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Chimeric antigen myeloma

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https://www.readbyqxmd.com/read/27913524/cellular-and-vaccine-immunotherapy-for-multiple-myeloma
#1
Alfred L Garfall, Edward A Stadtmauer
Allogeneic hematopoietic cell transplantation and donor lymphocyte infusion for multiple myeloma (MM) can induce graft-versus-myeloma immunity and long-term survivorship, but limited efficacy and associated toxicities have prevented its widespread use. Cellular immunotherapies and vaccines seek to induce more specific, reliable, and potent antimyeloma immune responses with less treatment-related risk than is possible with allogeneic transplantation. Advances in molecular biology, and basic and applied immunology, have led to promising approaches such as genetically engineered T cells with chimeric antigen receptors and T-cell receptors targeting myeloma-specific epitopes, vaccine primed ex vivo expanded autologous T cells, expanded marrow-infiltrating lymphocytes, and plasma cell/dendritic cell fusion vaccines...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27888901/-monoclonal-antibodies-against-pcsk9-from-bench-to-clinic
#2
Carlos Guijarro Herraiz
Antibodies are glycoproteins with high specificity binding to multiple antigens due to the large number of structural conformations of the variable chains. Hybridoma technology (fusion of myeloma cells with immunoglobulin-producing lymphocytes) has allowed the synthesis of large quantities of unique antibodies (monoclonal [mAb]). mAbs were initially murine. Subsequently, chimeric mAbs were developed, followed by humanized mAbs and finally human mAbs. The high selectivity and good tolerance of human mAbs allows their therapeutic administration to block specific exogenous or endogenous molecules...
May 2016: Clínica e Investigación en Arteriosclerosis
https://www.readbyqxmd.com/read/27875673/recent-advances-in-engineered-t-cell-therapies-targeting-b-cell-malignancies
#3
Nathan Singh
Immunotherapy using engineered autologous T cells has been attempted for decades, but clinical trials have only recently demonstrated efficacy. The combination of enhanced manufacturing techniques, highly efficient engineering, appropriate target selection and synthetic receptors with potent T cell activating domains has led to the development of highly-active cellular therapy products. B-cell malignancies have served as the paradigmatic diseases to initially evaluate and subsequently hone engineered T cells targeting cancer...
October 2016: Discovery Medicine
https://www.readbyqxmd.com/read/27870103/role-of-immunotherapy-in-targeting-the-bone-marrow-microenvironment-in-multiple-myeloma-an-evolving-therapeutic-strategy
#4
Clement Chung
Multiple myeloma (referred to henceforth as myeloma) is a B-cell malignancy characterized by unregulated growth of plasma cells in the bone marrow. The treatment paradigm for myeloma underwent significant evolution in the last decade, with an improved understanding of the pathogenesis of the disease as well as the development of therapeutic agents that target not only the tumor cells but also their microenvironment. Despite these therapeutic advances, the prognosis of patients with relapsed or refractory myeloma remains poor...
November 21, 2016: Pharmacotherapy
https://www.readbyqxmd.com/read/27865176/adoptive-immunotherapy-for-hematological-malignancies-current-status-and-new-insights-in-chimeric-antigen-receptor-t-cells
#5
REVIEW
Alessandro Allegra, Vanessa Innao, Demetrio Gerace, Doriana Vaddinelli, Caterina Musolino
Hematological malignancies frequently express cancer-associated antigens that are shared with normal cells. Such tumor cells elude the host immune system because several T cells targeted against self-antigens are removed during thymic development, and those that persist are eliminated by a regulatory population of T cells. Chimeric antigen receptor-modified T cells (CAR-Ts) have emerged as a novel modality for tumor immunotherapy due to their powerful efficacy against tumor cells. These cells are created by transducing genes-coding fusion proteins of tumor antigen-recognition single-chain Fv connected to the intracellular signaling domains of T cell receptors, and are classed as first-, second- and third-generation, differing on the intracellular signaling domain number of T cell receptors...
November 2016: Blood Cells, Molecules & Diseases
https://www.readbyqxmd.com/read/27863374/magic-year-for-multiple-myeloma-therapeutics-key-takeaways-from-the-ash-2015-annual-meeting
#6
REVIEW
Kejie Zhang, Aakash Desai, Dongfeng Zeng, Tiejun Gong, Peihua Lu, Michael Wang
Despite the availability of various anticancer agents, Multiple Myeloma (MM) remains incurable in most cases, along with high relapse rate in the patients treated with these agents. The year 2015 saw major advancements in our battle against multiple myeloma. In 2015, the U.S. Food and Drug Administration (FDA) approved three new therapies for multiple myeloma, namely Ixazomib (an oral proteasome inhibitor), Daratumumab and Elotuzumab (monoclonal antibodies against CD38 and SLAMF7 respectively). The purpose of this review is to provide a detailed analysis of these aforementioned breakthrough therapies and two other newer agents, Filanesib (kinesis spindle inhibitor) and selinexor (SINE inhibitor), presented at the 2015 annual meeting of American Society of Hematology (ASH)...
November 11, 2016: Oncotarget
https://www.readbyqxmd.com/read/27696259/targeting-the-bone-marrow-microenvironment
#7
Michele Moschetta, Yawara Kawano, Klaus Podar
Unprecedented advances in multiple myeloma (MM) therapy during the last 15 years are predominantly based on our increasing understanding of the pathophysiologic role of the bone marrow (BM) microenvironment. Indeed, new treatment paradigms, which incorporate thalidomide, immunomodulatory drugs (IMiDs), and proteasome inhibitors, target the tumor cell as well as its BM microenvironment. Ongoing translational research aims to understand in more detail how disordered BM-niche functions contribute to MM pathogenesis and to identify additional derived targeting agents...
2016: Cancer Treatment and Research
https://www.readbyqxmd.com/read/27638367/chimeric-antigen-receptor-t-cells-and-hematopoietic-cell-transplantation-how-not-to-put-the-cart-before-the-horse
#8
Saad S Kenderian, David L Porter, Saar Gill
Hematopoietic cell transplantation (HCT) remains an important and potentially curative option for most hematologic malignancies. As a form of immunotherapy, allogeneic HCT (allo-HCT) offers the potential for durable remissions but is limited by transplantation- related morbidity and mortality owing to organ toxicity, infection, and graft-versus-host disease. The recent positive outcomes of chimeric antigen receptor T (CART) cell therapy in B cell malignancies may herald a paradigm shift in the management of these disorders and perhaps other hematologic malignancies as well...
September 13, 2016: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/27592405/review-current-clinical-applications-of-chimeric-antigen-receptor-car-modified-t-cells
#9
REVIEW
Mark B Geyer, Renier J Brentjens
The past several years have been marked by extraordinary advances in clinical applications of immunotherapy. In particular, adoptive cellular therapy utilizing chimeric antigen receptor (CAR)-modified T cells targeted to CD19 has demonstrated substantial clinical efficacy in children and adults with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) and durable clinical benefit in a smaller subset of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or B-cell non-Hodgkin lymphoma (B-NHL)...
November 2016: Cytotherapy
https://www.readbyqxmd.com/read/27412889/t-cells-expressing-an-anti-b-cell-maturation-antigen-chimeric-antigen-receptor-cause-remissions-of-multiple-myeloma
#10
Syed Abbas Ali, Victoria Shi, Irina Maric, Michael Wang, David F Stroncek, Jeremy J Rose, Jennifer N Brudno, Maryalice Stetler-Stevenson, Steven A Feldman, Brenna G Hansen, Vicki S Fellowes, Frances T Hakim, Ronald E Gress, James N Kochenderfer
Therapies with novel mechanisms of action are needed for multiple myeloma (MM). B-cell maturation antigen (BCMA) is expressed in most cases of MM. We conducted the first-in-humans clinical trial of chimeric antigen receptor (CAR) T cells targeting BCMA. T cells expressing the CAR used in this work (CAR-BCMA) specifically recognized BCMA-expressing cells. Twelve patients received CAR-BCMA T cells in this dose-escalation trial. Among the 6 patients treated on the lowest 2 dose levels, limited antimyeloma activity and mild toxicity occurred...
September 29, 2016: Blood
https://www.readbyqxmd.com/read/27384848/gene-modified-t-cell-therapy-using-chimeric-antigen-receptors-for-pediatric-hematologic-malignancies
#11
Yozo Nakazawa
Chimeric antigen receptor (CAR) is the generic name for synthetic T cell receptors redirected to tumor-associated antigens. Most CARs consist of an ectodomain (scFv or ligand), a hinge region, a transmembrane domain, and signaling endodomains derived from one or two co-stimulatory molecules (CD28, 4-1BB, etc) and from a CD3-ζ chain. CD19-targeted CAR T cell therapy has achieved major success in the treatment of B cell malignancies. CD19 CAR-T cells elicited complete remission in 70-90% of adult and pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL)...
June 2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/27270177/clinical-responses-with-t-lymphocytes-targeting-malignancy-associated-%C3%AE%C2%BA-light-chains
#12
Carlos A Ramos, Barbara Savoldo, Vicky Torrano, Brandon Ballard, Huimin Zhang, Olga Dakhova, Enli Liu, George Carrum, Rammurti T Kamble, Adrian P Gee, Zhuyong Mei, Meng-Fen Wu, Hao Liu, Bambi Grilley, Cliona M Rooney, Malcolm K Brenner, Helen E Heslop, Gianpietro Dotti
BACKGROUND: Treatment of B cell malignancies with adoptive transfer of T cells with a CD19-specific chimeric antigen receptor (CAR) shows remarkable clinical efficacy. However, long-term persistence of T cells targeting CD19, a pan-B cell marker, also depletes normal B cells and causes severe hypogammaglobulinemia. Here, we developed a strategy to target B cell malignancies more selectively by taking advantage of B cell light Ig chain restriction. We generated a CAR that is specific for the κ light chain (κ...
July 1, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27141398/lenalidomide-enhances-antitumor-functions-of-chimeric-antigen-receptor-modified-t-cells
#13
Pavel Otáhal, Dana Průková, Vlastimil Král, Milan Fabry, Petra Vočková, Lucie Latečková, Marek Trněný, Pavel Klener
Tumor immunotherapy based on the use of chimeric antigen receptor modified T cells (CAR T cells) is a promising approach for the treatment of refractory hematological malignancies. However, a robust response mediated by CAR T cells is observed only in a minority of patients and the expansion and persistence of CAR T cells in vivo is mostly unpredictable.Lenalidomide (LEN) is an immunomodulatory drug currently approved for the treatment of multiple myeloma (MM) and mantle cell lymphoma, while it is clinically tested in the therapy of diffuse large B-cell lymphoma of activated B cell immunophenotype...
April 2016: Oncoimmunology
https://www.readbyqxmd.com/read/27095318/t-cell-receptor-engineered-cells-for-the-treatment-of-hematologic-malignancies
#14
REVIEW
Nasheed M Hossain, Aude G Chapuis, Roland B Walter
Recent attention in adoptive immunotherapy for hematologic malignancies has focused on lymphocytes expressing chimeric antigen receptors. An alternative technique to redirect the immune system toward cancer cells involves the use of T-cells carrying an engineered tumor-recognizing T-cell receptor (TCR). This approach allows targeting of surface or intracellular/nuclear proteins as long as they are processed and presented on the cell surface by human leukocyte antigen molecules. Several trials in advanced solid tumors, particularly melanoma and synovial sarcoma, support the validity of this strategy, although tumor responses have often been short-lived...
August 2016: Current Hematologic Malignancy Reports
https://www.readbyqxmd.com/read/27068946/development-of-chimeric-antigen-receptors-for-multiple-myeloma
#15
REVIEW
Carolina Martínez-Cingolani, Jean Christophe Bories
Multiple myeloma (MM) is a haematologic malignancy characterized by the expansion of monoclonal plasma cells in the bone marrow. It is associated with serum or urine monoclonal protein and organ damage including renal failure, anaemia, hypercalcaemia and bone lesions. Despite recent improvements MM still remains an incurable disease. Previous studies have shown that the adoptive transfer of autologous T-cells modified to express chimeric antigen receptors (CAR) is effective in cases of acute and chronic lymphoid leukaemia...
April 15, 2016: Biochemical Society Transactions
https://www.readbyqxmd.com/read/26953076/the-prospects-and-promise-of-chimeric-antigen-receptor-immunotherapy-in-multiple-myeloma
#16
REVIEW
Antonia Rotolo, Valentina Caputo, Anastasios Karadimitris
Despite encouraging therapeutic advances, multiple myeloma (MM) remains an incurable malignancy. The exciting results of chimaeric antigen receptor (CAR)-based immunotherapy in CD19(+) B-cell malignancies have spurred a great interest in extending the use of the CAR technology to other cancers, including MM. Availability of a specific, tumour-restricted antigen is crucial for the design of successful antibody-based CAR therapy. However, in MM, as in other malignancies, the relative dearth of such antigens-targets represents the main obstacle for the wider pre-clinical development and clinical application of the CAR technology...
May 2016: British Journal of Haematology
https://www.readbyqxmd.com/read/26913437/-car-technology-and-its-application-in-treatment-of-multiple-myeloma-review
#17
REVIEW
Tong Li, Hong-Tao Wang, Zhuo-Gang Liu
Multiple myeloma (MM) is a hematologic malignancy resulted from genetic mutations in the process of B lymphocyte differentiating into plasma cells, the chemotherapy is the main treatment method, especially with the development of proteasome inhibitors and other drugs, the overall survival rate of MM patients has improved greatly, but the chemoresistance is still an important reason for treatment failure. Chimeric antigen receptor (CAR)-modified T lymphocyte therapy is a new method for tumor adoptive immunotherapy...
February 2016: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/26899275/reprint-of-fast-cars-and-no-brakes-autologous-stem-cell-transplantation-as-a-platform-for-novel-immunotherapies
#18
REVIEW
Miguel-Angel Perales, Craig S Sauter, Philippe Armand
Autologous stem cell transplantation (ASCT) is indicated in a number of hematologic malignancies, including multiple myeloma, non-Hodgkin lymphoma, and Hodgkin lymphoma. Relapse, however, remains 1 of the main causes of post-ASCT failure, and several strategies are being investigated to decrease the risk of relapse of progression. Recent advances in the treatment of hematological malignancies have included adoptive transfer of genetically modified T cells that express chimeric antigen receptors or T cell receptors, as well the use of checkpoint inhibitors...
March 2016: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/26874466/chimeric-antigen-receptor-t-cell-treatment-in-hematologic-malignancies
#19
REVIEW
Hakan Goker, Umit Yavuz Malkan, Haluk Demiroglu, Yahya Buyukasik
Adoptive transfer of T cells that have genetically engineered chimeric antigen receptors (CARs) is an encouraging treatment modality in the hematological malignancies. These T cells are capable of selectively recognizing tumor-associated antigens. There are a variety of reported, as well as ongoing studies on the utilization of CAR-T cells in the treatment of leukemia, myeloma, as well as B and T cell lymphomas. In this review, we aimed to highlight current understanding of this promising treatment modality, including its efficacy and adverse effects...
February 2016: Transfusion and Apheresis Science
https://www.readbyqxmd.com/read/26858358/pre-clinical-evaluation-of-cd38-chimeric-antigen-receptor-engineered-t-cells-for-the-treatment-of-multiple-myeloma
#20
Esther Drent, Richard W J Groen, Willy A Noort, Maria Themeli, Jeroen J Lammerts van Bueren, Paul W H I Parren, Jürgen Kuball, Zsolt Sebestyen, Huipin Yuan, Joost de Bruijn, Niels W C J van de Donk, Anton C M Martens, Henk M Lokhorst, Tuna Mutis
Adoptive transfer of chimeric antigen receptor-transduced T cells is a promising strategy for cancer immunotherapy. The CD38 molecule, with its high expression on multiple myeloma cells, appears a suitable target for antibody therapy. Prompted by this, we used three different CD38 antibody sequences to generate second-generation retroviral CD38-chimeric antigen receptor constructs with which we transduced T cells from healthy donors and multiple myeloma patients. We then evaluated the preclinical efficacy and safety of the transduced T cells...
May 2016: Haematologica
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