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[PMID]:29199989
[Au] Autor:Collins BC; Nakahara H; Acharya S; Cooper MD; Herrin BR; Wilson IA
[Ad] Endereço:Department of Integrative Structural and Computational Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
[Ti] Título:Crystal structure of an anti-idiotype variable lymphocyte receptor.
[So] Source:Acta Crystallogr F Struct Biol Commun;73(Pt 12):682-687, 2017 Dec 01.
[Is] ISSN:2053-230X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Variable lymphocyte receptors (VLRs), the leucine-rich repeat (LRR)-based antigen receptors of jawless fish, have great utility in a wide variety of biochemical and biological applications, similar to classical Ig-based antibodies. VLR-based reagents may be particularly useful when traditional antibodies are not available. An anti-idiotype lamprey VLR, VLR39, has previously been identified that recognizes the heavy-chain CDR3 of the B-cell receptor (BCR) of a leukemic clone from a patient with chronic lymphocytic leukemia (CLL). VLR39 was used successfully to track the re-emergence of this clone in the patient following chemotherapy. Here, the crystal structure of VLR39 is presented at 1.5 Šresolution and compared with those of other protein-specific VLRs. VLR39 adopts a curved solenoid fold and exhibits substantial structural similarity to other protein-binding VLRs. VLR39 has a short LRRCT loop that protrudes outwards away from the concave face and is similar to those of its protein-specific VLR counterparts. Analysis of the VLR39-BCR interaction by size-exclusion chromatography and biolayer interferometry using the scFv version of the BCR confirms that VLR39 recognizes the BCR Fv region. Such VLR-based reagents may be useful for identifying and monitoring leukemia in CLL patients and in other clinical diagnostic assays.
[Mh] Termos MeSH primário: Receptores de Antígenos/química
Receptores de Antígenos/imunologia
[Mh] Termos MeSH secundário: Cromatografia em Gel
Cristalografia por Raios X
Epitopos/metabolismo
Seres Humanos
Modelos Moleculares
Conformação Proteica
Receptores de Antígenos/genética
Receptores de Antígenos/metabolismo
Receptores de Antígenos de Linfócitos B/química
Receptores de Antígenos de Linfócitos B/imunologia
Receptores de Antígenos de Linfócitos B/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Epitopes); 0 (Receptors, Antigen); 0 (Receptors, Antigen, B-Cell); 0 (Recombinant Proteins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171205
[St] Status:MEDLINE
[do] DOI:10.1107/S2053230X1701620X


  2 / 1070 MEDLINE  
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[PMID]:28755873
[Au] Autor:Rodriguez A; Brown C; Badie B
[Ad] Endereço:Division of Neurosurgery, Department of Surgery, City of Hope National Medical Center, Duarte, Calif. Electronic address: arodriguez@uams.edu.
[Ti] Título:Chimeric antigen receptor T-cell therapy for glioblastoma.
[So] Source:Transl Res;187:93-102, 2017 Sep.
[Is] ISSN:1878-1810
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Chimeric antigen receptor (CAR) T-cell therapy has shown great promise in the treatment of hematological disease, and its utility for treatment of solid tumors is beginning to unfold. Glioblastoma continues to portend a grim prognosis and immunotherapeutic approaches are being explored as a potential treatment strategy. Identification of appropriate glioma-associated antigens, barriers to cell delivery, and presence of an immunosuppressive microenvironment are factors that make CAR T-cell therapy for glioblastoma particularly challenging. However, insights gained from preclinical studies and ongoing clinical trials indicate that CAR T-cell therapy will continue to evolve and likely become integrated with current therapeutic strategies for malignant glioma.
[Mh] Termos MeSH primário: Glioblastoma/terapia
Imunoterapia Adotiva/métodos
Receptores de Antígenos/metabolismo
Proteínas Recombinantes de Fusão/uso terapêutico
Linfócitos T/metabolismo
[Mh] Termos MeSH secundário: Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Receptors, Antigen); 0 (Recombinant Fusion Proteins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170731
[St] Status:MEDLINE


  3 / 1070 MEDLINE  
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[PMID]:28755872
[Au] Autor:Carrillo MA; Zhen A; Zack JA; Kitchen SG
[Ad] Endereço:Division of Hematology & Oncology, Department of Medicine, UCLA AIDS Institute, David Geffen School of Medicine University of California, Los Angeles, Calif.
[Ti] Título:New approaches for the enhancement of chimeric antigen receptors for the treatment of HIV.
[So] Source:Transl Res;187:83-92, 2017 Sep.
[Is] ISSN:1878-1810
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:HIV infection continues to be a life-long chronic disease in spite of the success of antiretroviral therapy (ART) in controlling viral replication and preventing disease progression. However, because of the high cost of treatment, severe side effects, and inefficiency in curing the disease with ART, there is a call for alternative therapies that will provide a functional cure for HIV. Cytotoxic T lymphocytes (CTLs) are vital in the control and clearance of viral infections and therefore immune-based therapies have attempted to engineer HIV-specific CTLs that would be able to clear the infection from the body. The development of chimeric antigen receptors (CARs) provides an opportunity to engineer superior HIV-specific CTLs that will be independent of the major histocompatibility complex for target recognition. A CD4-based CAR has been previously tested in clinical trials to test the antiviral efficacy of peripheral T cells armed with this CD4-based CAR. The results from these clinical trials showed the safety and feasibility of CAR T cell therapy for HIV infection; however, minimal antiviral efficacy was seen. In this review, we will discuss the various strategies being developed to enhance the therapeutic potency of anti-HIV CARs with the goal of generating superior antiviral responses that will lead to life-long HIV immunity and clearance of the virus from the body.
[Mh] Termos MeSH primário: Infecções por HIV/terapia
Receptores de Antígenos/metabolismo
Proteínas Recombinantes de Fusão/uso terapêutico
[Mh] Termos MeSH secundário: Antígenos CD4
Regulação da Expressão Gênica
Seres Humanos
Imunoterapia Adotiva
Receptores de Antígenos/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (CD4 Antigens); 0 (Receptors, Antigen); 0 (Recombinant Fusion Proteins)
[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:170731
[St] Status:MEDLINE


  4 / 1070 MEDLINE  
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[PMID]:28719798
[Au] Autor:Lichtman EI; Dotti G
[Ad] Endereço:Department of Medicine, University of North Carolina, Chapel Hill, NC; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC. Electronic address: eben.lichtman@unchealth.unc.edu.
[Ti] Título:Chimeric antigen receptor T-cells for B-cell malignancies.
[So] Source:Transl Res;187:59-82, 2017 Sep.
[Is] ISSN:1878-1810
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The adoptive transfer of T-lymphocytes modified to express chimeric antigen receptors (CAR-Ts) has produced impressive clinical responses among patients with B-cell malignancies. This has led to a rapid expansion in the number of clinical trials over the past several years. Although CD19-specific CAR-Ts are the most extensively evaluated, CAR-Ts specific for other B-cell-associated targets have also shown promise. However, despite this success, toxicities associated with CAR-T administration remain a significant concern. There continues to be substantial heterogeneity among CAR-T products, and differences in both CAR designs and CAR-T production strategies can substantially affect clinical outcomes. Ongoing clinical studies will further elucidate these differences and many other innovative approaches are being evaluated at the preclinical level. In this review, we will discuss the background and rationale for the use of CAR-Ts, provide an overview of advances in the field, and examine the application of CAR-Ts to the treatment of B-cell malignancies, including a summary of clinical trials published to date.
[Mh] Termos MeSH primário: Imunoterapia Adotiva/métodos
Leucemia de Células B/terapia
Linfoma de Células B/terapia
Receptores de Antígenos/metabolismo
Linfócitos T/fisiologia
[Mh] Termos MeSH secundário: Seres Humanos
Receptores de Antígenos/genética
Proteínas Recombinantes de Fusão
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Receptors, Antigen); 0 (Recombinant Fusion Proteins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170719
[St] Status:MEDLINE


  5 / 1070 MEDLINE  
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[PMID]:28688236
[Au] Autor:Dawson NAJ; Levings MK
[Ad] Endereço:Department of Surgery, University of British Columbia & British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada.
[Ti] Título:Antigen-specific regulatory T cells: are police CARs the answer?
[So] Source:Transl Res;187:53-58, 2017 Sep.
[Is] ISSN:1878-1810
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cellular therapy with T-regulatory cells (Tregs) is a promising strategy to control immune responses and restore immune tolerance in a variety of immune-mediated diseases, such as transplant rejection and autoimmunity. Multiple clinical trials are currently testing this approach, typically by infusing a single dose of polyclonal Tregs that have been expanded in vitro. However, evidence from animal models of Treg therapy has clearly shown that antigen-specific Tregs are vastly superior to polyclonal cells, meaning that fewer cells are needed for the desired therapeutic effect. Traditional methods to obtain antigen-specific Tregs include antigen-stimulated expansion or T-cell receptor (TCR) overexpression. However, these methods are limited by low cell numbers, complex manufacturing procedures, and knowledge of patient-specific TCRs which recognize disease-relevant MHC-peptide complexes. Recently, several groups have explored the potential to use chimeric antigen receptors (CARs) to generate antigen-specific Tregs. Here, we discuss the progress in this field and highlight the major outstanding questions that remain to be addressed as this approach moves toward clinical applications.
[Mh] Termos MeSH primário: Doenças Autoimunes/terapia
Rejeição de Enxerto/terapia
Imunoterapia Adotiva/métodos
Receptores de Antígenos/metabolismo
Linfócitos T Reguladores/fisiologia
[Mh] Termos MeSH secundário: Regulação Neoplásica da Expressão Gênica
Variação Genética
Receptores de Antígenos/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Receptors, Antigen)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170709
[St] Status:MEDLINE


  6 / 1070 MEDLINE  
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[PMID]:28651074
[Au] Autor:Bollino D; Webb TJ
[Ad] Endereço:Department of Microbiology and Immunology, University of Maryland School of Medicine and the Marlene and Stewart Greenebaum Cancer Center, Baltimore, Md.
[Ti] Título:Chimeric antigen receptor-engineered natural killer and natural killer T cells for cancer immunotherapy.
[So] Source:Transl Res;187:32-43, 2017 Sep.
[Is] ISSN:1878-1810
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Natural killer (NK) cells of the innate immune system and natural killer T (NKT) cells, which have roles in both the innate and adaptive responses, are unique lymphocyte subsets that have similarities in their functions and phenotypes. Both cell types can rapidly respond to the presence of tumor cells and participate in immune surveillance and antitumor immune responses. This has incited interest in the development of novel cancer therapeutics based on NK and NKT cell manipulation. Chimeric antigen receptors (CARs), generated through the fusion of an antigen-binding region of a monoclonal antibody or other ligand to intracellular signaling domains, can enhance lymphocyte targeting and activation toward diverse malignancies. Most of the CAR studies have focused on their expression in T cells; however, the functional heterogeneity of CAR T cells limits their therapeutic potential and is associated with toxicity. CAR-modified NK and NKT cells are becoming more prevalent because they provide a method to direct these cells more specifically to target cancer cells, with less risk of adverse effects. This review will outline current NK and NKT cell CAR constructs and how they compare to conventional CAR T cells, and discuss future modifications that can be explored to advance adoptive cell transfer of NK and NKT cells.
[Mh] Termos MeSH primário: Imunoterapia Adotiva/métodos
Células Matadoras Naturais/metabolismo
Neoplasias/terapia
Receptores de Antígenos/metabolismo
Proteínas Recombinantes de Fusão/metabolismo
Linfócitos T/metabolismo
[Mh] Termos MeSH secundário: Seres Humanos
Receptores de Antígenos/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Receptors, Antigen); 0 (Recombinant Fusion Proteins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170627
[St] Status:MEDLINE


  7 / 1070 MEDLINE  
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[PMID]:28648487
[Au] Autor:Kim S; Moon EK
[Ad] Endereço:Division of Pulmonary, Allergy, and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa.
[Ti] Título:Development of novel avenues to overcome challenges facing CAR T cells.
[So] Source:Transl Res;187:22-31, 2017 Sep.
[Is] ISSN:1878-1810
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:There has been dramatic success in treating patients with adoptive transfer of autologous T cells genetically modified to express a chimeric antigen receptor redirecting them to the antigen CD19. Despite this success, the application of chimeric antigen receptor T-cell therapy in solid malignancies has encountered many challenges that need to be overcome if similar success across other cancers is to become a reality. These challenges can be classified into 6 categories: the heterogeneity of tumor cell clones and tumor-associated antigen expression; poor T-cell trafficking into the tumor site; poor T-cell survival and persistence; the presence of suppressive immune cells; the secretion of suppressive soluble factors in the tumor microenvironment; and the upregulation of T-cell intrinsic inhibitory pathways. We outline specific representative hurdles in each of these categories and summarize the progress made in understanding them and developing strategies to overcome them.
[Mh] Termos MeSH primário: Imunoterapia Adotiva/métodos
Neoplasias/terapia
Receptores de Antígenos/metabolismo
Linfócitos T/fisiologia
[Mh] Termos MeSH secundário: Regulação Neoplásica da Expressão Gênica
Variação Genética
Seres Humanos
Receptores de Antígenos/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Receptors, Antigen)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170627
[St] Status:MEDLINE


  8 / 1070 MEDLINE  
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[PMID]:28641074
[Au] Autor:Chen D; Yang J
[Ad] Endereço:Surgery Branch, National Cancer Institute National Institutes of Health, Bethesda, Md. Electronic address: david.chen4@nih.gov.
[Ti] Título:Development of novel antigen receptors for CAR T-cell therapy directed toward solid malignancies.
[So] Source:Transl Res;187:11-21, 2017 Sep.
[Is] ISSN:1878-1810
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Development of chimeric antigen receptor (CAR) T cells have led to remarkable successes in the treatment of B-cell malignancies with anti-CD19 CAR. Here we discuss the development of novel antigen receptors for use in solid malignancies with respect to target antigens, receptor design, and T cell manipulations.
[Mh] Termos MeSH primário: Imunoterapia Adotiva/métodos
Neoplasias/terapia
Receptores de Antígenos/metabolismo
Linfócitos T/fisiologia
[Mh] Termos MeSH secundário: Regulação Neoplásica da Expressão Gênica
Seres Humanos
Receptores de Antígenos/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Receptors, Antigen)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170623
[St] Status:MEDLINE


  9 / 1070 MEDLINE  
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[PMID]:28490575
[Au] Autor:Jacobsen JA; Woodard J; Mandal M; Clark MR; Bartom ET; Sigvardsson M; Kee BL
[Ad] Endereço:Committee on Immunology, The University of Chicago, Chicago, IL 60637.
[Ti] Título:EZH2 Regulates the Developmental Timing of Effectors of the Pre-Antigen Receptor Checkpoints.
[So] Source:J Immunol;198(12):4682-4691, 2017 Jun 15.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The histone methyltransferase EZH2 is required for B and T cell development; however, the molecular mechanisms underlying this requirement remain elusive. In a murine model of lymphoid-specific EZH2 deficiency we found that EZH2 was required for proper development of adaptive, but not innate, lymphoid cells. In adaptive lymphoid cells EZH2 prevented the premature expression of and the consequent stabilization of p53, an effector of the pre-Ag receptor checkpoints. Deletion of in EZH2-deficient lymphocytes prevented p53 stabilization, extended lymphocyte survival, and restored differentiation resulting in the generation of mature B and T lymphocytes. Our results uncover a crucial role for EZH2 in adaptive lymphocytes to control the developmental timing of effectors of the pre-Ag receptor checkpoints.
[Mh] Termos MeSH primário: Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo
Receptores de Antígenos/metabolismo
Linfócitos T/imunologia
Linfócitos T/metabolismo
[Mh] Termos MeSH secundário: Imunidade Adaptativa
Animais
Linfócitos B/imunologia
Inibidor p16 de Quinase Dependente de Ciclina/deficiência
Inibidor p16 de Quinase Dependente de Ciclina/genética
Inibidor p16 de Quinase Dependente de Ciclina/metabolismo
Proteína Potenciadora do Homólogo 2 de Zeste/deficiência
Proteína Potenciadora do Homólogo 2 de Zeste/genética
Regulação da Expressão Gênica
Genes p53
Células Matadoras Naturais/imunologia
Linfopoese
Camundongos
Receptores de Antígenos/genética
Receptores de Antígenos/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cdkn2a protein, mouse); 0 (Cyclin-Dependent Kinase Inhibitor p16); 0 (Receptors, Antigen); EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein); EC 2.1.1.43 (Ezh2 protein, mouse)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170927
[Lr] Data última revisão:
170927
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170512
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1700319


  10 / 1070 MEDLINE  
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[PMID]:28428075
[Au] Autor:Hoseini SS; Cheung NV
[Ad] Endereço:Department of Pediatrics, Memorial Sloan Kettering Cancer Center, United States.
[Ti] Título:Immunotherapy of hepatocellular carcinoma using chimeric antigen receptors and bispecific antibodies.
[So] Source:Cancer Lett;399:44-52, 2017 Jul 28.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide with an overall survival rate of less than 15% in developed countries. Despite attempts at new therapeutic strategies, the majority of patients succumb to this cancer. Buttressed by the highly successful clinical impact in melanoma, immunotherapy is gaining momentum as the next treatment modality for many human cancers. Chimeric antigen receptors (CAR) contain the antigen binding moieties of a monoclonal antibody and the co-stimulatory and signaling domains associated with effector receptor signaling. Bispecific antibodies (BsAb) combine the binding specificities of two different monoclonal antibodies, one activating a receptor on a killer effector cell, while the other engaging a tumor-associated antigen to initiate tumor cytotoxicity. In this review, we survey the HCC targets for which CARs and bispecific antibodies have been generated. The pros and cons of these targets for T-cell and Natural Killer cell based immunotherapy will be discussed.
[Mh] Termos MeSH primário: Anticorpos Biespecíficos/uso terapêutico
Antígenos de Neoplasias/imunologia
Antineoplásicos/uso terapêutico
Carcinoma Hepatocelular/tratamento farmacológico
Imunoterapia/métodos
Neoplasias Hepáticas/tratamento farmacológico
Receptores de Antígenos/imunologia
Proteínas Recombinantes de Fusão/uso terapêutico
[Mh] Termos MeSH secundário: Animais
Anticorpos Biespecíficos/efeitos adversos
Especificidade de Anticorpos
Antineoplásicos/efeitos adversos
Carcinoma Hepatocelular/imunologia
Carcinoma Hepatocelular/patologia
Morte Celular/efeitos dos fármacos
Citotoxicidade Imunológica
Seres Humanos
Imunoterapia/efeitos adversos
Neoplasias Hepáticas/imunologia
Neoplasias Hepáticas/patologia
Proteínas Recombinantes de Fusão/efeitos adversos
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antibodies, Bispecific); 0 (Antigens, Neoplasm); 0 (Antineoplastic Agents); 0 (Receptors, Antigen); 0 (Recombinant Fusion Proteins)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170821
[Lr] Data última revisão:
170821
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170422
[St] Status:MEDLINE



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