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Chimeric antigen myeloma

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https://www.readbyqxmd.com/read/28689001/immuno-oncologic-approaches-car-t-cells-and-checkpoint-inhibitors
#1
REVIEW
Francesca Gay, Mattia D'Agostino, Luisa Giaccone, Mariella Genuardi, Moreno Festuccia, Mario Boccadoro, Benedetto Bruno
Advances in understanding myeloma biology have shown that disease progression is not only the consequence of intrinsic tumor changes but also of interactions between the tumor and the microenvironment in which the cancer grows. The immune system is an important component of the tumor microenvironment in myeloma, and acting on the immune system is an appealing new treatment strategy. There are 2 ways to act toward immune cells and boost antitumor immunity: (1) to increase antitumor activity (acting on T and NK cytotoxic cells), and (2) to reduce immunosuppression (acting on myeloid-derived stem cells and T regulatory cells)...
June 17, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28625826/drug-discovery-and-therapeutic-delivery-for-the-treatment-of-b-and-t-cell-tumors
#2
Regan Stephenson, Ankur Singh
Hematological malignancies manifest as lymphoma, leukemia, and myeloma, and remain a burden on society. From initial therapy to endless relapse-related treatment, societal burden is felt not only in the context of healthcare cost, but also in the compromised quality of life of patients. Long-term therapeutic strategies have become the standard in keeping hematological malignancies at bay as these cancers develop resistance to each round of therapy with time. As a result, there is a continual need for the development of new drugs to combat resistant disease in order to prolong patient life, if not to produce a cure...
June 15, 2017: Advanced Drug Delivery Reviews
https://www.readbyqxmd.com/read/28588060/sending-car-t-cells-after-multiple-myeloma
#3
(no author information available yet)
Preliminary results from an ongoing phase I clinical trial in China suggest that chimeric antigen receptor T cells engineered to home in on a protein called BCMA may be a potent therapeutic option for multiple myeloma. The therapy was well tolerated and induced complete, durable responses in patients with relapsed/refractory disease.
June 6, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28561703/hematologic-malignancies-plasma-cell-disorders
#4
Madhav V Dhodapkar, Ivan Borrello, Adam D Cohen, Edward A Stadtmauer
Multiple myeloma (MM) is a plasma cell malignancy characterized by the growth of tumor cells in the bone marrow. Properties of the tumor microenvironment provide both potential tumor-promoting and tumor-restricting properties. Targeting underlying immune triggers for evolution of tumors as well as direct attack of malignant plasma cells is an emerging focus of therapy for MM. The monoclonal antibodies daratumumab and elotuzumab, which target the plasma cell surface proteins CD38 and SLAMF7/CS1, respectively, particularly when used in combination with immunomodulatory agents and proteasome inhibitors, have resulted in high response rates and improved survival for patients with relapsed and refractory MM...
2017: American Society of Clinical Oncology Educational Book
https://www.readbyqxmd.com/read/28506593/a-rational-strategy-for-reducing-on-target-off-tumor-effects-of-cd38-chimeric-antigen-receptors-by-affinity-optimization
#5
Esther Drent, Maria Themeli, Renée Poels, Regina de Jong-Korlaar, Huipin Yuan, Joost de Bruijn, Anton C M Martens, Sonja Zweegman, Niels W C J van de Donk, Richard W J Groen, Henk M Lokhorst, Tuna Mutis
Chimeric antigen receptors (CARs) can effectively redirect cytotoxic T cells toward highly expressed surface antigens on tumor cells. The low expression of several tumor-associated antigens (TAAs) on normal tissues, however, hinders their safe targeting by CAR T cells due to on-target/off-tumor effects. Using the multiple myeloma (MM)-associated CD38 antigen as a model system, here, we present a rational approach for effective and tumor-selective targeting of such TAAs. Using "light-chain exchange" technology, we combined the heavy chains of two high-affinity CD38 antibodies with 176 germline light chains and generated ∼124 new antibodies with 10- to >1,000-fold lower affinities to CD38...
May 13, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28483281/preclinical-data-support-leveraging-cs1-chimeric-antigen-receptor-t-cell-therapy-for-systemic-light-chain-amyloidosis
#6
Michael Rosenzweig, Ryan Urak, Miriam Walter, Laura Lim, James F Sanchez, Amrita Krishnan, Stephen Forman, Xiuli Wang
BACKGROUND AIMS: Light chain amyloidosis (AL) is a protein deposition disorder that is a result of a plasma cell dyscrasia, similar to multiple myeloma (MM). Immunotherapy is an attractive approach because of the low burden of disease, but the optimal target for AL is unclear. CS1 and B-cell maturation antigen (BCMA) are two potential targets because they are expressed on normal plasma cells and MM cells. METHODS: We performed a prospective study evaluating bone marrow specimens of 20 patients with plasma cell diseases, 10 with AL and 10 with MM...
July 2017: Cytotherapy
https://www.readbyqxmd.com/read/28259300/immunotherapy-for-the-treatment-of-multiple-myeloma
#7
REVIEW
Sung-Hoon Jung, Hyun-Ju Lee, Manh-Cuong Vo, Hyeoung-Joon Kim, Je-Jung Lee
Immunotherapy has recently emerged as a promising treatment for multiple myeloma (MM). There are now several monoclonal antibodies that target specific surface antigens on myeloma cells or the checkpoints of immune and myeloma cells. Elotuzumab (targeting SLAMF7), daratumumab (targeting CD38), and pembrolizumab (targeting PD-1) have shown clinical activity in clinical studies with relapsed/refractory MM. Dendritic cell vaccination is a safe strategy that has shown some efficacy in a subset of myeloma patients and may become a crucial part of MM treatment when combined with immunomodulatory drugs or immune check-point blockade...
March 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/28201977/targeting-the-immune-niche-within-the-bone-marrow-microenvironment-the-rise-of-immunotherapy-in-multiple-myeloma
#8
Klaus Podar, D Jäger
Multiple Myeloma (MM) cells inhibit the development of an effective anti-MM immune response via defects in T cell function, ineffective antigen presentation; reduced phagocytic capacity; natural killer and dendritic cell dysfunction; decreased responsiveness to IL-2 and defects in B cell immunity; upregulation of inhibitory pathways; and production of excessive pro-inflammatory cytokines. Moreover, immune cells including plasmacytoid dendritic cells and macrophages trigger tumor cell proliferation, survival, and drug resistance...
February 13, 2017: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/28151713/immune-therapies-in-multiple-myeloma
#9
EDITORIAL
Shaji K Kumar, Kenneth C Anderson
Treatment paradigms have changed rapidly for multiple myeloma, and immune therapies have taken center stage. Advances in therapies for myeloma have led to a dramatic improvement in the survival of patients with this incurable malignancy. The immune system is significantly impaired in patients with myeloma as a result of the disease leading to suppression of normal plasma cells as well the negative effects on cellular immunity. Given this scenario, immune approaches have not been successful until recently. Monoclonal antibodies directed against CD38 (daratumumab) and SLAMF7 (elotuzumab) are already in the clinic, and several other antibodies directed against different plasma cell antigens are under evaluation...
November 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28053195/tcr-based-therapy-for-multiple-myeloma-and-other-b-cell-malignancies-targeting-intracellular-transcription-factor-bob1
#10
Lorenz Jahn, Pleun Hombrink, Renate S Hagedoorn, Michel G D Kester, Dirk M van der Steen, Tania Rodriguez, Tsvetelina Pentcheva-Hoang, Arnoud H de Ru, Marjolein P Schoonakker, Miranda H Meeuwsen, Marieke Griffioen, Peter A van Veelen, J H Frederik Falkenburg, Mirjam H M Heemskerk
Immunotherapy for hematological malignancies or solid tumors by administration of monoclonal antibodies or T cells engineered to express chimeric antigen receptors or T-cell receptors (TCRs) has demonstrated clinical efficacy. However, antigen-loss tumor escape variants and the absence of currently targeted antigens on several malignancies hamper the widespread application of immunotherapy. We have isolated a TCR targeting a peptide of the intracellular B cell-specific transcription factor BOB1 presented in the context of HLA-B*07:02...
March 9, 2017: Blood
https://www.readbyqxmd.com/read/27999737/immunotherapies-targeting-cd38-in-multiple-myeloma
#11
REVIEW
Djordje Atanackovic, Mary Steinbach, Sabarinath Venniyil Radhakrishnan, Tim Luetkens
Recently, the monoclonal antibody daratumumab was approved as a single agent for the treatment of patients with relapsed/refractory Multiple Myeloma (MM). Daratumumab is an antibody targeting surface molecule CD38 on myeloma cells and the agent is already widely being used based on its good tolerability and proven efficacy. We believe, however, that the efficacy of this drug and other anti-CD38 monoclonal antibodies can be further improved by combining it with other types of immunotherapies. Furthermore, surface molecule CD38 can be used as a target for immunotherapies other than just naked monoclonal antibodies...
2016: Oncoimmunology
https://www.readbyqxmd.com/read/27941287/adoptive-immunotherapy-utilizing-anti-cd19-chimeric-antigen-receptor-t-cells-for-b-cell-malignancies
#12
Iekuni Oh, Yukiko Oh, Ken Ohmine
Genetically modified T-cells with forced expression of anti-CD19 chimeric antigen receptor (CD19 CAR) have demonstrated promising clinical results for relapsed and refractory B cell malignancies in early clinical trial settings. The first beneficial tumor regressions were identified among approximately half of CLL patients in 2011. Similarly, CD19 CAR T-cells achieved remissions in about 80% of aggressive B-cell lymphomas in 2012. Furthermore, in 2013 this cellular therapy showed an extremely high rate of efficacy against refractory CD19 positive acute lymphoid leukemia, which had been regarded as the most difficult to treat hematologic disease...
2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/27941285/basics-of-cancer-immunotherapy
#13
Yuki Fujioka, Hiroyoshi Nishikawa
The immune system is the body's defense against infectious organisms and other invaders including cancer cells. Cancer immunotherapy, which employs our own immune systems to attack cancer cells, is now emerging as a promising modality of cancer treatment based upon the clinical successes of immune checkpoint blockade and adoptive T cell transfer. In hematologic malignancies, clinical application of anti-PD-1 mAb and CAR (chimeric antigen receptor) T therapy is now being extensively tested in Hodgkin's disease, multiple myeloma, and CD19(+) acute lymphocytic leukemia...
2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/27913524/cellular-and-vaccine-immunotherapy-for-multiple-myeloma
#14
REVIEW
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
#15
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
#16
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
#17
REVIEW
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...
January 2017: Pharmacotherapy
https://www.readbyqxmd.com/read/27865176/adoptive-immunotherapy-for-hematological-malignancies-current-status-and-new-insights-in-chimeric-antigen-receptor-t-cells
#18
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
#19
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)...
February 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/27696259/targeting-the-bone-marrow-microenvironment
#20
REVIEW
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
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