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https://www.readbyqxmd.com/read/29230672/the-role-of-b-cell-maturation-antigen-in-the-biology-and-management-of-and-as-a-potential-therapeutic-target-in-multiple-myeloma
#1
Eric Sanchez, Emily J Smith, Moryel A Yashar, Saurabh Patil, Mingjie Li, Autumn L Porter, Edward J Tanenbaum, Remy E Schlossberg, Camilia M Soof, Tara Hekmati, George Tang, Cathy S Wang, Haiming Chen, James R Berenson
B-cell maturation antigen (BCMA) was originally identified as a cell membrane receptor, expressed exclusively on late stage B-cells and plasma cells (PCs). Investigations of BCMA as a target for therapeutic intervention in multiple myeloma (MM) were initiated in 2007, using cSG1 as a naked antibody (Ab) as well as an Ab-drug conjugate (ADC) targeting BCMA, ultimately leading to ongoing clinical studies for previously treated MM patients. Since then, multiple companies have developed anti-BCMA-directed ADCs...
December 11, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/29228683/lenalidomide-overcomes-the-immunosuppression-of-regulatory-cd8-cd28-t-cells
#2
Brigitte Neuber, Jingying Dai, Wjahat A Waraich, Mohamed H S Awwad, Melanie Engelhardt, Michael Schmitt, Sergej Medenhoff, Mathias Witzens-Harig, Anthony D Ho, Hartmut Goldschmidt, Michael Hundemer
Although lenalidomide and pomalidomide are well-established treatment options in patients with multiple myeloma, their immune-modulating effects are not fully understood. While CD8+CD28- regulatory T-cells in patients with hematologic disorders display a known immune-escape mechanism, we show that lenalidomide can overcome the immunosuppressive impact of CD8+CD28- T-cells. We analyzed in vitro the antigen-specific T-cell responses of healthy donors and patients with multiple myeloma with or without the addition of autologous CD8+CD28- T-cells in the absence and presence of lenalidomide...
November 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29222300/emerging-options-in-multiple-myeloma-targeted-immune-and-epigenetic-therapies
#3
REVIEW
Shaji Kumar
Considerable progress has been made in the treatment of multiple myeloma in the past decade with median survival for the disease improving significantly. This has come through a combination of better understanding of the disease biology and coordinated research into new treatment approaches including better supportive care. However, patients eventually become refractory to available treatments and succumb to the disease, highlighting the need to develop new treatment approaches. The genetic heterogeneity in the disease and clonal evolution under treatment pressure underlie the development of resistance, underscoring the need to develop more effective therapies that can eradicate the disease at initial treatment as well as the need for new classes of drugs with varying mechanisms of action...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29217780/from-transplant-to-novel-cellular-therapies-in-multiple-myeloma-emn-guidelines-and-future-perspectives
#4
Francesca Gay, Monika Engelhardt, Evangelos Terpos, Ralph Wäsch, Luisa Giaccone, Holger W Auner, Jo Caers, Martin Gramatzki, Niels van de Donk, Stefania Oliva, Elena Zamagni, Laurent Garderet, Christian Straka, Roman Hajek, Heinz Ludwig, Hermann Einsele, Meletios Dimopoulos, Mario Boccadoro, Nicolaus Kröger, Michele Cavo, Hartmut Goldschmidt, Benedetto Bruno, Pieter Sonneveld
Survival of myeloma patients has greatly improved with the use of autologous stem cell transplantation and novel agents, such as proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies. Compared to bortezomib- and lenalidomide-based regimens alone, the addition of high-dose melphalan followed by autologous transplantation significantly improves progression-free survival; although an overall survival benefit was not observed in all trials. Moreover, follow-up of recent trials is still too short to show any difference in survival...
December 7, 2017: Haematologica
https://www.readbyqxmd.com/read/29216227/immunoparesis-in-newly-diagnosed-multiple-myeloma-patients-effects-on-overall-survival-and-progression-free-survival-in-the-danish-population
#5
Rasmus Sørrig, Tobias W Klausen, Morten Salomo, Annette J Vangsted, Ulf Christian Frølund, Kristian T Andersen, Anja Klostergaard, Carsten Helleberg, Robert S Pedersen, Per T Pedersen, Sissel Helm-Petersen, Elena Manuela Teodorescu, Birgitte Preiss, Niels Abildgaard, Peter Gimsing
Immunoparesis (hypogammaglobulinemia) is associated to an unfavorable prognosis in newly diagnosed Multiple myeloma (MM) patients. However, this finding has not been validated in an unselected population-based cohort. We analyzed 2558 newly diagnosed MM patients in the Danish Multiple Myeloma Registry representing the entire MM population in Denmark from 2005-2013. Two-thousand two hundred and fifty three patients (90%) presented with reduction below lower normal levels of at least one uninvolved immunoglobulin...
2017: PloS One
https://www.readbyqxmd.com/read/29212806/syndecan-1-promotes-wnt-%C3%AE-catenin-signaling-in-multiple-myeloma-by-presenting-wnts-and-r-spondins
#6
Zemin Ren, Harmen van Andel, Wim de Lau, Robin B Hartholt, Madelon M Maurice, Hans Clevers, Marie José Kersten, Marcel Spaargaren, Steven T Pals
Multiple myeloma (MM) is characterized by the expansion of malignant plasma cells in the bone marrow (BM). Most MMs display aberrant Wnt/β-catenin signaling, which drives proliferation; however, they lack oncogenic Wnt-pathway mutations, suggesting activation by autocrine Wnt ligands and/or paracrine Wnts from the BM microenvironment. Expression of the heparan sulfate proteoglycan (HSPG) syndecan-1 is a hallmark of MM. Syndecan-1 is a critical player in the complex reciprocal interaction between MM cells and their BM niche, mediating growth factor/cytokine binding and signaling by its heparan sulfate (HS) chains...
December 6, 2017: Blood
https://www.readbyqxmd.com/read/29208938/oncolytic-virotherapy-as-an-immunotherapeutic-strategy-for-multiple-myeloma
#7
REVIEW
Daniel E Meyers, Satbir Thakur, Chandini M Thirukkumaran, Don G Morris
Multiple Myeloma (MM), a clonal malignancy of antibody-producing plasma cells, is the second most common hematologic malignancy and results in significant patient morbidity and mortality. The high degree of immune dysregulation in MM, including T cell imbalances and up-regulation of immunosuppressive checkpoint proteins and myeloid derived suppressor cells, allows this malignancy to escape from host immune control. Despite advances in the therapeutic landscape of MM over the last decade, including the introduction of immunomodulatory drugs, the prognosis for this disease is poor, with less than 50% of patients surviving 5 years...
December 5, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/29206983/cytogenetic-profiling-of-myelomas-association-with-complete-blood-count-study-of-180-patients
#8
Anil Tarigopula, Vani Chandrashekar, Perumal Govindasamy
Objectives: To analyze the most common primary and secondary cytogenetic events in myelomas using a probe panel designed in our laboratory, and to associate those events with hematological and biochemical findings. Methods: Blood specimens from patients diagnosed with myeloma were processed to determine complete blood count and levels of albumin, creatinine, and beta-2 microglobulin. We evaluated bone-marrow specimens for plasma-cell percentage by light microscopy and for cytogenetic abnormalities by fluorescence in situ hybridization (FISH)...
December 1, 2017: Laboratory Medicine
https://www.readbyqxmd.com/read/29204156/sp17-protein-expression-and-major-histocompatibility-class-i-and-ii-epitope-presentation-in-diffuse-large-b-cell-lymphoma-patients
#9
Kamel Ait-Tahar, Amanda P Anderson, Martin Barnardo, Graham P Collins, Chris S R Hatton, Alison H Banham, Karen Pulford
Improved therapies are urgently needed for patients with diffuse large B cell lymphoma (DLBCL). Success using immune checkpoint inhibitors and chimeric antigen receptor T cell technology has fuelled demand for validated cancer epitopes. Immunogenic cancer testis antigens (CTAs), with their widespread expression in many tumours but highly restricted normal tissue distribution, represent attractive immunotherapeutic targets that may improve treatment options for DLBCL and other malignancies. Sperm protein 17 (Sp17), a CTA reported to be immunogenic in ovarian cancer and myeloma patients, is expressed in DLBCL...
2017: Advances in Hematology
https://www.readbyqxmd.com/read/29202016/inhibition-of-ngly1-inactivates-the-transcription-factor-nrf1-and-potentiates-proteasome-inhibitor-cytotoxicity
#10
Frederick M Tomlin, Ulla I M Gerling-Driessen, Yi-Chang Liu, Ryan A Flynn, Janakiram R Vangala, Christian S Lentz, Sandra Clauder-Muenster, Petra Jakob, William F Mueller, Diana Ordoñez-Rueda, Malte Paulsen, Naoko Matsui, Deirdre Foley, Agnes Rafalko, Tadashi Suzuki, Matthew Bogyo, Lars M Steinmetz, Senthil K Radhakrishnan, Carolyn R Bertozzi
Proteasome inhibitors are used to treat blood cancers such as multiple myeloma (MM) and mantle cell lymphoma. The efficacy of these drugs is frequently undermined by acquired resistance. One mechanism of proteasome inhibitor resistance may involve the transcription factor Nuclear Factor, Erythroid 2 Like 1 (NFE2L1, also referred to as Nrf1), which responds to proteasome insufficiency or pharmacological inhibition by upregulating proteasome subunit gene expression. This "bounce-back" response is achieved through a unique mechanism...
November 22, 2017: ACS Central Science
https://www.readbyqxmd.com/read/29191842/targeting-the-anion-exchanger-2-with-specific-peptides-as-a-new-therapeutic-approach-in-b-lymphoid-neoplasms
#11
Jon Celay, Teresa Lozano, Axel R Concepcion, Elena Beltrán, Francesc Rudilla, María José García-Barchino, Eloy F Robles, Obdulia Rabal, Irene de Miguel, Carlos Panizo, Noelia Casares, Julen Oyarzabal, Jesús Prieto, Juan F Medina, Juan José Lasarte, José Ángel Martínez-Climent
Regulatory T (Treg) cells can weaken antitumor immune responses, and inhibition of their function appears as a promising immunotherapeuticimmunotherapy therapeutic approach in cancer patients. Mice with targeted deletion of the gene encoding the Cl-HCO3-anion exchanger AE2 (also termed SLC4A2), a membrane-bound carrier involved in intracellular pH regulation, showed a progressive decrease in the number of Treg cells. We therefore challenged AE2 as a potential target for tumor immune therapy, and generated linear peptides designed to bind the third extracellular loop of AE2, which is crucial for its exchange activity...
November 30, 2017: Haematologica
https://www.readbyqxmd.com/read/29177954/pharmacogenetic-study-of-the-impact-of-abcb1-single-nucleotide-polymorphisms-on-lenalidomide-treatment-outcomes-in-patients-with-multiple-myeloma-results-from-a-phase-iv-observational-study-and-subsequent-phase-ii-clinical-trial
#12
Ingrid Jakobsen Falk, Johan Lund, Henrik Gréen, Astrid Gruber, Evren Alici, Birgitta Lauri, Cecilie Blimark, Ulf-Henrik Mellqvist, Agneta Swedin, Karin Forsberg, Conny Carlsson, Mats Hardling, Lucia Ahlberg, Kourosh Lotfi, Hareth Nahi
PURPOSE: Despite therapeutic advances, patients with multiple myeloma (MM) continue to experience disease relapse and treatment resistance. The gene ABCB1 encodes the drug transporter P-glycoprotein, which confers resistance through drug extrusion across the cell membrane. Lenalidomide (Len) is excreted mainly via the kidneys, and, given the expression of P-gp in the renal tubuli, single-nucleotide polymorphisms (SNPs) in the ABCB1 gene may influence Len plasma concentrations and, subsequently, the outcome of treatment...
November 25, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/29169873/modified-hypercvad-versus-bortezomib-hypercad-in-patients-with-relapsed-refractory-multiple-myeloma
#13
Megan M Saraceni, Emma Scott, Richard T Maziarz, Matthew B Siegel, Solange Bassale, Susie Jiing, Eva Medvedova
INTRODUCTION: Multiple myeloma (MM) is an incurable plasma cell malignancy, in which aggressive relapses might require salvage cytotoxic infusional chemotherapy. Several clinical trials that reported the efficacy of bortezomib led to institutional practice changes in which vincristine was replaced with bortezomib in the modified hyperCVAD regimen, creating a new treatment regimen, named "bortezomib-hyperCAD." PATIENTS AND METHODS: We retrospectively describe the effectiveness and tolerability of 2 chemotherapy regimens among 33 patients with relapsed and/or refractory MM...
November 2, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/29167449/structure-of-human-immunoproteasome-with-a-reversible-and-noncompetitive-inhibitor-that-selectively-inhibits-activated-lymphocytes
#14
Ruda de Luna Almeida Santos, Lin Bai, Pradeep K Singh, Naoka Murakami, Hao Fan, Wenhu Zhan, Yingrong Zhu, Xiuju Jiang, Kaiming Zhang, Jean Pierre Assker, Carl F Nathan, Huilin Li, Jamil Azzi, Gang Lin
Proteasome inhibitors benefit patients with multiple myeloma and B cell-dependent autoimmune disorders but exert toxicity from inhibition of proteasomes in other cells. Toxicity should be minimized by reversible inhibition of the immunoproteasome β5i subunit while sparing the constitutive β5c subunit. Here we report β5i-selective inhibition by asparagine-ethylenediamine (AsnEDA)-based compounds and present the high-resolution cryo-EM structural analysis of the human immunoproteasome. Despite inhibiting noncompetitively, an AsnEDA inhibitor binds the active site...
November 22, 2017: Nature Communications
https://www.readbyqxmd.com/read/29165008/building-upon-the-success-of-cart19-chimeric-antigen-receptor-t-cells-for-hematologic-malignancies
#15
Antonia Rotolo, Anastasios Karadimitris, Marco Ruella
Chimeric antigen receptor T cell (CART) therapy has dramatically changed the therapeutic prospects for B cell malignancies. Over the last decade CD19-redirected CART have demonstrated the ability to induce deep, long-lasting remissions and possibly cure patients with relapsing B cell neoplasms. Such impressive results with CART19 fostered efforts to expand this technology to other incurable malignancies that naturally do not express CD19, such as acute myeloid leukemia (AML), Hodgkin lymphoma (HL) and multiple myeloma (MM)...
November 22, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29158558/protein-arginine-methyltransferase-5-prmt5-has-prognostic-relevance-and-is-a-druggable-target-in-multiple-myeloma
#16
A Gullà, T Hideshima, G Bianchi, M Fulciniti, M K Samur, J Qi, Y-T Tai, T Harada, E Morelli, N Amodio, R Carrasco, P Tagliaferri, N C Munshi, P Tassone, K C Anderson
Arginine methyltransferases critically regulate cellular homeostasis by modulating the functional outcome of their substrates. The protein arginine methyltransferase 5 (PRMT5) is an enzyme involved in growth and survival pathways promoting tumorigenesis. However, little is known about the biologic function of PRMT5 and its therapeutic potential in multiple myeloma (MM). In the present study, we identified and validated PRMT5 as a new therapeutic target in MM. PRMT5 is overexpressed in patient MM cells and associated with decreased PFS and OS...
November 21, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29158557/mir-29b-antagonizes-the-pro-inflammatory-tumor-promoting-activity-of-multiple-myeloma-educated-dendritic-cells
#17
C Botta, M Cucè, M R Pitari, D Caracciolo, A Gullà, E Morelli, C Riillo, L Biamonte, M E G Cantafio, R Prabhala, C Mignogna, A Di Vito, E Altomare, N Amodio, M T Di Martino, P Correale, M Rossi, A Giordano, N C Munshi, P Tagliaferri, P Tassone
Dendritic cells (DCs) play a key role in regulating tumor immunity, tumor cell growth and drug resistance. We hypothesized that multiple myeloma (MM) cells might recruit and reprogram DCs to a tumor-permissive phenotype by changes within their miRNA network. By analyzing 6 different miRNA-profiling datasets, miR-29b was identified as the only miRNA upregulated in normal mature DCs and significantly downregulated in tumor associated DCs. This finding was validated in primary DCs co-cultured in vitro with MM cell lines and in primary bone marrow DCs from MM patients...
November 21, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29157092/single-agent-and-synergistic-combinatorial-efficacy-of-first-in-class-small-molecule-imipridone-onc201-in-hematological-malignancies
#18
Varun V Prabhu, Mala K Talekar, Amriti R Lulla, C Leah B Kline, Lanlan Zhou, Junior Hall, A Pieter J Van den Heuvel, David T Dicker, Jawad Babar, Stephan A Grupp, Mathew J Garnett, Ultan McDermott, Cyril H Benes, Jeffrey J Pu, David F Claxton, Nadia Khan, Wolfgang Oster, Joshua E Allen, Wafik S El-Deiry
ONC201, founding member of the imipridone class of small molecules, is currently being evaluated in advancer cancer clinical trials. We explored single agent and combinatorial efficacy of ONC201 in preclinical models of hematological malignancies. ONC201 demonstrated (GI50 1-8 µM) dose- and time-dependent efficacy in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt's lymphoma, anaplastic large cell lymphoma (ALCL), cutaneous T-cell lymphoma (CTCL), Hodgkin's lymphoma (nodular sclerosis) and multiple myeloma (MM) cell lines including cells resistant to standard of care (dexamethasone in MM) and primary samples...
November 20, 2017: Cell Cycle
https://www.readbyqxmd.com/read/29156727/bone-marrow-irf4-level-in-multiple-myeloma-an-indicator-of-peripheral-blood-th17-and-disease
#19
Hua Bai, Shuang Wu, Rong Wang, Ji Xu, Lijuan Chen
Interferon regulator factor 4 (IRF4) is characterized to be a member of interferon regulatory family, which is predominantly expressed in bone marrow plasma cells of patients with multiple myeloma (MM). Recent studies indicated IRF4 is critical for T-help cells (Th17) differentiation and interleukin-17 (IL-17) secretion. Here, a total of 58 MM patients were enrolled in this study, the proportions of Th17 cells and T regulatory (Treg) cells in peripheral blood mononuclear cells (PBMCs) were determined by flow cytometric analysis...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156688/frequency-of-expression-and-generation-of-t-cell-responses-against-antigens-on-multiple-myeloma-cells-in-patients-included-in-the-gmmg-mm5-trial
#20
Michael Schmitt, Angela G Hückelhoven, Michael Hundemer, Anita Schmitt, Susanne Lipp, Martina Emde, Hans Salwender, Mathias Hänel, Katja Weisel, Uta Bertsch, Jan Dürig, Anthony D Ho, Igor Wolfgang Blau, Hartmut Goldschmidt, Anja Seckinger, Dirk Hose
Background: Raising T-cell response against antigens either expressed on normal and malignant plasma cells (e.g. HM1.24) or aberrantly on myeloma cells only (e.g. cancer testis antigens, CTA) by vaccination is a potential treatment approach for multiple myeloma. Results: Expression by GEP is found for HM1.24 in all, HMMR in 318/458 (69.4%), MAGE-A3 in 209/458 (45.6%), NY-ESO-1/2 in 40/458 (8.7%), and WT-1 in 4/458 (0.8%) of samples with the pattern being confirmed by RNA-sequencing...
October 17, 2017: Oncotarget
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