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Sipuleucel-T immunotherapy for castration-resistant prostate cancer.
Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, Xu Y, Frohlich MW, Schellhammer PF, IMPACT Study Investigators
(2010) N Engl J Med 363: 411-22
MeSH Terms: Aged, Aged, 80 and over, Androgen Antagonists, Antigen-Presenting Cells, Antineoplastic Agents, Cancer Vaccines, Cell Culture Techniques, Combined Modality Therapy, Disease Progression, Double-Blind Method, Humans, Immunotherapy, Infusions, Intravenous, Intercellular Adhesion Molecule-1, Kaplan-Meier Estimate, Male, Middle Aged, Proportional Hazards Models, Prostatic Neoplasms, Tissue Extracts
Show Abstract · Added March 5, 2014
BACKGROUND - Sipuleucel-T, an autologous active cellular immunotherapy, has shown evidence of efficacy in reducing the risk of death among men with metastatic castration-resistant prostate cancer.
METHODS - In this double-blind, placebo-controlled, multicenter phase 3 trial, we randomly assigned 512 patients in a 2:1 ratio to receive either sipuleucel-T (341 patients) or placebo (171 patients) administered intravenously every 2 weeks, for a total of three infusions. The primary end point was overall survival, analyzed by means of a stratified Cox regression model adjusted for baseline levels of serum prostate-specific antigen (PSA) and lactate dehydrogenase.
RESULTS - In the sipuleucel-T group, there was a relative reduction of 22% in the risk of death as compared with the placebo group (hazard ratio, 0.78; 95% confidence interval [CI], 0.61 to 0.98; P=0.03). This reduction represented a 4.1-month improvement in median survival (25.8 months in the sipuleucel-T group vs. 21.7 months in the placebo group). The 36-month survival probability was 31.7% in the sipuleucel-T group versus 23.0% in the placebo group. The treatment effect was also observed with the use of an unadjusted Cox model and a log-rank test (hazard ratio, 0.77; 95% CI, 0.61 to 0.97; P=0.02) and after adjustment for use of docetaxel after the study therapy (hazard ratio, 0.78; 95% CI, 0.62 to 0.98; P=0.03). The time to objective disease progression was similar in the two study groups. Immune responses to the immunizing antigen were observed in patients who received sipuleucel-T. Adverse events that were more frequently reported in the sipuleucel-T group than in the placebo group included chills, fever, and headache.
CONCLUSIONS - The use of sipuleucel-T prolonged overall survival among men with metastatic castration-resistant prostate cancer. No effect on the time to disease progression was observed. (Funded by Dendreon; ClinicalTrials.gov number, NCT00065442.)
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20 MeSH Terms
Development of spontaneous anergy in invariant natural killer T cells in a mouse model of dyslipidemia.
Braun NA, Mendez-Fernandez YV, Covarrubias R, Porcelli SA, Savage PB, Yagita H, Van Kaer L, Major AS
(2010) Arterioscler Thromb Vasc Biol 30: 1758-65
MeSH Terms: Animals, Antigen-Presenting Cells, Antigens, Surface, Apolipoproteins E, Apoptosis Regulatory Proteins, Cell Proliferation, Cells, Cultured, Chronic Disease, Clonal Anergy, Cytokines, Dendritic Cells, Disease Models, Animal, Galactosylceramides, Hyperlipidemias, Injections, Intraperitoneal, Interleukin-2, Lymphocyte Activation, Lymphocyte Count, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, NK Cell Lectin-Like Receptor Subfamily A, Natural Killer T-Cells, Phenotype, Programmed Cell Death 1 Receptor, Receptors, Antigen, T-Cell, Time Factors
Show Abstract · Added February 11, 2014
OBJECTIVE - In this study, we investigated whether dyslipidemia-associated perturbed invariant natural killer T (iNKT) cell function is due to intrinsic changes in iNKT cells or defects in the ability of antigen-presenting cells to activate iNKT cells.
METHODS AND RESULTS - We compared iNKT cell expansion and cytokine production in C57BL/6J (B6) and apolipoprotein E-deficient (apoE(-/-)) mice. In response to in vivo stimulation with alpha-galactosylceramide, a prototypic iNKT cell glycolipid antigen, apoE(-/-) mice showed significantly decreased splenic iNKT cell expansion at 3 days after injection, a profile associated with iNKT cell anergy due to chronic stimulation. This decrease in expansion and cytokine production was accompanied by a 2-fold increase in percentage of iNKT cells expressing the inhibitory marker programmed death-1 in apoE(-/-) mice compared with controls. However, in vivo and in vitro blockade of programmed death-1 using monoclonal antibody was not able to restore functions of iNKT cells from apoE(-/-) mice to B6 levels. iNKT cells from apoE(-/-) mice also had increased intracellular T cell receptor and Ly49 expression, a phenotype associated with previous activation. Changes in iNKT cell functions were cell autonomous, because dendritic cells from apoE(-/-) mice were able to activate B6 iNKT cells, but iNKT cells from apoE(-/-) mice were not able to respond to B6 dendritic cells.
CONCLUSIONS - These data suggest that chronic dyslipidemia induces an iNKT cell phenotype that is unresponsive to further simulation by exogenous glycolipid and that sustained unresponsiveness is iNKT cell intrinsic.
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28 MeSH Terms
Blockade of GITR-GITRL interaction maintains Treg function to prolong allograft survival.
Kim JI, Sonawane SB, Lee MK, Lee SH, Duff PE, Moore DJ, O'Connor MR, Lian MM, Deng S, Choi Y, Yeh H, Caton AJ, Markmann JF
(2010) Eur J Immunol 40: 1369-74
MeSH Terms: Adoptive Transfer, Animals, Antibodies, Monoclonal, Antigen-Presenting Cells, Binding, Competitive, CD40 Ligand, Glucocorticoid-Induced TNFR-Related Protein, Graft Survival, Histocompatibility Antigens Class I, Humans, Immune Tolerance, Immunosuppressive Agents, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Minor Histocompatibility Antigens, Receptors, Nerve Growth Factor, Receptors, Tumor Necrosis Factor, Recombinant Fusion Proteins, Skin Transplantation, T-Lymphocytes, Regulatory, Transplantation, Homologous, Tumor Necrosis Factor Inhibitors, Tumor Necrosis Factors
Show Abstract · Added October 24, 2013
Involvement of Treg in transplant tolerance has been demonstrated in multiple models. During the active process of graft rejection, these regulatory cells are themselves regulated and inactivated, a process termed counter-regulation. We hypothesize that ligation of the costimulatory molecule glucocorticoid-induced TNF receptor-related protein (GITR) on Treg inhibits their ability to promote graft survival, and by blocking GITR ligation graft survival can be prolonged. To this aim, we have designed a soluble GITR fusion protein (GITR-Fc), which binds GITR ligand and inhibits activation of GITR. Here, we show that GITR-Fc prolonged mouse skin graft survival, and this prolongation is dependent on Treg. In a full MHC-mismatched skin graft setting, GITR-Fc significantly improved graft survival when used in combination with MR1, anti-CD40L, while GITR-Fc alone did not demonstrate graft prolongation. These results demonstrate that disruption of binding of GITR with GITR ligand may be an important strategy in prolonging allograft survival.
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25 MeSH Terms
piggyBac transposon/transposase system to generate CD19-specific T cells for the treatment of B-lineage malignancies.
Manuri PV, Wilson MH, Maiti SN, Mi T, Singh H, Olivares S, Dawson MJ, Huls H, Lee DA, Rao PH, Kaminski JM, Nakazawa Y, Gottschalk S, Kebriaei P, Shpall EJ, Champlin RE, Cooper LJ
(2010) Hum Gene Ther 21: 427-37
MeSH Terms: Antigen-Presenting Cells, Antigens, CD19, Cell Line, Tumor, Cells, Cultured, Coculture Techniques, DNA Transposable Elements, Electroporation, Genetic Therapy, Genetic Vectors, Glioblastoma, Humans, K562 Cells, Lymphoma, B-Cell, Plasmids, Receptors, Antigen, T-Lymphocytes, Transgenes, Transposases
Show Abstract · Added August 22, 2013
Nonviral integrating vectors can be used for expression of therapeutic genes. piggyBac (PB), a transposon/transposase system, has been used to efficiently generate induced pluripotent stems cells from somatic cells, without genetic alteration. In this paper, we apply PB transposition to express a chimeric antigen receptor (CAR) in primary human T cells. We demonstrate that T cells electroporated to introduce the PB transposon and transposase stably express CD19-specific CAR and when cultured on CD19(+) artificial antigen-presenting cells, numerically expand in a CAR-dependent manner, display a phenotype associated with both memory and effector T cell populations, and exhibit CD19-dependent killing of tumor targets. Integration of the PB transposon expressing CAR was not associated with genotoxicity, based on chromosome analysis. PB transposition for generating human T cells with redirected specificity to a desired target such as CD19 is a new genetic approach with therapeutic implications.
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18 MeSH Terms
Regulatory T-cell counter-regulation by innate immunity is a barrier to transplantation tolerance.
Kim JI, Lee MK, Moore DJ, Sonawane SB, Duff PE, O'Connor MR, Yeh H, Lian MM, Deng S, Caton AJ, Markmann JF
(2009) Am J Transplant 9: 2736-44
MeSH Terms: Animals, Antigen-Presenting Cells, Forkhead Transcription Factors, Graft Rejection, Immune Tolerance, Immunity, Innate, Inflammation, Mice, Mice, Transgenic, Skin Transplantation, T-Lymphocytes, Regulatory
Show Abstract · Added October 24, 2013
Innate immune signals foster adaptive immunity through activation of antigen-presenting cells. Recent in vitro evidence suggests that innate signaling may also contribute to immunity by countering the effects of regulatory T cells (T-regs), counter-regulation. We present in vivo evidence using a transgenic skin allograft model that the function of T-regs is lost in the setting of acute skin transplantation but remains intact when grafts were transplanted 1 month prior to allow surgery-induced inflammation to abate. Our findings identify T-reg counter-regulation as a naturally occurring process that accompanies transplantation and an important barrier to T-reg-mediated tolerance. Our finding further highlights the central role of regulatory cell deactivation in the initiation of the immune response.
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11 MeSH Terms
Invariant natural killer T cells: innate-like T cells with potent immunomodulatory activities.
Wu L, Gabriel CL, Parekh VV, Van Kaer L
(2009) Tissue Antigens 73: 535-45
MeSH Terms: Animals, Antigen-Presenting Cells, Antigens, CD1d, Galactosylceramides, Glycolipids, Humans, Immunity, Innate, Immunotherapy, Lymphocyte Activation, Mice, Natural Killer T-Cells, Signal Transduction, T-Lymphocyte Subsets
Show Abstract · Added December 10, 2013
Invariant natural killer T (iNKT) cells are a subset of T lymphocytes that react with glycolipid antigens presented by the major histocompatibility complex class I-related glycoprotein CD1d. Although iNKT cells express an antigen-specific receptor of the adaptive immune system, they behave more like cells of the innate immune system. A hallmark of iNKT cells is their capacity to produce copious amounts of immunoregulatory cytokines quickly after activation. The cytokines produced by iNKT cells can influence the level of activation of many cell types of the innate and adaptive immune systems as well as the quality of an adaptive immune response. As such, iNKT cells have emerged as important regulators of immune responses, playing a role in microbial immunity, autoimmunity, tumor immunity, and a variety of inflammatory conditions. Although several endogenous and exogenous glycolipid antigens of iNKT cells have been identified, how these glycolipids orchestrate iNKT-cell functions remains poorly understood. Nevertheless, iNKT cells hold substantial promise as targets for development of vaccine adjuvants and immunotherapies. These properties of iNKT cells have been investigated most extensively in mouse models of human disease using the marine sponge-derived agent alpha-galactosylceramide (alpha-GalCer) and related iNKT-cell antigens. While these preclinical studies have raised enthusiasm for developing iNKT-cell-based immunotherapies, they also showed potential health risks associated with iNKT cell activation. Although alpha-GalCer treatment in humans was shown to be safe in the short term, further studies are needed to develop safe and effective iNKT-cell-based therapies.
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13 MeSH Terms
The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1.
Thomas PG, Dash P, Aldridge JR, Ellebedy AH, Reynolds C, Funk AJ, Martin WJ, Lamkanfi M, Webby RJ, Boyd KL, Doherty PC, Kanneganti TD
(2009) Immunity 30: 566-75
MeSH Terms: Animals, Antigen-Presenting Cells, Carrier Proteins, Caspase 1, Cells, Cultured, Gene Expression Regulation, Genetic Predisposition to Disease, Immunity, Innate, Influenza A virus, Interleukin-1beta, Mice, Mice, Inbred C57BL, Mice, Knockout, NLR Family, Pyrin Domain-Containing 3 Protein
Show Abstract · Added March 5, 2014
Virus-induced interlukin-1beta (IL-1beta) and IL-18 production in macrophages are mediated via caspase-1 pathway. Multiple microbial components, including viral RNA, are thought to trigger assembly of the cryopyrin inflammasome resulting in caspase-1 activation. Here, we demonstrated that Nlrp3(-/-) and Casp1(-/-) mice were more susceptible than wild-type mice after infection with a pathogenic influenza A virus. This enhanced morbidity correlated with decreased neutrophil and monocyte recruitment and reduced cytokine and chemokine production. Despite the effect on innate immunity, cryopyrin-deficiency was not associated with any obvious defect in virus control or on the later emergence of the adaptive response. Early epithelial necrosis was, however, more severe in the infected mutants, with extensive collagen deposition leading to later respiratory compromise. These findings reveal a function of the cryopyrin inflammasome in healing responses. Thus, cryopyrin and caspase-1 are central to both innate immunity and to moderating lung pathology in influenza pneumonia.
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14 MeSH Terms
Lung NKT cell commotion takes your breath away.
Joyce S, Van Kaer L
(2008) Nat Med 14: 609-10
MeSH Terms: Animals, Antigen-Presenting Cells, Asthma, Bronchoalveolar Lavage Fluid, Cells, Cultured, Disease Models, Animal, Interleukin-13, Killer Cells, Natural, Lung, Macrophage Activation, Macrophages, Alveolar, Mice, Models, Biological, Pulmonary Disease, Chronic Obstructive, Respiratory Physiological Phenomena
Added December 10, 2013
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15 MeSH Terms
Characterization and functional analysis of mouse invariant natural T (iNKT) cells.
Bezbradica JS, Stanic AK, Joyce S
(2006) Curr Protoc Immunol Chapter 14: Unit 14.13
MeSH Terms: Animals, Antigen-Presenting Cells, Antigens, CD1, Antigens, CD1d, Antigens, Surface, Cytokines, Immunomagnetic Separation, Killer Cells, Natural, Lymphocyte Activation, Mice, T-Lymphocyte Subsets
Show Abstract · Added May 19, 2014
Invariant natural T (iNKT) cells are innate lymphocytes that recognize CD1d-restricted lipid antigens and have immunoregulatory properties. Human and mouse CD1d-restricted glycolipid antigen(s) and the iNKT cell functions they elicit are highly conserved, whereby, making the mouse an excellent animal model for understanding iNKT cell biology in vivo. This unit describes basic methods for the characterization and quantification (see Basic Protocol 1) and functional analysis of murine iNKT cells in vivo or in vitro (see Basic Protocols 2, 3, and 4). This unit also contains protocols that describe enrichment of iNKT cells (see Support Protocol 1), generation of CD1d-tetramer (see Support Protocol 2), and lipid antigen loading on cell-bound (see Support Protocol 3) or soluble (see Support Protocol 3) CD1d.
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11 MeSH Terms
Immune responses to abacavir in antigen-presenting cells from hypersensitive patients.
Martin AM, Almeida CA, Cameron P, Purcell AW, Nolan D, James I, McCluskey J, Phillips E, Landay A, Mallal S
(2007) AIDS 21: 1233-44
MeSH Terms: Antigen-Presenting Cells, CD40 Antigens, Cells, Cultured, Dideoxynucleosides, Drug Hypersensitivity, Endoplasmic Reticulum, Endosomes, Fluorescent Antibody Technique, HIV Seropositivity, HLA-B Antigens, HSP70 Heat-Shock Proteins, Histocompatibility Antigens Class I, Humans, Immunophenotyping, Interferon-gamma, Microscopy, Confocal, Monocytes, Receptors, Cell Surface, Reverse Transcriptase Inhibitors
Show Abstract · Added March 30, 2020
OBJECTIVES - A potentially life-threatening hypersensitive reaction accompanies the use of HIV nucleoside analogue abacavir (ABC) in 4-8% of Caucasian individuals. HLA-B*5701 and Hsp70 493T alleles have been shown to predict susceptibility to this hypersensitivity.
DESIGN AND METHODS - This study was undertaken to provide a mechanistic understanding of the highly significant genetic association of HLA Class I and Hsp70 alleles with ABC hypersensitivity.
RESULTS - In this study an ABC-induced localization of intracellular HSP70 to endosomal vesicles of antigen-presenting cells was demonstrated. This ABC-stimulated redistribution of endogenous HSP70 was substantially higher in the genetically homogenous HLA-B*5701, Hsp70 493T ABC-hypersensitive individuals and ABC-naive individuals in comparison with the heterogeneous tolerant patients (P = 0.023). Increased expression of HSP70 was also detected in the hypersensitive group as measured by flow cytometry (P = 0.032). Blocking of HSP70 and HSP70 cell surface receptors CD14 and TLR2 abrogated ABC-stimulated HSP70 redistribution in sensitized individuals to basal levels (P < 0.004). In addition, the use of TcRalphabeta and HLA-B57/58 antibodies also ablated the expression of HSP70. Cells expressing the activation markers CD40 were increased after ABC stimulation in the hypersensitive patients (P = 0.006). ABC-stimulated interferon-gamma levels were higher in hypersensitive patients in comparison with ABC-tolerant individuals with a mean of 123.54 versus 0 pg/ml (P = 0.001).
CONCLUSION - The present data indicates that ABC stimulates an innate immune response and activates antigen-presenting cells via the endogenous HSP70-mediated Toll-like receptor pathway in genetically susceptible individuals potentially initiating the immuno-pathological hypersensitive response.
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MeSH Terms