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Jooeun Bae, Mehmet Samur, Paul Richardson, Nikhil C Munshi, Kenneth C Anderson
To expand the breadth and extent of current multiple myeloma (MM)-specific immunotherapy, we have identified various antigens on CD138+ tumor cells from newly diagnosed MM patients (n = 616) and confirmed B-cell maturation antigen (BCMA) as a key myeloma-associated antigen. The aim of this study is to target the BCMA, which promotes MM cell growth and survival, by generating BCMA-specific memory CD8+ CTL that mediate effective and long-lasting immunity against MM. Here we report the identification of novel engineered peptides specific to BCMA, BCMA72-80 (YLMFLLRKI), and BCMA54-62 (YILWTCLGL), which display improved affinity/stability to HLA-A2 compared to their native peptides and induce highly functional BCMA-specific CTL with increased activation (CD38, CD69) and co-stimulatory (CD40L, OX40, GITR) molecule expression...
March 12, 2019: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Maria Gavriatopoulou, Ioannis Ntanasis-Stathopoulos, Meletios Athanasios Dimopoulos, Evangelos Terpos
B-cell maturation antigen (BCMA) belongs to the tumor necrosis factor receptor family and is expressed on late B-cells and plasma cells. Serum BCMA is elevated in patients with multiple myeloma (MM) and chronic lymphocytic leukemia (CLL), and might represent a novel prognostic and monitoring tool. Serum BCMA levels can predict both progression free survival (PFS) and overall survival (OS). Several therapeutic strategies are currently under investigation including BCMA-directed monoclonal Abs (either naked or with drug conjugates, and bispecific Abs) and cellular T-cell therapies (chimeric antigen receptor T-cells) with impressive clinical results...
February 27, 2019: Expert Review of Anticancer Therapy
Francisco Josué Carrillo-Ballesteros, Edith Oregon-Romero, Ramon Antonio Franco-Topete, Luis Humberto Govea-Camacho, Alvaro Cruz, José Francisco Muñoz-Valle, Felipe Jesús Bustos-Rodríguez, Ana Laura Pereira-Suárez, Claudia Azucena Palafox-Sánchez
B-cell activating factor (BAFF) is a major cytokine that regulates B-cell survival, maturation and differentiation through its binding with its receptors: BAFF receptor (BAFF-R), transmembrane activator and cyclophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA). These receptors have been demonstrated to be involved in tertiary lymphoid structure formation; however, their role in germinal centers (GCs) has remained elusive. The aim of the present study was to determine the expression profiles of BAFF and its receptors in secondary lymphoid tissues...
March 2019: Experimental and Therapeutic Medicine
Zoë Shancer, Xiu-Fen Liu, Satoshi Nagata, Qi Zhou, Tapan K Bera, Ira Pastan
Multiple myeloma (MM) is a B cell malignancy for which new treatments are urgently needed. The B cell maturation antigen (BCMA) is a lineage-restricted differentiation protein highly expressed on myeloma. Recombinant immunotoxins (RITs) are proteins composed of the Fv or Fab portion of an antibody fused to a bacterial toxin. We previously treated H929 myeloma s.c. tumors with anti-BCMA immunotoxins, very active on killing cultured cells, and observed tumor growth inhibition but not complete tumor responses...
February 19, 2019: Proceedings of the National Academy of Sciences of the United States of America
Shih-Feng Cho, Kenneth C Anderson, Yu-Tzu Tai
No abstract text is available yet for this article.
December 2018: Annals of Translational Medicine
Tiantian Ma, Jing Shi, Huasheng Liu
Multiple myeloma (MM) remains an incurable plasma cells malignancy because of its complex genetic heterogeneity and high relapse rate post immunotherapy. The encouraging results of chimeric antigen receptor T cell (CAR-T) targeting B cell maturation antigen (BCMA) immunotherapy clinical trials have shed light on curing MM in recent years. However, many therapeutic side effects limit the promotion and clinical use of this novel effective approach such as cytokine release syndrome, antigen escape, and neurotoxicity...
January 28, 2019: Annals of Hematology
Jun Li, Julia Koerner, Michael Basler, Thomas Brunner, Christopher J Kirk, Marcus Groettrup
Chronic antibody-mediated rejection is the leading cause of allograft dysfunction and loss after kidney transplantation, and current immunosuppressive regimens fail to target the plasma cells that produce alloantibodies. We previously showed that treatment with the immunoproteasome inhibitor ONX 0914 prevented the expansion of plasma cells and prevented chronic allograft nephropathy and organ failure after kidney transplantation in rats, but the mechanism has remained elusive. In the current study, we confirmed a long-term reduction in alloantibody production and improvements in allograft histology in rats treated with ONX 0914 or with the broad-spectrum proteasome inhibitor bortezomib...
January 22, 2019: Kidney International
Szymon Kowalski, Dariusz Wyrzykowski, Stanislaw Hac, Michal Rychlowski, Marek Witold Radomski, Iwona Inkielewicz-Stepniak
Pancreatic cancer is characterized by one of the lowest five-year survival rates. In search for new treatments, some studies explored several metal complexes as potential anticancer drugs. Therefore, we investigated three newly synthesized oxidovanadium(IV) complexes with 2-methylnitrilotriacetate (bcma3- ), N -(2-carbamoylethyl)iminodiacetate (ceida3- ) and N -(phosphonomethyl)-iminodiacetate (pmida4- ) ligands as potential anticancer compounds using pancreatic cancer cell lines. We measured: Cytotoxicity using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), neutral red (NR) and lactate dehydrogenase (LDH) assay; antiproliferative activity by bromodeoxyuridine BrdU assay; reactive oxygen species (ROS) generation and cell cycle analysis by flow cytometry; protein level by Western blot and cellular morphology by confocal laser scanning microscopy...
January 10, 2019: International Journal of Molecular Sciences
Kristine M Thompson, Kristi M Swanson, Debra L Cox, Robert B Kirchner, Jennifer J Russell, Robert A Wermers, Curtis B Storlie, Matthew G Johnson, James M Naessens
Objective: To assess the impact of implementing bar-code medication administration (BCMA) technology on the rate of medication administration errors in the inpatient setting, specifically those that affect the patient and result in harm. Patients and Methods: Implementation of the new technology began in September 2008 in a staged rollout of 4 or 5 units at a time in 11 separate waves. All corresponding medication administrations and voluntarily reported medication-related adverse events from March 1, 2007, through September 30, 2013, were included for analyses...
December 2018: Mayo Clinic Proceedings. Innovations, Quality & Outcomes
Andreas Pahl, Christian Lutz, Torsten Hechler
Amanitin-based ADCs represent a new class of ADCs using a novel mode of action. This payload introduces a novel mode of action into oncology therapy, the inhibition of RNA Polymerase II. The high potency of the toxin leads to highly efficacious ADCs. The development of the technology around this toxin will be described. These developments support the clinical development of amanitin-based ADCs by using a toxin with a new mode of action and with a favorable therapeutic index. HDP-101 is an Amanitin based ADC directed against BCMA and will be advancing to the clinical phase in 2019...
December 2018: Drug Discovery Today. Technologies
Fatih M Uckun, Sanjive Qazi, Taner Demirer, Richard E Champlin
Recurrence of disease due to chemotherapy drug resistance remains a major obstacle to a more successful survival outcome of multiple myeloma (MM). Overcoming drug resistance and salvaging patients with relapsed and/or refractory (R/R) MM is an urgent and unmet medical need. Several new personalized treatment strategies have been developed against molecular targets to overcome this drug resistance. There are several targeted therapeutics with anti-MM activity in clinical pipeline, including inhibitors of anti-apoptotic proteins, monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, fusion proteins, and various cell therapy platforms...
December 10, 2018: EBioMedicine
Hanley N Abramson
The past two decades have seen a revolution in multiple myeloma (MM) therapy with the introduction of several small molecules, mostly orally effective, whose mechanisms are based on proteasome inhibition, histone deacetylase (HDAC) blockade, and immunomodulation. Immunotherapeutic approaches to MM treatment using monoclonal antibodies (mAbs), while long in development, began to reap success with the identification of CD38 and SLAMF7 as suitable targets for development, culminating in the 2015 Food and Drug Administration (FDA) approval of daratumumab and elotuzumab, respectively...
December 7, 2018: International Journal of Molecular Sciences
Jesus Melendez, Rita Bodine, Karen Park
BACKGROUND: A quality improvement initiative of the Veterans Health Administration (VHA) aims to reduce frequency of medication administration to Veterans per day. Medication administration practices in our community living center (CLC) units are similar to an acute care medical unit versus a home environment. The objective of this project was to reduce medication administration frequency in order to minimize the number of interruptions to both Veterans and nurses. METHODS: A retrospective chart review was conducted for Veterans residing in a pilot CLC from January through March 2018...
November 28, 2018: Journal of Pharmacy Practice
(no author information available yet)
Targeting BCMA with the antibody-drug conjugate GSK2857916 is well tolerated in a phase I trial.
January 2019: Cancer Discovery
Suzanne Trudel, Nikoletta Lendvai, Rakesh Popat, Peter M Voorhees, Brandi Reeves, Edward N Libby, Paul G Richardson, Larry D Anderson, Heather J Sutherland, Kwee Yong, Axel Hoos, Michele M Gorczyca, Soumi Lahiri, Zangdong He, Daren J Austin, Joanna B Opalinska, Adam D Cohen
BACKGROUND: B-cell maturation antigen (BCMA) is a cell-surface receptor of the tumour necrosis superfamily required for plasma cell survival. BMCA is universally detected on patient-derived myeloma cells and has emerged as a selective antigen to be targeted by novel treatments in multiple myeloma. We assessed the safety, tolerability, and preliminary clinical activity of GSK2857916, a novel anti-BCMA antibody conjugated to microtubule-disrupting agent monomethyl auristatin F, in patients with relapsed and refractory multiple myeloma...
December 2018: Lancet Oncology
Marcel Boonen, Frans J H Vosman, Alistair Niemeijer
OBJECTIVES: This study aims to assess how care is mediated through technology by analyzing the interaction between nurses, patients, and a Bar Coded Medication Administration (BCMA) system. The objective is to explore how patients experience care through medication technology, with the main focus of our observations and interviews on nurses rather than patients. METHODS: A qualitative ethnographic study was conducted in an orthopedic ward of a Dutch general hospital...
October 26, 2018: International Journal of Technology Assessment in Health Care
Yixiang Chen, Chloé Peubez, Victoria Smith, Shiqiu Xiong, Gabriella Kocsis-Fodor, Ben Kennedy, Simon Wagner, Constantine Balotis, Sandrine Jayne, Martin J S Dyer, Salvador Macip
CUDC-907, a dual PI3K/HDAC inhibitor, has been proposed to have therapeutic potential in hematopoietic malignancies. However, the molecular mechanisms of its effects in chronic lymphocytic leukaemia (CLL) remain elusive. We show that CLL cells are sensitive to CUDC-907, even under conditions similar to the protective microenvironment of proliferation centres. CUDC-907 inhibited PI3K/AKT and HDAC activity, as expected, but also suppressed RAF/MEK/ERK and STAT3 signalling and reduced the expression of anti-apoptotic BCL-2 family proteins BCL-2, BCL-xL, and MCL-1...
October 24, 2018: Journal of Cellular and Molecular Medicine
Jinhuan Xu, Qiuxiang Wang, Hao Xu, Chaojiang Gu, Lijun Jiang, Jue Wang, Di Wang, Bin Xu, Xia Mao, Jin Wang, Zhiqiong Wang, Yi Xiao, Yicheng Zhang, Chunrui Li, Jianfeng Zhou
BACKGROUND: POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome still has no standard treatment. On the basis that both POEMS syndrome and myeloma have an underlying plasma cell dyscrasia, anti-myeloma therapy can be expected to be useful for POEMS syndrome. Chimeric antigen receptor T (CAR-T) cells targeting B cell maturation antigen (BCMA) has been used in the treatment of relapsed and refractory multiple myeloma (RRMM). No POEMS syndrome cases treated with anti-BCMA CAR-T cells have been reported...
October 22, 2018: Journal of Hematology & Oncology
Krista Kinneer, Matt Flynn, Suneetha B Thomas, John Meekin, Reena Varkey, Xiaodong Xiao, Haihong Zhong, Shannon Breen, Paul G Hynes, Ryan Fleming, Binyam Bezabeh, Cui Tracy Chen, Leslie Wetzel, Ruoyan Chen, Nazzareno Dimasi, Yu-Tzu Tai, Kenneth C Anderson, Ronald Herbst, Philip W Howard, Elaine M Hurt, David A Tice
No abstract text is available yet for this article.
October 12, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Hideto Tamura
Multiple myeloma (MM) involves the immune dysregulation not only of B cells but also of NK, T, and dendritic cells. Furthermore, the number of regulatory T and myeloid-derived immunosuppressive cells, which are associated with disease progression, also increases. Immunomodulatory drugs (IMiDs) such as lenalidomide and pomalidomide exhibit an antimyeloma effect and improve the immune status. Thus, IMiD-enhanced antibody-dependent cell cytotoxicity increases the cytotoxic activity of monoclonal antibody treatment...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
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