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https://www.readbyqxmd.com/read/28933361/lysosomal-storage-disorders-and-malignancy
#1
REVIEW
Gregory M Pastores, Derralynn A Hughes
Lysosomal storage disorders (LSDs) are infrequent to rare conditions caused by mutations that lead to a disruption in the usual sequential degradation of macromolecules or their transit within the cell. Gaucher disease (GD), a lipidosis, is among the most common LSD, with an estimated incidence of 1 in 40,000 among the Caucasian, non-Jewish population. Studies have indicated an increased frequency of polyclonal and monoclonal gammopathy among patients with GD. It has been shown that two major sphingolipids that accumulate in GD, namely, β-glucosylceramide 22:0 (βGL1-22) and glucosylsphingosine (LGL1), can be recognized by a distinct subset of CD1d-restricted human and murine type II natural killer T (NKT) cells...
February 27, 2017: Diseases (Basel)
https://www.readbyqxmd.com/read/28932638/the-anti-slamf7-antibody-elotuzumab-mediates-nk-cell-activation-through-both-cd16-dependent-and-independent-mechanisms
#2
Tatiana Pazina, Ashley M James, Alexander W MacFarlane, Natalie A Bezman, Karla A Henning, Christine Bee, Robert F Graziano, Michael D Robbins, Adam D Cohen, Kerry S Campbell
Elotuzumab is a humanized therapeutic monoclonal antibody directed to the surface glycoprotein SLAMF7 (CS1, CRACC, CD319), which is highly expressed on multiple myeloma (MM) tumor cells. Improved clinical outcomes have been observed following treatment of MM patients with elotuzumab in combination with lenalidomide or bortezomib. Previous work showed that elotuzumab stimulates NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC), via Fc-domain engagement with FcγRIIIa (CD16). SLAMF7 is also expressed on NK cells, where it can transmit stimulatory signals...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28926977/mouse-monoclonal-antibodies-generated-from-full-length-human-cereblon-detection-of-cereblon-protein-in-patients-with-multiple-myeloma
#3
Xiubao Chang, Qinqin Xu, Yuexian Hou, Cynthia Li, Ye Xu, A Keith Stewart
Immunomodulatory drugs (IMiDs) are profoundly active compounds in the treatment of patients with multiple myeloma (MM). However, despite the fact that treatment with IMiDs has dramatically improved survival for patients with MM, the majority of MM patients develop IMiDs resistance over time. We have found that expression of functional cereblon is required for IMiDs' action. In addition, it has been reported that cells expressing high levels of cereblon are resistant to proteasome inhibitor, implying that patients with high levels of cereblon should be resistant to proteasome inhibitor...
September 17, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28915615/expression-of-cd38-in-myeloma-bone-niche-a-rational-basis-for-the-use-of-anti-cd38-immunotherapy-to-inhibit-osteoclast-formation
#4
Federica Costa, Denise Toscani, Antonella Chillemi, Valeria Quarona, Marina Bolzoni, Valentina Marchica, Rosanna Vescovini, Cristina Mancini, Eugenia Martella, Nicoletta Campanini, Chiara Schifano, Sabrina Bonomini, Fabrizio Accardi, Alberto L Horenstein, Franco Aversa, Fabio Malavasi, Nicola Giuliani
It is known that multiple myeloma (MM) cells express CD38 and that a recently developed human anti-CD38 monoclonal antibody Daratumumab mediates myeloma killing. However, the expression of CD38 and other functionally related ectoenzymes within the MM bone niche and the potential effects of Daratumumab on bone cells are still unknown. This study firstly defines by flow cytometry and immunohistochemistry the expression of CD38 by bone marrow cells in a cohort of patients with MM and indolent monoclonal gammopathies...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28904172/fda-approval-summary-daratumumab-for-treatment-of-multiple-myeloma-after-one-prior-therapy
#5
Vishal Bhatnagar, Nicole J Gormley, Lola Luo, Yuan Li Shen, Rajeshwari Sridhara, Sriram Subramaniam, Guoxiang Shen, Lian Ma, Stacy Shord, Kirsten B Goldberg, Ann T Farrell, Amy E McKee, Richard Pazdur
On November 21, 2016, the U.S. Food and Drug Administration granted regular approval to daratumumab in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy. Approval was based on two randomized, open-label trials in which daratumumab was added to these backbone therapies. The MMY3003 trial demonstrated substantial improvement in progression-free survival (PFS) when daratumumab was added to lenalidomide and dexamethasone compared with lenalidomide and dexamethasone alone...
September 13, 2017: Oncologist
https://www.readbyqxmd.com/read/28899972/facts-and-hopes-in-immunotherapy-of-lymphoma-and-myeloma
#6
Matthew J Pianko, Alison J Moskowitz, Alexander M Lesokhin
Immune checkpoint blockade has driven a revolution in modern oncology, and robust drug development of immune checkpoint inhibitors is underway in both solid tumors and hematologic malignancies. High response rates to programmed cell death 1 (PD-1) blockade using nivolumab or pembrolizumab in classical Hodgkin lymphoma (cHL) and several variants of non-Hodgkin lymphoma (NHL) revealed an intrinsic biologic sensitivity to this approach, and work is ongoing exploring combinations with immune checkpoint inhibitors in both cHL and NHL...
September 12, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28888912/chemotherapy-induces-secretion-of-exosomes-loaded-with-heparanase-that-degrades-extracellular-matrix-and-impacts-tumor-and-host-cell-behavior
#7
Shyam K Bandari, Anurag Purushothaman, Vishnu C Ramani, Garrett J Brinkley, Darshan S Chandrashekar, Sooryanarayana Varambally, James A Mobley, Yi Zhang, Elizabeth E Brown, Israel Vlodavsky, Ralph D Sanderson
The heparan sulfate-degrading enzyme heparanase promotes the progression of many cancers by driving tumor cell proliferation, metastasis and angiogenesis. Heparanase accomplishes this via multiple mechanisms including its recently described effect on enhancing biogenesis of tumor exosomes. Because we recently discovered that heparanase expression is upregulated in myeloma cells that survive chemotherapy, we were prompted to investigate the impact of anti-myeloma drugs on exosome biogenesis. When myeloma cells were exposed to the commonly utilized anti-myeloma drugs bortezomib, carfilzomib or melphalan, exosome secretion by the cells was dramatically enhanced...
September 6, 2017: Matrix Biology: Journal of the International Society for Matrix Biology
https://www.readbyqxmd.com/read/28883264/treatment-algorithms-for-multiple-myeloma-in-japan
#8
Shuji Ozaki
Recent progress in the development of novel therapeutic agents has remarkably improved the treatment outcome for multiple myeloma (MM). Proteasome inhibitors such as bortezomib, carfilzomib, and ixazomib; immunomodulatory drugs (IMiDs) such as thalidomide, lenalidomide, and pomalidomide; the histone deacetylase (HDAC) inhibitor panobinostat; and the monoclonal antibody, elotuzumab, have all been approved in Japan, although only bortezomib and lenalidomide have been approved for initial therapy. Accordingly, the Japanese Society of Hematology has released updated treatment guidelines for MM...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28883263/combination-therapy-with-monoclonal-antibodies-for-treatment-of-newly-diagnosed-multiple-myeloma
#9
Noriko Nishimura, Yasuhito Terui, Kiyohiko Hatake
Monoclonal antibodies (mAbs) with new mechanisms of action are emerging as promising agents for patients with multiple myeloma (MM). Of these, anti-CD38 antibodies and anti-signaling lymphocytic activation molecule F7 (SLAMF7) antibody have demonstrated efficacy for relapsed and refractory myeloma (RRMM). Two CD38-targeting antibodies, daratumumab and isatuximab had significant activity as single agents, whereas the SLAMF7-targeting antibody, elotuzumab, did not. Patients with RRMM treated with 16 mg/kg daratumumab achieved at least PR of 36% and 29% in two distinct phase 2 studies...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28882484/synthesis-and-biological-evaluation-of-the-natural-product-komaroviquinone-and-related-compounds-aiming-at-a-potential-therapeutic-lead-compound-for-high-risk-multiple-myeloma
#10
Yutaka Suto, Mariko Sato, Kota Fujimori, Shotaro Kitabatake, Mikio Okayama, Daiju Ichikawa, Maiko Matsushita, Noriyuki Yamagiwa, Genji Iwasaki, Fumiyuki Kiuchi, Yutaka Hattori
Alternatives of treatments for multiple myeloma (MM) have become increasingly available with the advent of new drugs such as proteasome inhibitors, thalidomide derivatives, histone deacetylase inhibitors, and antibody drugs. However, high-risk MM cases that are refractory to novel drugs remain, and further optimization of chemotherapeutics is urgently needed. We had achieved asymmetric total synthesis of komaroviquinone, which is a natural product from the plant Dracocephalum komarovi. Similar to several leading antitumor agents that have been developed from natural compounds, we describe the antitumor activity and cytotoxicity of komaroviquinone and related compounds in bone marrow cells...
August 30, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28875836/coinhibitory-molecule-pd-1-as-a-therapeutic-target-in-the-microenvironment-of-multiple-myeloma
#11
Djordje Atanackovic, Tim Luetkens, Mary Steinbach, Nicolaus Kröger
Immunological dysfunction in the microenvironment of multiple myeloma is a potential target for immune-mediated therapies. The programmed death 1 (PD-1) receptor is expressed on the surface of exhausted T and B cells and its ligand PD-L1 is expressed on tumor cells and inhibits T-cell-mediated apoptosis. Inhibiting such "checkpoint" by monoclonal antibodies recently has been shown high activity in solid tumors and malignant lymphomas. In patients with multiple myeloma PD-L1 is overexpressed on myeloma cells and PD1 on T-cells suggesting an active role of PD- 1/PD-L1 in the immunosuppressive microenvironment...
September 6, 2017: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/28865180/automated-and-simplified-identification-of-normal-and-abnormal-plasma-cells-in-multiple-myeloma-by-flow-cytometry
#12
Elina Alaterre, Sébastien Raimbault, Jean-Michel Garcia, Thierry Rème, Guilhem Requirand, Bernard Klein, Jérôme Moreaux
BACKGROUND: Multiple myeloma (MM) is an incurable disease characterized by clonal plasma cell (PC) proliferation within the bone marrow (BM). Next-generation flow cytometry has become the reference tool to follow minimal residual disease (MRD). We developed a new simpler and cheaper flow cytometry method to analyze bone marrow samples in patients with MM. METHODS: To identify and characterize abnormal PC, we designed a simple panel composed of anti-CD38, anti-kappa and anti-lambda light chain antibodies, combined with two antibody pools with the same fluorophore (anti-CD19 and anti-CD27 for the negative pool, and anti-CD56, anti-CD117 and anti-CD200 antibodies for the positive pool)...
September 2, 2017: Cytometry. Part B, Clinical Cytometry
https://www.readbyqxmd.com/read/28861320/cs1-slamf7-cd319-is-an-effective-immunotherapeutic-target-for-multiple-myeloma
#13
REVIEW
Joseph D Malaer, Porunelloor A Mathew
CS1 (also known as CD319, CRACC and SLAMF7) was identified as an NK cell receptor regulating immune functions. It is also expressed on B cells, T cells, Dendritic cells, NK-T cells, and monocytes. CS1 is overexpressed in multiple myeloma and makes it a target for immunotherapy. A humanized anti-CS1 antibody, Elotuzumab or Empliciti has shown promising results in clinical studies. This review focuses on the biology of CS1 in NK and other hematopoietic cells and multiple myeloma. Anti-CS1 mAb can activate natural cytotoxicity of NK cells as well as enhance ADCC (antibody-dependent cell-mediated cytotoxicity) and thus makes an effective target for immunotherapy of MM...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/28857616/adoptive-cell-therapy-in-multiple-myeloma
#14
S Vallet, M Pecherstorfer, K Podar
Recent breakthrough advances in Multiple Myeloma (MM) immunotherapy have been achieved with the approval of the first two monoclonal antibodies, elotuzumab and daratumumab. Adoptive cell therapy (ACT) represents yet another, maybe the most powerful modality of immunotherapy, in which allogeneic or autologous effector cells are expanded and activated ex vivo followed by their re-infusion back into patients. Infused effector cells belong to two categories: naturally occurring, non-engineered cells (donor lymphocyte infusion, myeloma infiltrating lymphocytes, deltagamma T cells) or genetically- engineered antigen-specific cells (chimeric antigen receptor T or NK cells, TCR-engineered cells)...
August 31, 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/28852198/extracellular-vesicles-as-potential-biomarkers-of-acute-graft-vs-host-disease
#15
G Lia, L Brunello, S Bruno, A Carpanetto, P Omedè, M Festuccia, L Tosti, E Maffini, L Giaccone, M Arpinati, G Ciccone, M Boccadoro, A Evangelista, G Camussi, B Bruno
Acute Graft-vs.-Host Disease (GVHD) is a serious complication after allografting. We carried out an exploratory study to investigate a potential correlation of surface antigens on Extracellular Vesicles (EVs) and acute GVHD. EVs were extracted from serum samples from 41 multiple myeloma patients who underwent allografting. EVs were characterized by flow-cytometry using a panel of 13 antibodies against specific membrane proteins which were reported to be predictive of acute GVHD. We observed a correlation between 3 potential biomarkers expressed on EVs surface and acute GVHD onset by both logistic regression analysis and Cox proportional hazard model...
August 30, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28840598/therapeutic-monoclonal-antibodies-in-combination-with-pomalidomide-can-overcome-refractoriness-to-both-agents-in-multiple-myeloma-a-case-based-approach
#16
Marc-Andrea Baertsch, Michael Hundemer, Jens Hillengass, Hartmut Goldschmidt, Marc S Raab
In multiple myeloma (MM), the synergy between immunomodulatory drugs (IMiDs) and monoclonal antibodies (MABs) has been demonstrated in several pivotal trials. However, disease refractory to either class of compounds remains a major therapeutic challenge. We here report on 3 heavily pretreated MM patients who were refractory to pomalidomide as well as to MABs against CD38 (daratumumab) or CD20 (rituximab), respectively, but who responded to retreatment with the same agents in combination. Responses were durable with PFS of 7, 10 (ongoing), and 30 months from initiation of combination treatment...
August 25, 2017: Hematological Oncology
https://www.readbyqxmd.com/read/28831320/rapid-onset-of-b12-deficiency-in-the-setting-of-worsening-multiple-myeloma-correlations-between-b12-deficiency-and-multiple-myeloma
#17
Karan Seegobin, Satish Maharaj, Grant Nelson, Jeremy Carlson, Cherisse Baldeo, Rafik Jacob
A 67-year-old female with a relapse of multiple myeloma after being in remission for approximately 2 years following autologous stem cell transplant presented with worsening pancytopenia, over a three-month period. There were an increase in her monoclonal spike at 3.13 g/dL on serum protein electrophoresis, low serum B12 levels, and positive intrinsic factor antibodies. Three months before, she had normal B12 levels and a significantly lower monoclonal spike of 1.07 g/dL. She was diagnosed with B12 deficiency with pernicious anaemia in the setting of her worsening myeloma...
2017: Case Reports in Oncological Medicine
https://www.readbyqxmd.com/read/28829415/simultaneous-measurement-of-hdac1-and-hdac6-activity-in-hela-cells-using-uhplc-ms
#18
Claudia A Simões-Pires, Vincent Zwick, Sylvian Cretton, Muriel Cuendet
The search for new histone deacetylase (HDAC) inhibitors is of increasing interest in drug discovery. Isoform selectivity has been in the spotlight since the approval of romidepsin, a class I HDAC inhibitor for cancer therapy, and the clinical investigation of HDAC6-specific inhibitors for multiple myeloma. The present method is used to determine the inhibitory activity of test compounds on HDAC1 and HDAC6 in cells. The isoform activity is measured using the ultra-high-performance liquid chromatography - mass spectrometry (UHPLC-MS) analysis of specific substrates incubated with treated and untreated HeLa cells...
August 10, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28819882/novel-immunotherapies-for-multiple-myeloma
#19
REVIEW
Mattia D'Agostino, Mario Boccadoro, Eric L Smith
PURPOSE OF REVIEW: The treatment landscape of multiple myeloma is rapidly changing; however, despite improvement in patients' survival, it still remains a largely incurable disease. One hallmark of myeloma is substantial immune dysfunction leading to an increased infection rate and the inability of immune surveillance to detect neoplastic cells. Here, we critically analyze clinical approaches to harness the immune system to overcome this defect with a focus on antibody based and adoptive cellular therapies...
August 18, 2017: Current Hematologic Malignancy Reports
https://www.readbyqxmd.com/read/28806822/-multiple-myeloma-current-status-in-diagnostic-testing-and-therapy
#20
Michael Kehrer, Sebastian Koob, Andreas Strauss, Dieter Christian Wirtz, Jan Schmolders
Background Multiple myeloma is a haematological blood cancer of the bone marrow and is classified by the World Health Organisation (WHO) as a plasma cell neoplasm. In multiple myeloma, normal plasma cells transform into malignant myeloma cells and produce large quantities of an abnormal immunoglobulin called monoclonal protein or M protein. This ultimately causes multiple myeloma symptoms such as bone damage or kidney problems. The annual worldwide incidence of multiple myeloma is estimated to be 6 - 7/100,000 and accounts for 1% of all cancer...
August 14, 2017: Zeitschrift Für Orthopädie und Unfallchirurgie
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