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[PMID]: 28789924 [Au] Autor: Mbanwi AN; Lin GHY; Wang KC; Watts TH [Ad] Endereço: Department of Immunology, University of Toronto, Toronto, ON M5S1A8, Canada. [Ti] Título: Constitutive interaction between 4-1BB and 4-1BBL on murine LPS-activated bone marrow dendritic cells masks detection of 4-1BBL by TKS-1 but not 19H3 antibody. [So] Source: J Immunol Methods;450:81-89, 2017 Nov. [Is] ISSN: 1872-7905 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: 4-1BB is a TNFR family member associated with NF-κB mediated survival signaling. 4-1BB is widely expressed on activated cells of the immune system, including activated T cells, NK cells and dendritic cells. Its ligand, 4-1BBL, is transiently expressed on activated antigen presenting cells and at low levels on activated T cells. Although 4-1BBL-deficient mice clearly demonstrate a role for 4-1BBL in CD8 T cell responses to viruses such as influenza, 4-1BBL can be difficult to detect following infection of mice. Here we provide evidence for a constitutive interaction between endogenous 4-1BB and 4-1BBL on LPS activated bone marrow-derived murine dendritic cells that can mask its detection, with implications for measurement of 4-1BBL expression. The masking of 4-1BBL by its receptor results in loss of reactivity to the anti-4-1BBL antibody TKS-1, whereas the 19H3 antibody binds to 4-1BBL in the presence or absence of 4-1BB. Moreover, 4-1BB/4-1BBL interaction can occur in trans between 4-1BB and 4-1BB dendritic cells in culture. These data suggest that 19H3 is the preferable antibody to use to detect 4-1BBL in the presence of its receptor. [Mh] Termos MeSH primário: Ligante 4-1BB/imunologia Anticorpos/imunologia Células da Medula Óssea/efeitos dos fármacos Separação Celular/métodos Células Dendríticas/efeitos dos fármacos Citometria de Fluxo Lipopolissacarídeos/farmacologia Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia [Mh] Termos MeSH secundário: Ligante 4-1BB/genética Ligante 4-1BB/metabolismo Animais Especificidade de Anticorpos Células da Medula Óssea/imunologia Células da Medula Óssea/metabolismo Células Cultivadas Células Dendríticas/imunologia Células Dendríticas/metabolismo Epitopos Genótipo Camundongos Camundongos Endogâmicos C57BL Camundongos Knockout Fenótipo Ligação Proteica Reprodutibilidade dos Testes Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (4-1BB Ligand); 0 (Antibodies); 0 (Epitopes); 0 (Lipopolysaccharides); 0 (Tnfrsf9 protein, mouse); 0 (Tnfsf9 protein, mouse); 0 (Tumor Necrosis Factor Receptor Superfamily, Member 9) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170810 [St] Status: MEDLINE

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[PMID]: 28363905 [Au] Autor: Forsberg MH; Ciecko AE; Bednar KJ; Itoh A; Kachapati K; Ridgway WM; Chen YG [Ad] Endereço: Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226. [Ti] Título: CD137 Plays Both Pathogenic and Protective Roles in Type 1 Diabetes Development in NOD Mice. [So] Source: J Immunol;198(10):3857-3868, 2017 May 15. [Is] ISSN: 1550-6606 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: We previously reported that CD137 (encoded by ) deficiency suppressed type 1 diabetes (T1D) progression in NOD mice. We also demonstrated that soluble CD137 produced by regulatory T cells contributed to their autoimmune-suppressive function in this model. These results suggest that CD137 can either promote or suppress T1D development in NOD mice depending on where it is expressed. In this study, we show that NOD. CD8 T cells had significantly reduced diabetogenic capacity, whereas absence of CD137 in non-T and non-B cells had a limited impact on T1D progression. In contrast, NOD. CD4 T cells highly promoted T1D development. We further demonstrated that CD137 was important for the accumulation of ß cell-autoreactive CD8 T cells but was dispensable for their activation in pancreatic lymph nodes. The frequency of islet-infiltrating CD8 T cells was reduced in NOD. mice in part because of their decreased proliferation. Furthermore, CD137 deficiency did not suppress T1D development in NOD mice expressing the transgenic NY8.3 CD8 TCR. This suggests that increased precursor frequency of ß cell-autoreactive CD8 T cells in NY8.3 mice obviated a role for CD137 in diabetogenesis. Finally, blocking CD137-CD137 ligand interaction significantly delayed T1D onset in NOD mice. Collectively, our results indicate that one important diabetogenic function of CD137 is to promote the expansion and accumulation of ß cell-autoreactive CD8 T cells, and in the absence of CD137 or its interaction with CD137 ligand, T1D progression is suppressed. [Mh] Termos MeSH primário: Diabetes Mellitus Tipo 1/imunologia Diabetes Mellitus Tipo 1/fisiopatologia Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo [Mh] Termos MeSH secundário: Ligante 4-1BB/antagonistas & inibidores Ligante 4-1BB/metabolismo Animais Linfócitos T CD8-Positivos/imunologia Proliferação Celular Progressão da Doença Células Secretoras de Insulina/imunologia Camundongos Camundongos Endogâmicos NOD Camundongos Transgênicos Linfócitos T Reguladores/imunologia Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/deficiência Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (4-1BB Ligand); 0 (Tnfsf9 protein, mouse); 0 (Tumor Necrosis Factor Receptor Superfamily, Member 9) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170402 [St] Status: MEDLINE [do] DOI: 10.4049/jimmunol.1601851

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[PMID]: 28275260 [Au] Autor: Croft M; Siegel RM [Ad] Endereço: Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, and Department of Medicine, University of California San Diego, La Jolla, California 92037, USA. [Ti] Título: Beyond TNF: TNF superfamily cytokines as targets for the treatment of rheumatic diseases. [So] Source: Nat Rev Rheumatol;13(4):217-233, 2017 Apr. [Is] ISSN: 1759-4804 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: TNF blockers are highly efficacious at dampening inflammation and reducing symptoms in rheumatic diseases such as rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, and also in nonrheumatic syndromes such as inflammatory bowel disease. As TNF belongs to a superfamily of 19 structurally related proteins that have both proinflammatory and anti-inflammatory activity, reagents that disrupt the interaction between proinflammatory TNF family cytokines and their receptors, or agonize the anti-inflammatory receptors, are being considered for the treatment of rheumatic diseases. Biologic agents that block B cell activating factor (BAFF) and receptor activator of nuclear factor-κB ligand (RANKL) have been approved for the treatment of systemic lupus erythematosus and osteoporosis, respectively. In this Review, we focus on additional members of the TNF superfamily that could be relevant for the pathogenesis of rheumatic disease, including those that can strongly promote activity of immune cells or increase activity of tissue cells, as well as those that promote death pathways and might limit inflammation. We examine preclinical mouse and human data linking these molecules to the control of damage in the joints, muscle, bone or other tissues, and discuss their potential as targets for future therapy of rheumatic diseases. [Mh] Termos MeSH primário: Terapia de Alvo Molecular Doenças Reumáticas/tratamento farmacológico Doenças Reumáticas/imunologia Fatores de Necrose Tumoral/antagonistas & inibidores Fatores de Necrose Tumoral/metabolismo [Mh] Termos MeSH secundário: Ligante 4-1BB/antagonistas & inibidores Ligante 4-1BB/metabolismo Animais Ligante CD27/antagonistas & inibidores Ligante CD27/metabolismo Ligante de CD40/antagonistas & inibidores Ligante de CD40/metabolismo Morte Celular Citocina TWEAK Células Dendríticas/imunologia Proteína Ligante Fas/antagonistas & inibidores Proteína Ligante Fas/metabolismo Seres Humanos Tolerância Imunológica Ativação Linfocitária Linfotoxina-alfa/antagonistas & inibidores Linfotoxina-alfa/metabolismo Ligante OX40/antagonistas & inibidores Ligante OX40/metabolismo Transdução de Sinais Linfócitos T/imunologia Ligante Indutor de Apoptose Relacionado a TNF/antagonistas & inibidores Ligante Indutor de Apoptose Relacionado a TNF/metabolismo Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidores Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidores Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo Fatores de Necrose Tumoral/imunologia [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (4-1BB Ligand); 0 (CD27 Ligand); 0 (Cytokine TWEAK); 0 (Fas Ligand Protein); 0 (Lymphotoxin-alpha); 0 (OX40 Ligand); 0 (TNF-Related Apoptosis-Inducing Ligand); 0 (TNFSF12 protein, human); 0 (TNFSF18 protein, human); 0 (Tumor Necrosis Factor Ligand Superfamily Member 14); 0 (Tumor Necrosis Factor Ligand Superfamily Member 15); 0 (Tumor Necrosis Factors); 147205-72-9 (CD40 Ligand) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170310 [St] Status: MEDLINE [do] DOI: 10.1038/nrrheum.2017.22

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[PMID]: 28074529 [Au] Autor: Cacan E [Ad] Endereço: Department of Molecular Biology Genetics, Gaziosmanpasa University, Tokat, 60250, Turkey. [Ti] Título: Epigenetic-mediated immune suppression of positive co-stimulatory molecules in chemoresistant ovarian cancer cells. [So] Source: Cell Biol Int;41(3):328-339, 2017 Mar. [Is] ISSN: 1095-8355 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The immunological response against cancer is a critical balance between immune-activating and immune-suppressing mechanisms. Ovarian cancer creates a suppressive microenvironment to escape immune elimination; however, the molecular mechanisms are poorly understood, and it is unclear whether chemotherapeutic drugs exert an immunoreactive or immunosuppressive effect on the tumor microenvironment. 4-1BB ligand (4-1BBL/CD157) and OX-40 ligand (OX-40L/CD252) are important regulators of effector cytotoxic T-cells activity. This study demonstrates that expression of positive co-stimulatory molecules, OX-40L and 4-1BBL, is suppressed while expression of immunosuppressive molecule programmed death ligand-1 (PD-L1/CD274) is enhanced in chemoresistant cells compared to parental chemosensitive ovarian cancer cells. Here, the molecular mechanisms of silencing of OX-40L and 4-1BBL expression were investigated in chemoresistant A2780-AD ovarian cancer cells. The suppression of OX-40L and 4-1BBL are due to DNA hypermethylation and histone deacetylation, two important mechanisms that contribute to gene silencing during cancer progression. We identify important epigenetic regulators, histone deacetylase 1/3 (HDAC1/HDAC3) and DNA methyltransferase 1 (DNMT1), that exhibit aberrant association with OX-40L and 4-1BBL promoters in chemoresistant ovarian cancer cells. Knockdown of HDAC1 or DNMT1 expression, and pharmacological inhibition of DNMT or HDAC enzymatic activity, significantly increase OX-40L and 4-1BBL expression in chemoresistant cells. This study suggests that loss of histone acetylation and accumulation of DNA methylation correlates with suppressed expression of OX-40L and 4-1BBL in chemoresistant ovarian cancer cells. This study marks the first report of the regulation of these two molecules by histone deacetylation and DNA methylation in chemoresistant ovarian cancer cells. [Mh] Termos MeSH primário: Antineoplásicos/farmacologia Resistência a Medicamentos Antineoplásicos/fisiologia Epigênese Genética/fisiologia Tolerância Imunológica/fisiologia Neoplasias Ovarianas/imunologia [Mh] Termos MeSH secundário: Ligante 4-1BB/biossíntese Ligante 4-1BB/imunologia Linhagem Celular Tumoral Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos Epigênese Genética/efeitos dos fármacos Feminino Seres Humanos Tolerância Imunológica/efeitos dos fármacos Ligante OX40/biossíntese Ligante OX40/imunologia Neoplasias Ovarianas/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (4-1BB Ligand); 0 (Antineoplastic Agents); 0 (OX40 Ligand); 0 (TNFSF4 protein, human) [Em] Mês de entrada: 1702 [Cu] Atualização por classe: 170222 [Lr] Data última revisão: 170222 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170112 [St] Status: MEDLINE [do] DOI: 10.1002/cbin.10729

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[PMID]: 28074066 [Au] Autor: Chen KH; Wada M; Pinz KG; Liu H; Lin KW; Jares A; Firor AE; Shuai X; Salman H; Golightly M; Lan F; Senzel L; Leung EL; Jiang X; Ma Y [Ad] Endereço: iCell Gene Therapeutics LLC, Research &Development Division, Long Island High Technology Incubator, Stony Brook, NY, USA. [Ti] Título: Preclinical targeting of aggressive T-cell malignancies using anti-CD5 chimeric antigen receptor. [So] Source: Leukemia;31(10):2151-2160, 2017 Oct. [Is] ISSN: 1476-5551 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The outlook for T-cell malignancies remain poor due to the lack of effective therapeutic options. Chimeric antigen receptor (CAR) immunotherapy has recently shown promise in clinical trials for B-cell malignancies, however, designing CARs for T-cell based disease remain a challenge due to the shared surface antigen pool between normal and malignant T-cells. Normal T-cells express CD5 but NK (natural killer) cells do not, positioning NK cells as attractive cytotoxicity cells for CD5CAR design. Additionally, CD5 is highly expressed in T-cell acute lymphoblastic leukemia (T-ALL) and peripheral T-cell lymphomas (PTCLs). Here, we report a robust anti-CD5 CAR (CD5CAR) transduced into a human NK cell line NK-92 that can undergo stable expansion ex vivo. We found that CD5CAR NK-92 cells possessed consistent, specific, and potent anti-tumor activity against a variety of T-cell leukemia and lymphoma cell lines as well as primary tumor cells. Furthermore, we were able to demonstrate significant inhibition and control of disease progression in xenograft mouse models of T-ALL. The data suggest that CAR redirected targeting for T-cell malignancies using NK cells may be a viable method for new and complementary therapeutic approaches that could improve the current outcome for patients. [Mh] Termos MeSH primário: Antígenos de Neoplasias/imunologia Antígenos CD5/imunologia Imunoterapia Adotiva/métodos Células Matadoras Naturais/imunologia Linfoma de Células T Periférico/terapia Terapia de Alvo Molecular Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia Proteínas Recombinantes de Fusão/imunologia [Mh] Termos MeSH secundário: Ligante 4-1BB/genética Ligante 4-1BB/imunologia Animais Antígenos CD28/imunologia Complexo CD3/genética Complexo CD3/imunologia Antígenos CD8/imunologia Linhagem Celular Tumoral Técnicas de Cocultura Citotoxicidade Imunológica Seres Humanos Células Matadoras Naturais/transplante Linfoma de Células T Periférico/patologia Camundongos Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia Terapia de Salvação Anticorpos de Cadeia Única/genética Anticorpos de Cadeia Única/imunologia Transdução Genética Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia Ensaios Antitumorais Modelo de Xenoenxerto [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (4-1BB Ligand); 0 (Antigens, Neoplasm); 0 (CD28 Antigens); 0 (CD3 Complex); 0 (CD3 antigen, zeta chain); 0 (CD5 Antigens); 0 (CD8 Antigens); 0 (Recombinant Fusion Proteins); 0 (Single-Chain Antibodies); 0 (TNFRSF9 protein, human); 0 (Tumor Necrosis Factor Receptor Superfamily, Member 9) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170112 [St] Status: MEDLINE [do] DOI: 10.1038/leu.2017.8

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[PMID]: 28067900 [Au] Autor: Ghosh A; Smith M; James SE; Davila ML; Velardi E; Argyropoulos KV; Gunset G; Perna F; Kreines FM; Levy ER; Lieberman S; Jay HV; Tuckett AZ; Zakrzewski JL; Tan L; Young LF; Takvorian K; Dudakov JA; Jenq RR; Hanash AM; Motta AC; Murphy GF; Liu C; Schietinger A; Sadelain M; van den Brink MR [Ad] Endereço: Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA. [Ti] Título: Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity. [So] Source: Nat Med;23(2):242-249, 2017 Feb. [Is] ISSN: 1546-170X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies. However, graft-versus-host disease (GVHD) and relapse after allo-HSCT remain major impediments to the success of allo-HSCT. Chimeric antigen receptors (CARs) direct tumor cell recognition of adoptively transferred T cells. CD19 is an attractive CAR target, which is expressed in most B cell malignancies, as well as in healthy B cells. Clinical trials using autologous CD19-targeted T cells have shown remarkable promise in various B cell malignancies. However, the use of allogeneic CAR T cells poses a concern in that it may increase risk of the occurrence of GVHD, although this has not been reported in selected patients infused with donor-derived CD19 CAR T cells after allo-HSCT. To understand the mechanism whereby allogeneic CD19 CAR T cells may mediate anti-lymphoma activity without causing a significant increase in the incidence of GVHD, we studied donor-derived CD19 CAR T cells in allo-HSCT and lymphoma models in mice. We demonstrate that alloreactive T cells expressing CD28-costimulated CD19 CARs experience enhanced stimulation, resulting in the progressive loss of both their effector function and proliferative potential, clonal deletion, and significantly decreased occurrence of GVHD. Concurrently, the other CAR T cells that were present in bulk donor T cell populations retained their anti-lymphoma activity in accordance with the requirement that both the T cell receptor (TCR) and CAR be engaged to accelerate T cell exhaustion. In contrast, first-generation and 4-1BB-costimulated CAR T cells increased the occurrence of GVHD. These findings could explain the reduced risk of GVHD occurring with cumulative TCR and CAR signaling. [Mh] Termos MeSH primário: Reação Enxerto-Hospedeiro/imunologia Efeito Enxerto vs Tumor/imunologia Transplante de Células-Tronco Hematopoéticas Linfoma/imunologia Receptores de Antígenos de Linfócitos T/imunologia Linfócitos T/imunologia [Mh] Termos MeSH secundário: Ligante 4-1BB/imunologia Transferência Adotiva Animais Antígenos CD19/metabolismo Linfócitos B/imunologia Antígenos CD28 Quimera Citocinas/imunologia Modelos Animais de Doenças Citometria de Fluxo Doença Enxerto-Hospedeiro/imunologia Camundongos Linfócitos T/metabolismo Transplante Homólogo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (4-1BB Ligand); 0 (Antigens, CD19); 0 (CD28 Antigens); 0 (Cytokines); 0 (Receptors, Antigen, T-Cell) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170110 [St] Status: MEDLINE [do] DOI: 10.1038/nm.4258

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[PMID]: 27942918 [Au] Autor: Das A; McDonald D; Lowe S; Bredlau AL; Vanek K; Patel SJ; Cheshier S; Eskandari R [Ad] Endereço: Department of Neurosurgery and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina, Charleston, SC, 29425, USA. dasa@musc.edu. [Ti] Título: Immunological low-dose radiation modulates the pediatric medulloblastoma antigens and enhances antibody-dependent cellular cytotoxicity. [So] Source: Childs Nerv Syst;33(3):429-436, 2017 Mar. [Is] ISSN: 1433-0350 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: BACKGROUND: Immunotherapy can be an effective treatment for pediatric medulloblastoma (MB) patients. However, major subpopulations do not respond to immunotherapy, due to the lack of antigenic mutations or the immune-evasive properties of MB cells. Clinical observations suggest that radiation therapy (RT) may expand the therapeutic reach of immunotherapy. The aim of the present investigation is to study the effect of low-dose X-ray radiation (LDXR, 1 Gy) on the functional immunological responses of MB cells (DAOY, D283, and D341). METHODS: Induction of MB cell death was examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Production of reactive oxygen species (ROS) was measured by fluorescent probes. Changes in the expression of  human leukocyte antigen (HLA) molecules and caspase-3 activities during treatment were analyzed using Western blotting and caspase-3 assay. RESULTS: Western blot analysis demonstrated that LDXR upregulated the expression of HLA class I and HLA II molecules by more than 20% compared with control and high-dose (12 Gy) groups in vitro. Several of these HLA subtypes, such as MAGE C1, CD137, and ICAM-1, have demonstrated upregulation. In addition, LDXR increases ROS production in association with phosphorylation of NF-κB and cell surface expression of mAb target molecules (HER2 and VEGF). These data suggest that a combined LDXR and mAb therapy can create a synergistic effect in vitro. CONCLUSION: These results suggest that LDXR modulates HLA molecules, leading to alterations in T-cell/tumor-cell interaction and enhancement of T-cell-mediated MB cell death. Also, low-dose radiotherapy combined with monoclonal antibody therapy may one day augment the standard treatment for MB, but more investigation is needed to prove its utility as a new therapeutic combination for MB patients. [Mh] Termos MeSH primário: Anticorpos Monoclonais/farmacologia Linhagem Celular Tumoral/efeitos da radiação Regulação Neoplásica da Expressão Gênica/efeitos da radiação Antígenos HLA/metabolismo Meduloblastoma/metabolismo Radiação [Mh] Termos MeSH secundário: Ligante 4-1BB/metabolismo Análise de Variância Caspase 3/metabolismo Sobrevivência Celular/efeitos dos fármacos Relação Dose-Resposta à Radiação Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos Antígenos HLA/imunologia Seres Humanos Molécula 1 de Adesão Intercelular/metabolismo Meduloblastoma/patologia NF-kappa B/metabolismo Espécies Reativas de Oxigênio/metabolismo Receptor ErbB-2/imunologia Fatores de Tempo Fator A de Crescimento do Endotélio Vascular/imunologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (4-1BB Ligand); 0 (Antibodies, Monoclonal); 0 (HLA Antigens); 0 (NF-kappa B); 0 (Reactive Oxygen Species); 0 (TNFSF9 protein, human); 0 (Vascular Endothelial Growth Factor A); 126547-89-5 (Intercellular Adhesion Molecule-1); EC 2.7.10.1 (ERBB2 protein, human); EC 2.7.10.1 (Receptor, ErbB-2); EC 3.4.22.- (Caspase 3) [Em] Mês de entrada: 1704 [Cu] Atualização por classe: 170926 [Lr] Data última revisão: 170926 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161213 [St] Status: MEDLINE [do] DOI: 10.1007/s00381-016-3305-x

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[PMID]: 27756788 [Au] Autor: Segal NH; Logan TF; Hodi FS; McDermott D; Melero I; Hamid O; Schmidt H; Robert C; Chiarion-Sileni V; Ascierto PA; Maio M; Urba WJ; Gangadhar TC; Suryawanshi S; Neely J; Jure-Kunkel M; Krishnan S; Kohrt H; Sznol M; Levy R [Ad] Endereço: Memorial Sloan Kettering Cancer Center, New York, New York. [Ti] Título: Results from an Integrated Safety Analysis of Urelumab, an Agonist Anti-CD137 Monoclonal Antibody. [So] Source: Clin Cancer Res;23(8):1929-1936, 2017 04 15. [Is] ISSN: 1078-0432 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Urelumab is an agonist antibody to CD137 with potential application as an immuno-oncology therapeutic. Data were analyzed to assess safety, tolerability, and pharmacodynamic activity of urelumab, including the dose selected for ongoing development in patients with advanced solid tumors and lymphoma. A total of 346 patients with advanced cancers who had progressed after standard treatment received at least one dose of urelumab in one of three dose-escalation, monotherapy studies. Urelumab was administered at doses ranging from 0.1 to 15 mg/kg. Safety analyses included treatment-related and serious adverse events (AEs), as well as treatment-related AEs leading to discontinuation and death, with a focus on liver function test abnormalities and hepatic AEs. Urelumab doses between 1 and 15 mg/kg given every 3 weeks resulted in a higher frequency of treatment-related AEs than 0.1 or 0.3 mg/kg every 3 weeks. Dose was the single most important factor contributing to transaminitis development, which was more frequent and severe at doses ≥1 mg/kg. At the MTD of 0.1 mg/kg every 3 weeks, urelumab was relatively well tolerated, with fatigue (16%) and nausea (13%) being the most common treatment-related AEs, and was associated with immunologic and pharmacodynamic activity demonstrated by the induction of IFN-inducible genes and cytokines. Integrated evaluation of urelumab safety data showed significant transaminitis was strongly associated with doses of ≥1 mg/kg. However, urelumab 0.1 mg/kg every 3 weeks was demonstrated to be safe, with pharmacodynamic activity supporting continued clinical evaluation of this dose as monotherapy and in combination with other immuno-oncology agents. . [Mh] Termos MeSH primário: Ligante 4-1BB/agonistas Anticorpos Monoclonais/efeitos adversos Antineoplásicos/efeitos adversos Neoplasias/tratamento farmacológico [Mh] Termos MeSH secundário: Adulto Idoso Anticorpos Monoclonais/administração & dosagem Anticorpos Monoclonais/farmacocinética Antineoplásicos/administração & dosagem Antineoplásicos/farmacocinética Relação Dose-Resposta a Droga Feminino Seres Humanos Masculino Dose Máxima Tolerável Melanoma/tratamento farmacológico Meia-Idade [Pt] Tipo de publicação: CLINICAL TRIAL, PHASE I; CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (4-1BB Ligand); 0 (Antibodies, Monoclonal); 0 (Antineoplastic Agents); 0 (TNFSF9 protein, human); 0 (urelumab) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 171107 [Lr] Data última revisão: 171107 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161101 [St] Status: MEDLINE [do] DOI: 10.1158/1078-0432.CCR-16-1272

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[PMID]: 27598810 [Au] Autor: Benaduce AP; Brenneman R; Schrand B; Pollack A; Gilboa E; Ishkanian A [Ad] Endereço: Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida. [Ti] Título: 4-1BB Aptamer-Based Immunomodulation Enhances the Therapeutic Index of Radiation Therapy in Murine Tumor Models. [So] Source: Int J Radiat Oncol Biol Phys;96(2):458-461, 2016 Oct 01. [Is] ISSN: 1879-355X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: PURPOSE: To report a novel strategy using oligonucleotide aptamers to 4-1BB as an alternate method for costimulation, and show that combinatorial therapy with radiation improves the therapeutic ratio over equivalent monoclonal antibodies. METHODS AND MATERIALS: Subcutaneous 4T1 (mouse mammary carcinoma) tumors were established (approximately 100 mm(3)), and a radiation therapy (RT) dose/fractionation schedule that optimally synergizes with 4-1BB monoclonal antibody (mAb) was identified. Comparable tumor control and animal survival was observed when either 4-1BB antibody or aptamer were combined with RT using models of breast cancer and melanoma (4T1 and B16-F10). Off-target CD8(+) T-cell toxicity was evaluated by quantification of CD8(+) T cells in livers and spleens of treated animals. RESULTS: When combined with 4-1BB mAb, significant differences in tumor control were observed by varying RT dose and fractionation schedules. Optimal synergy between RT and 4-1BB mAb was observed at 5 Gy × 6. Testing 4-1BB mAb and aptamer independently using the optimal RT (5 Gy × 6 for 4T1/Balb/c and 12 Gy × 1 for B16/C57BL6J mouse models) revealed equivalent tumor control using 4-1BB aptamer and 4-1BB mAb. 4-1BB mAb, but not 4-1BB aptamer-treated animals, exhibited increased lymphocytic liver infiltrates and increased splenic and liver CD8(+) T cells. CONCLUSIONS: Radiation therapy synergizes with 4-1BB mAb, and this effect is dependent on RT dose and fractionation. Tumor control by 4-1BB aptamer is equivalent to 4-1BB mAb when combined with optimal RT dose, without eliciting off-target liver and spleen CD8(+) expansion. 4-1BB aptamer-based costimulation affords a comparable and less toxic strategy to augment RT-mediated tumor control. [Mh] Termos MeSH primário: Ligante 4-1BB/antagonistas & inibidores Aptâmeros de Nucleotídeos/administração & dosagem Quimiorradioterapia/métodos Neoplasias Experimentais/patologia Neoplasias Experimentais/terapia [Mh] Termos MeSH secundário: Ligante 4-1BB/imunologia Animais Linhagem Celular Tumoral Terapia Combinada/métodos Relação Dose-Resposta à Radiação Feminino Fatores Imunológicos/administração & dosagem Camundongos Camundongos Endogâmicos BALB C Tolerância a Radiação/efeitos dos fármacos Radiossensibilizantes/administração & dosagem Radioimunoterapia/métodos Dosagem Radioterapêutica Resultado do Tratamento [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (4-1BB Ligand); 0 (Aptamers, Nucleotide); 0 (Immunologic Factors); 0 (Radiation-Sensitizing Agents) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 170821 [Lr] Data última revisão: 170821 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160907 [St] Status: MEDLINE

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[PMID]: 27346273 [Au] Autor: Yin YJ; Zhong W; Yan JC [Ti] Título: [Research progress of CD137 signaling and CD137L reverse signaling in atherosclerosis]. [So] Source: Zhonghua Xin Xue Guan Bing Za Zhi;44(6):557-60, 2016 Jun 24. [Is] ISSN: 0253-3758 [Cp] País de publicação: China [La] Idioma: chi [Mh] Termos MeSH primário: Ligante 4-1BB/metabolismo Aterosclerose/metabolismo Transdução de Sinais Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo [Mh] Termos MeSH secundário: Seres Humanos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (4-1BB Ligand); 0 (Tumor Necrosis Factor Receptor Superfamily, Member 9) [Em] Mês de entrada: 1612 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160628 [St] Status: MEDLINE [do] DOI: 10.3760/cma.j.issn.0253-3758.2016.06.019

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