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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.
November 21, 2018: 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...
November 12, 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
Zoe Shancer, Matthew Williams, Austin Igelman, Satoshi Nagata, Tomoko Ise, Ira Pastan, Tapan K Bera
Background: Multiple myeloma (MM) is a B-cell malignancy that is incurable for the majority of patients. New treatments are urgently needed. Recombinant immunotoxins (RITs) are chimeric proteins that are composed of the Fv or Fab portion of an antibody fused to a bacterial toxin. B-cell maturation antigen (BCMA) is a lineage-restricted differentiation protein and an ideal target for antibody-based treatments for MM. Methods: RITs were produced by expressing plasmids encoding the components of the anti-BCMA RITs in Escherichia coli followed by inclusion body preparation, solubilization, renaturation, and purification by column chromatography...
June 2018: Antibody therapeutics
Adam D Cohen
Cellular therapies are a rapidly evolving approach to myeloma treatment, which bring a unique mechanism of action with the potential to overcome drug resistance and induce long-term remissions. Two primary approaches are being studied: non-gene-modified strategies, which rely on the endogenous anti-myeloma T-cell repertoire, and gene-modified strategies, which introduce a new T-cell receptor (TCR) or a chimeric antigen receptor (CAR) to confer novel antigen specificity. CAR T cells show the greatest activity to date...
May 23, 2018: American Society of Clinical Oncology Educational Book
Robert Berahovich, Hua Zhou, Shirley Xu, Yuehua Wei, Jasper Guan, Jian Guan, Hizkia Harto, Shuxiang Fu, Kaihuai Yang, Shuying Zhu, Le Li, Lijun Wu, Vita Golubovskaya
The cell-surface protein B cell maturation antigen (BCMA, CD269) has emerged as a promising target for CAR-T cell therapy for multiple myeloma. In order to create a novel BCMA CAR, we generated a new BCMA monoclonal antibody, clone 4C8A. This antibody exhibited strong and selective binding to human BCMA. BCMA CAR-T cells containing the 4C8A scFv were readily detected with recombinant BCMA protein by flow cytometry. The cells were cytolytic for RPMI8226, H929, and MM1S multiple myeloma cells and secreted high levels of IFN-γ in vitro...
September 11, 2018: Cancers
Ken Ohmine
A chimeric antigen receptor (CAR) comprises an extracellular ligand recognition domain linked to CD3ζ and induces T-cell activation upon antigen binding. Recently, the potential of CD19-targeted CAR T-cells (CAR-T) to treat multiple myeloma has been explored. A group in the University of Pennsylvania reported that 4 out of 10 patients with refractory myeloma achieved an objective response (sCR: 1, VGPR: 1, and PR: 2). Although the resultant cancer ablation was an arresting sight, it remains unclear whether CD19 is a suitable target for myeloma...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Lorena Perez-Amill, Berta Marzal, Alvaro Urbano-Ispizua, Manel Juan, Beatriz Martín-Antonio
Seven years ago a chronic lymphocytic leukemia patient was for the first time successfully treated with chimeric antigen receptor (CAR)-modified T cells (CAR-T cells) to target CD19 overexpression in tumor cells. This was the beginning of the development of a new type of immunotherapy treatment in cancer patients. Since then, identification of novel antigens expressed in tumor cells and optimization of both CAR constructs and protocols of administration have opened up new avenues for the successful treatment of other hematological malignancies...
November 13, 2018: Turkish Journal of Haematology: Official Journal of Turkish Society of Haematology
Shih-Feng Cho, Kenneth C Anderson, Yu-Tzu Tai
The approval of the first two monoclonal antibodies targeting CD38 (daratumumab) and SLAMF7 (elotuzumab) in late 2015 for treating relapsed and refractory multiple myeloma (RRMM) was a critical advance for immunotherapies for multiple myeloma (MM). Importantly, the outcome of patients continues to improve with the incorporation of this new class of agents with current MM therapies. However, both antigens are also expressed on other normal tissues including hematopoietic lineages and immune effector cells, which may limit their long-term clinical use...
2018: Frontiers in Immunology
Vasiliki Pelekanou, George Notas, Paraskevi Athanasouli, Konstantinos Alexakis, Fotini Kiagiadaki, Nikolaos Peroulis, Konstantina Kalyvianaki, Errika Kampouri, Hara Polioudaki, Panayiotis Theodoropoulos, Andreas Tsapis, Elias Castanas, Marilena Kampa
Recent advances in cancer immunology revealed immune-related properties of cancer cells as novel promising therapeutic targets. The two TNF superfamily members, APRIL (TNFSF13), and BAFF (TNFSF13B), which are type II membrane proteins, released in active forms by proteolytic cleavage and are primarily involved in B-lymphocyte maturation, have also been associated with tumor growth and aggressiveness in several solid tumors, including breast cancer. In the present work we studied the effect of APRIL and BAFF on epithelial to mesenchymal transition, migration, and stemness of breast cancer cells...
2018: Frontiers in Oncology
Krista Kinneer, John Meekin, Arnaud C Tiberghien, Yu-Tzu Tai, Sandrina Phipps, Christine Mione Kiefer, Marlon C Rebelatto, Nazzareno Dimasi, Alyssa Moriarty, Kyriakos P Papadopoulos, Sriram Sridhar, Stephen J Gregson, Michael J Wick, Luke Masterson, Kenneth C Anderson, Ronald Herbst, Philip W Howard, David A Tice
Purpose: Antibody-drug conjugates (ADC) utilizing noncleavable linker drugs have been approved for clinical use, and several are in development targeting solid and hematologic malignancies including multiple myeloma. Currently, there are no reliable biomarkers of activity for these ADCs other than presence of the targeted antigen. We observed that certain cell lines are innately resistant to such ADCs, and sought to uncover the underlying mechanism of resistance. Experimental Design: The expression of 43 lysosomal membrane target genes was evaluated in cell lines resistant to ADCs bearing the noncleavable linker, pyrrolobenzodiazepine payload SG3376, in vitro The functional relevance of SLC46A3, a lysosomal transporter of noncleavable ADC catabolites whose expression uniquely correlated with SG3376 resistance, was assessed using EPHA2-, HER2-, and BCMA-targeted ADCs and isogenic cells overexpressing or genetically inactivated for SLC46A3 SLC46A3 expression was also examined in patient-derived xenograft and in vitro models of acquired T-DM1 resistance and multiple myeloma bone marrow samples by RT-PCR...
August 21, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Julia Bluhm, Elisa Kieback, Stephen F Marino, Felix Oden, Jörg Westermann, Markus Chmielewski, Hinrich Abken, Wolfgang Uckert, Uta E Höpken, Armin Rehm
Autologous T cells genetically modified with a chimeric antigen receptor (CAR) redirected at CD19 have potent activity in the treatment of B cell leukemia and B cell non-Hodgkin's lymphoma (B-NHL). Immunotherapies to treat multiple myeloma (MM) targeted the B cell maturation antigen (BCMA), which is expressed in most cases of MM. We developed a humanized CAR with specificity for BCMA based on our previously generated anti-BCMA monoclonal antibody. The targeting single-chain variable fragment (scFv) domain exhibited a binding affinity in the low nanomolar range, conferring T cells with high functional avidity...
August 1, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Edgar Meinl, Franziska S Thaler, Stefan F Lichtenthaler
Proteolytic shedding of the receptors BCMA, TACI, and BAFFR reduces their cell-surface expression and ligand-mediated survival of B cell subsets. This shedding is executed by protease γ-secretase or by metalloproteases, and is partially dependent on ligand binding and receptor interactions. Shed receptors may serve as biomarkers for autoimmunity and lymphoma.
September 2018: Trends in Immunology
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