Melanoma/tratamento farmacológico , Melanoma/imunologia , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/imunologia
9.
Rev. Hosp. Ital. B. Aires (2004) ; 39(4): 146-148, dic. 2019. ilus
Artigo em Espanhol | LILACS | ID: biblio-1099838

RESUMO

Los anticuerpos monoclonales que inhiben los puntos de control PD-1 y CTLA-4 se usan actualmente en el tratamiento del melanoma y cáncer metastásico de pulmón de células no pequeñas, entre otros. Se refiere el caso de una paciente con cáncer de pulmón en tratamiento con pembrolizumab. La paciente se presentó con edema facial y parálisis facial periférica. En el laboratorio se observó la hormona tirotrofina (TSH) elevada y se llegó al diagnóstico de hipotiroidismo por pembrolizumab. Inició tratamiento con levotiroxina con mejoría clínica. Se presenta este caso por el importante papel del dermatólogo en el manejo multidisciplinario del paciente oncológico. (AU)


Monoclonal antibodies that inhibit PD-1 and CTLA-4 control points are currently used in the treatment of melanoma and metastatic non-small cell lung cancer, among others. The case of a patient, with lung cancer being treated with Pembrolizumab. The patient was presented with facial edema and peripheral facial paralysis and in the laboratory the elevated hormone Tyrotrophin (TSH) was observed, the diagnosis of pembrolizumab hypothyroidism was reached. She started treatment with levothyroxine with clinical improvement. This case is presented by the important role of the dermatologist in the multidisciplinary management of the cancer patient. (AU)


Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Imunoterapia/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Tiroxina/uso terapêutico , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/tratamento farmacológico , Tireotropina/análise , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proteínas Supressoras de Tumor/efeitos dos fármacos , Dermatologia , Traumatismos Faciais , Paralisia Facial , Antígeno CTLA-4/efeitos dos fármacos , Antígeno CTLA-4/fisiologia , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Receptor de Morte Celular Programada 1/fisiologia , Pemetrexede/administração & dosagem , Melanoma/complicações , Melanoma/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Metástase Neoplásica/tratamento farmacológico
10.
JCI Insight ; 4(19)2019 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-31578309

RESUMO

Immune checkpoint blockade has revolutionized cancer treatment. Patients developing immune mediated adverse events, such as colitis, appear to particularly benefit from immune checkpoint inhibition. Yet, the contributing mechanisms are largely unknown. We identified a systemic LPS signature in melanoma patients with colitis following anti-cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4) checkpoint inhibitor treatment and hypothesized that intestinal microbiota-derived LPS contributes to therapeutic efficacy. Because activation of immune cells within the tumor microenvironment is considered most promising to effectively control cancer, we analyzed human and murine melanoma for known sentinels of LPS. We identified mast cells (MCs) accumulating in and around melanomas and showed that effective melanoma immune control was dependent on LPS-activated MCs recruiting tumor-infiltrating effector T cells by secretion of CXCL10. Importantly, CXCL10 was also upregulated in human melanomas with immune regression and in patients with colitis induced by anti-CTLA-4 antibody. Furthermore, we demonstrate that CXCL10 upregulation and an MC signature at the site of melanomas are biomarkers for better patient survival. These findings provide conclusive evidence for a "Trojan horse treatment strategy" in which the plasticity of cancer-resident immune cells, such as MCs, is used as a target to boost tumor immune defense.


Assuntos
Antineoplásicos/imunologia , Antineoplásicos/farmacologia , Antígeno CTLA-4/efeitos dos fármacos , Mastócitos/efeitos dos fármacos , Melanoma/tratamento farmacológico , Animais , Biomarcadores Tumorais , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Quimiocina CXCL10/metabolismo , Quimiocinas , Modelos Animais de Doenças , Humanos , Imunoterapia , Mastócitos/patologia , Melanoma/imunologia , Melanoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microambiente Tumoral/efeitos dos fármacos
11.
Clin Immunol ; 197: 118-129, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30248398

RESUMO

Endotoxin tolerance is an important state for the prevention of lethal infection and inflammatory response, which is closely associated with the participation of innate immune cells. Moreover, mesenteric lymph nodes (MLNs)-resident immune cells, such as CD4+Foxp3+ regulatory T (Treg) cells and dendritic cells, play important roles in the maintenance of peripheral immune tolerance. However, the potential roles of these cells in MLNs in the development of endotoxin tolerance remain largely unknown. Recent research work showed that CD4+Foxp3+ Treg cells contributed to the development of endotoxin tolerance. Here, we further analyzed the possible change on CD4+Foxp3+Tregs population in MLNs in murine LPS-induced endotoxin tolerance model. Our data showed that the proportion and absolute number of CD4+Foxp3+Tregs, expressing altered levels of CTLA4 and GITR, significantly increased in MLNs of murine LPS-induced tolerance model. Moreover, the expression level of TGF-ß in MLNs also increased obviously. Furthermore, TGF-ß blockade could obviously reduce the proportion and absolute number of CD4+Foxp3+Tregs in MLNs and subsequently impair the protection effect against LPS rechallenge. Of note, we found that tolerogenic dendritic cell (Tol-DC), expressing lower levels of MHC-II and CD86 molecules, dominantly secreted TGF-ß in MLNs in murine LPS-induced tolerance model. In all, our data provided an unknown phenomenon that the total cell number of CD4+Foxp3+Tregs significantly increased in MLNs in endotoxin tolerance, which was related to MLN-resident TGF-ß secreting CD11c+DCs, providing a new fundamental basis for the understanding on the potential roles of MLN-resident immune cells in the development of endotoxin tolerance.


Assuntos
Células Dendríticas/imunologia , Tolerância Imunológica/imunologia , Linfonodos/imunologia , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta/imunologia , Animais , Antígenos CD11 , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Antígeno CTLA-4/efeitos dos fármacos , Antígeno CTLA-4/imunologia , Citocinas/efeitos dos fármacos , Citocinas/genética , Citocinas/imunologia , Células Dendríticas/efeitos dos fármacos , Fatores de Transcrição Forkhead , Proteína Relacionada a TNFR Induzida por Glucocorticoide/efeitos dos fármacos , Proteína Relacionada a TNFR Induzida por Glucocorticoide/imunologia , Tolerância Imunológica/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Linfonodos/citologia , Linfonodos/efeitos dos fármacos , Mesentério , Camundongos , Fenótipo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T Reguladores/efeitos dos fármacos , Fator de Crescimento Transformador beta/efeitos dos fármacos , Fator de Crescimento Transformador beta/genética
12.
Sci Rep ; 8(1): 13543, 2018 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-30201974

RESUMO

T lymphocytes have a crucial role in initiating and promoting type I allergies. Their responses are tightly regulated by numerous activating and inhibitory signals provided by APCs. Here we have addressed the role of the major coinhibitory receptors PD-1, CTLA-4, BTLA and LAG-3 in allergen-specific CD4+ T cell responses. PBMCs of healthy individuals and 41 patients allergic to house dust mites, birch, grass or mugwort pollen were stimulated with allergenic extracts and expression of coinhibitory receptors on responding CD4+ T cells was assessed. Blocking antibodies to PD-1, CTLA-4, BTLA and LAG-3 were used to evaluate the role of coinhibitory pathways. Allergen-specific CD4+ T cells showed strong upregulation of PD-1, LAG-3 and CTLA-4 upon stimulation, whereas BTLA was downregulated. Blockade of PD-1 strongly enhanced proliferation and cytokine production (IL-10; TH1 cytokines IFN-γ, TNF-α; TH2 cytokines IL-5, IL-13) of allergen-specific CD4+ T cells derived from allergic as well as non-allergic individuals. BTLA blockade enhanced proliferation but not cytokine production in response to house dust mite extract. Blocking LAG-3 was ineffective and surprisingly, we observed reduced proliferation and cytokine production in presence of a CTLA-4 antibody. Our results point to a unique potency of PD-1 pathways to dampen allergen-specific human T cells.


Assuntos
Alérgenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Hipersensibilidade/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais/imunologia , Adulto , Antígenos CD/efeitos dos fármacos , Antígenos CD/imunologia , Antígenos CD/metabolismo , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Antígeno CTLA-4/efeitos dos fármacos , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/metabolismo , Proliferação de Células/efeitos dos fármacos , Estudos de Coortes , Citocinas/imunologia , Citocinas/metabolismo , Regulação para Baixo/imunologia , Feminino , Voluntários Saudáveis , Humanos , Hipersensibilidade/sangue , Hipersensibilidade/tratamento farmacológico , Ativação Linfocitária , Masculino , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Receptores Imunológicos/efeitos dos fármacos , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/imunologia , Proteína do Gene 3 de Ativação de Linfócitos
13.
JCI Insight ; 3(13)2018 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-29997292

RESUMO

Recent years have witnessed the groundbreaking success of immune checkpoint blockage (ICB) in metastasized malignant melanoma. However, biomarkers predicting the response to ICB are still urgently needed. In the present study, we investigated CTLA4 promoter methylation (mCTLA4) in 470 malignant melanoma patients from The Cancer Genome Atlas (non-ICB cohort) and in 50 individuals with metastasized malignant melanomas under PD-1/CTLA-4-targeted immunotherapy (ICB cohort). mCTLA4 levels were quantified using the Infinium HumanMethylation450 BeadChip (non-ICB cohort) and methylation-specific quantitative real-time PCR in DNA formalin-fixed and paraffin-embedded tissues (ICB cohort). Methylation levels were associated with molecular and clinicopathological variables and analyzed with respect to response (irRECIST) and overall survival. CTLA-4 mRNA and mCTLA4 showed a significant inverse correlation (non-ICB cohort: Spearman's ρ = -0.416, P < 0.001). In ICB-treated melanoma patients, low mCTLA4 was further strongly correlated with response to therapy (P = 0.009, ANOVA) and overall survival (hazard ratio = 2.06 [95% CI: 1.29-3.29], P = 0.003). Our data strongly support the assumption that mCTLA4 predicts response to both anti-PD-1 and anti-CTLA-4 targeted ICB in melanoma and provides paramount information for the selection of patients likely to respond to ICB.


Assuntos
Antígeno CTLA-4/imunologia , Imunoterapia , Melanoma/imunologia , Receptor de Morte Celular Programada 1/imunologia , Antígeno CTLA-4/efeitos dos fármacos , Antígeno CTLA-4/genética , Antígeno CTLA-4/metabolismo , Epigenômica , Humanos , Estimativa de Kaplan-Meier , Melanoma/terapia , Metilação , Receptor de Morte Celular Programada 1/efeitos dos fármacos , RNA Mensageiro/metabolismo , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/terapia , Melanoma Maligno Cutâneo
14.
World J Urol ; 36(11): 1727-1740, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29855698

RESUMO

PURPOSE: Over the past 3 decades, no major treatment breakthrough has been reported for advanced bladder cancer. Recent Food and Drug Administration (FDA) approval of five immune checkpoint inhibitors in the management of advanced bladder cancer represent new therapeutic opportunities. This review examines the available data of the clinical trials leading to the approval of ICIs in the management of metastatic bladder cancer and the ongoing trials in advanced and localized settings. METHODS: A literature search was performed on PubMed and ClinicalTrials.gov combining the MeSH terms: 'urothelial carcinoma' OR 'bladder cancer', and 'immunotherapy' OR 'CTLA-4' OR 'PD-1' OR 'PD-L1' OR 'atezolizumab' OR 'nivolumab' OR 'ipilimumab' OR 'pembrolizumab' OR 'avelumab' OR 'durvalumab' OR 'tremelimumab'. Prospectives studies evaluating anti-PD(L)1 and anti-CTLA-4 monoclonal antibodies were included. RESULTS: Evidence-data related to early phase and phase III trials evaluating the 5 ICIs in the advanced urothelial carcinoma are detailed in this review. Anti-tumour activity of the 5 ICIs supporting the FDA approval in the second-line setting are reported. The activity of PD(L)1 inhibitors in the first-line setting in cisplatin-ineligible patients are also presented. Ongoing trials in earlier disease-states including non-muscle-invasive and muscle-invasive bladder cancer are discussed. CONCLUSIONS: Blocking the PD-1 negative immune receptor or its ligand, PD-L1, results in unprecedented rates of anti-tumour activity in patients with metastatic urothelial cancer. However, a large majority of patients do not respond to anti-PD(L)1 drugs monotherapy. Investigations exploring the potential value of predictive biomarkers, optimal combination and sequences are ongoing to improve such treatment strategies.


Assuntos
Antígeno CTLA-4/efeitos dos fármacos , Carcinoma de Células de Transição/terapia , Fatores Imunológicos/uso terapêutico , Imunoterapia/métodos , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Neoplasias da Bexiga Urinária/terapia , Biomarcadores/metabolismo , Antígeno CTLA-4/metabolismo , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/patologia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Terapia de Alvo Molecular , Prognóstico , Receptor de Morte Celular Programada 1/metabolismo , Medição de Risco , Análise de Sobrevida , Resultado do Tratamento , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia
15.
Bull Hosp Jt Dis (2013) ; 75(3): 155-163, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28902599

RESUMO

Psoriasis is a common autoimmune disorder that affects the skin. Approximately 30% of individuals with psoriasis will develop inflammatory arthritis, often in the setting of human leukocyte antigen B27. Both forms of disease are thought to be the result of prolonged inflammation mediated by T lymphocytes, dendritic cells, and keratinocytes. While there are treatments aimed at immunomodulation, targeting T cell co-inhibitory receptors signaling pathways may provide therapeutic benefit. This review will discuss in detail four T cell co-inhibitory receptors and their potential application for the treatment of psoriasis and psoriatic arthritis.


Assuntos
Antígenos CD/fisiologia , Antígeno CTLA-4/fisiologia , Receptor Celular 2 do Vírus da Hepatite A/fisiologia , Receptor de Morte Celular Programada 1/fisiologia , Psoríase/terapia , Antígenos CD/efeitos dos fármacos , Antígeno CTLA-4/efeitos dos fármacos , Receptor Celular 2 do Vírus da Hepatite A/efeitos dos fármacos , Humanos , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Psoríase/imunologia , Transdução de Sinais , Proteína do Gene 3 de Ativação de Linfócitos
16.
J Cutan Pathol ; 44(12): 1080-1086, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28901560

RESUMO

Immunotherapies targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1) receptor and its ligand (PD-L1) have showed substantial therapeutic benefit in patients with clinically advanced solid malignancies. However, autoimmune toxicities are common and often significant adverse events with these agents. While rash and pruritus remain the most common cutaneous complications in treated patients, novel dermatologic toxicities related to immune checkpoint blockade continue to emerge as the number of patients exposed to immunotherapy increases. Here, we describe 2 patients treated with combination immunotherapy with ipilimumab and nivolumab who developed painful subcutaneous nodules. Although the findings were clinically concerning for disease recurrence, histopathologic examination of biopsies from the lesions revealed a subcutaneous mixed septal and lobular erythema nodosum-like panniculitis. Notably, neither patient received immunosuppressive therapy for these lesions, which subsequently remained stable, and both patients' cancer remained controlled. These cases show that the dermatologic toxicity profile of immune checkpoint blockade is diverse and continues to expand, and illustrates that recognition of such toxicities is critical to optimal patient management.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Toxidermias/patologia , Eritema Nodoso/induzido quimicamente , Imunoterapia/efeitos adversos , Ipilimumab/efeitos adversos , Paniculite/induzido quimicamente , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1/efeitos dos fármacos , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/efeitos dos fármacos , Antígeno CTLA-4/metabolismo , Eritema Nodoso/patologia , Feminino , Humanos , Imunoterapia/métodos , Ipilimumab/uso terapêutico , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/complicações , Nivolumabe , Paniculite/patologia , Receptor de Morte Celular Programada 1/metabolismo
17.
Magy Onkol ; 61(2): 116-125, 2017 Jun 06.
Artigo em Húngaro | MEDLINE | ID: mdl-28585612

RESUMO

Cancer immunotherapy is coming of age, as outstanding results can be achieved in the therapy of cancer with poor prognosis by altering the patients' immune system and by promoting the immune response against tumours. Amongst immunotherapies, the immune checkpoint inhibitors (ICI) proved to be the most effective, primarily in the treatment of solid tumours, including melanoma, non-small cell lung carcinoma, and classical Hodgkin's lymphoma. The reason for this efficacy is the immunosuppressive microenvironment typical for many cancer types, directly and indirectly inhibiting effector T-cell responses. To date, three cytotoxic T-lymphocyte antigen 4 (CTLA-4) or programmed cell death protein 1 (PD-1) checkpoint inhibitors have been approved in Europe, and six in the USA. Furthermore, an increasing number of these drugs is available in the setting of clinical trials. For the optimal use of the numerous different ICIs there is an ever increasing need to identify reliable predictive biomarkers and to explore therapy-associated resistance mechanisms, which will represent the main challenge of the next years.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno CTLA-4/genética , Neoplasias Pulmonares/tratamento farmacológico , Receptor de Morte Celular Programada 1/genética , Microambiente Tumoral/efeitos dos fármacos , Anticorpos Monoclonais Humanizados/farmacologia , Antígeno CTLA-4/efeitos dos fármacos , Previsões , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/patologia , Humanos , Hungria , Fatores Imunológicos/uso terapêutico , Imunoterapia/métodos , Imunoterapia/tendências , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Terapia de Alvo Molecular , Prognóstico , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Medição de Risco , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Resultado do Tratamento , Microambiente Tumoral/imunologia
18.
J Surg Oncol ; 116(1): 55-62, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28628715

RESUMO

Immunotherapy has become a new modality of cancer treatment, but has had a limited success in treating PDAC. A combination approach to immunotherapy, using both immune checkpoint inhibitors and immune activating agonists, is needed, as PDAC does not respond to single-agent checkpoint inhibitors. Studies have also supported using vaccine-based therapies to prime the tumor microenvironment of PDAC with effector T-cells. Other therapeutic strategies including epigenetic agents, stroma modulators, radiotherapy, and T-cell transfer therapies may also prime the tumor microenvironment to overcome resistance to immune checkpoint inhibitors.


Assuntos
Imunoterapia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/terapia , Anticorpos Monoclonais/farmacologia , Antígenos CD/efeitos dos fármacos , Antígenos CD/imunologia , Antígenos CD/metabolismo , Antígeno B7-H1/efeitos dos fármacos , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Antígeno CTLA-4/efeitos dos fármacos , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/metabolismo , Vacinas Anticâncer , Citocinas/farmacologia , Humanos , Ipilimumab , Macrófagos/metabolismo , Células Supressoras Mieloides/metabolismo , Neoplasias Pancreáticas/metabolismo , Linfócitos T Reguladores/metabolismo , Microambiente Tumoral , Proteína do Gene 3 de Ativação de Linfócitos
19.
ACS Nano ; 11(5): 4463-4474, 2017 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-28362496

RESUMO

While immunotherapy has become a highly promising paradigm for cancer treatment in recent years, it has long been recognized that photodynamic therapy (PDT) has the ability to trigger antitumor immune responses. However, conventional PDT triggered by visible light has limited penetration depth, and its generated immune responses may not be robust enough to eliminate tumors. Herein, upconversion nanoparticles (UCNPs) are simultaneously loaded with chlorin e6 (Ce6), a photosensitizer, and imiquimod (R837), a Toll-like-receptor-7 agonist. The obtained multitasking UCNP-Ce6-R837 nanoparticles under near-infrared (NIR) irradiation with enhanced tissue penetration depth would enable effective photodynamic destruction of tumors to generate a pool of tumor-associated antigens, which in the presence of those R837-containing nanoparticles as the adjuvant are able to promote strong antitumor immune responses. More significantly, PDT with UCNP-Ce6-R837 in combination with the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint blockade not only shows excellent efficacy in eliminating tumors exposed to the NIR laser but also results in strong antitumor immunities to inhibit the growth of distant tumors left behind after PDT treatment. Furthermore, such a cancer immunotherapy strategy has a long-term immune memory function to protect treated mice from tumor cell rechallenge. This work presents an immune-stimulating UCNP-based PDT strategy in combination with CTLA-4 checkpoint blockade to effectively destroy primary tumors under light exposure, inhibit distant tumors that can hardly be reached by light, and prevent tumor reoccurrence via the immune memory effect.


Assuntos
Neoplasias Colorretais/terapia , Imunoterapia/métodos , Fotoquimioterapia/métodos , Animais , Antígeno CTLA-4/efeitos dos fármacos , Linhagem Celular Tumoral , Clorofilídeos , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/imunologia , Modelos Animais de Doenças , Feminino , Células HeLa , Humanos , Imiquimode , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/administração & dosagem , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas
20.
Diabetes ; 66(2): 448-459, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28108611

RESUMO

The introduction of ß-cell autoantigens via the gut through Lactococcus lactis (L. lactis) has been demonstrated to be a promising approach for diabetes reversal in NOD mice. Here we show that a combination therapy of low-dose anti-CD3 with a clinical-grade self-containing L. lactis, appropriate for human application, secreting human proinsulin and interleukin-10, cured 66% of mice with new-onset diabetes, which is comparable to therapy results with plasmid-driven L. lactis Initial blood glucose concentrations (<350 mg/dL) and insulin autoantibody positivity were predictors of the stable reversal of hyperglycemia, and decline in insulin autoantibody positivity was an immune biomarker of therapeutic outcome. The assessment of the immune changes induced by the L. lactis-based therapy revealed elevated frequencies of CD4+Foxp3+ T cells in the pancreas-draining lymph nodes, pancreas, and peripheral blood of all treated mice, independent of metabolic outcome. Neutralization of cytotoxic T-lymphocyte antigen 4 and transforming growth factor-ß partially abrogated the suppressive function of therapy-induced regulatory T cells (Tregs). Ablation or functional impairment of Foxp3+ Tregs in vivo at the start or stop of therapy impaired immune tolerance, highlighting the dependence of the therapy-induced tolerance in mice with new-onset diabetes on the presence and functionality of CD4+Foxp3+ T cells. Biomarkers identified in this study can potentially be used in the future to tailor the L. lactis-based combination therapy for individual patients.


Assuntos
Anticorpos/farmacologia , Glicemia/efeitos dos fármacos , Diabetes Mellitus/metabolismo , Tolerância Imunológica/efeitos dos fármacos , Interleucina-10/metabolismo , Lactobacillus/metabolismo , Proinsulina/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Anticorpos Neutralizantes/farmacologia , Glicemia/metabolismo , Complexo CD3/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Antígeno CTLA-4/efeitos dos fármacos , Antígeno CTLA-4/imunologia , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/imunologia , Teste de Tolerância a Glucose , Tolerância Imunológica/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos NOD , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta/efeitos dos fármacos , Fator de Crescimento Transformador beta/imunologia
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