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https://www.readbyqxmd.com/read/29678657/development-and-evaluation-of-an-optimal-human-single-chain-variable-fragment-derived-bcma-targeted-car-t-cell-vector
#1
Eric L Smith, Mette Staehr, Reed Masakayan, Ishan J Tatake, Terence J Purdon, Xiuyan Wang, Pei Wang, Hong Liu, Yiyang Xu, Sarah C Garrett-Thomson, Steven C Almo, Isabelle Riviere, Cheng Liu, Renier J Brentjens
B cell maturation antigen (BCMA) has recently been identified as an important multiple myeloma (MM)-specific target for chimeric antigen receptor (CAR) T cell therapy. In CAR T cell therapy targeting CD19 for lymphoma, host immune anti-murine CAR responses limited the efficacy of repeat dosing and possibly long-term persistence. This clinically relevant concern can be addressed by generating a CAR incorporating a human single-chain variable fragment (scFv). We screened a human B cell-derived scFv phage display library and identified a panel of BCMA-specific clones from which human CARs were engineered...
March 28, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29676460/resistance-to-proteasome-inhibitors-and-other-targeted-therapies-in-myeloma
#2
REVIEW
Craig T Wallington-Beddoe, Magdalena Sobieraj-Teague, Bryone J Kuss, Stuart M Pitson
The number of novel therapies for the treatment of myeloma is rapidly increasing, as are the clinical trials evaluating them in combination with other novel and established therapies. Proteasome inhibitors, immunomodulatory agents and monoclonal antibodies are the most well known and studied classes of novel agents targeting myeloma, with histone deacetylase inhibitors, nuclear export inhibitors and several other approaches also being actively investigated. However, in parallel with the development and clinical use of these novel myeloma therapies is the emergence of novel mechanisms of resistance, many of which remain elusive, particularly for more recently developed agents...
April 20, 2018: British Journal of Haematology
https://www.readbyqxmd.com/read/29673407/hypercalcemia-as-a-rare-presentation-of-angioimmunoblastic-t-cell-lymphoma-a-case-report
#3
Sana Chams, Inaya Hajj Hussein, Skye El Sayegh, Nour Chams, Khalid Zakaria
BACKGROUND: Angioimmunoblastic T cell lymphoma is a rare malignancy, accounting for only 2% of all non-Hodgkin lymphomas, first described in the 1970s and subsequently accepted as a distinct entity in the current World Health Organization classification. Due to the paucity of this disease, there is still no identifiable etiology, no consistent risk factors, and the pathogenesis remains unclear. CASE PRESENTATION: An 83-year-old Caucasian man presented to an emergency department with palpitations and was found to have atrial fibrillation...
April 20, 2018: Journal of Medical Case Reports
https://www.readbyqxmd.com/read/29669947/anti-cd19-car-t-cells-with-high-dose-melphalan-and-autologous-stem-cell-transplantation-for-refractory-multiple-myeloma
#4
Alfred L Garfall, Edward A Stadtmauer, Wei-Ting Hwang, Simon F Lacey, Jan Joseph Melenhorst, Maria Krevvata, Martin P Carroll, William H Matsui, Qiuju Wang, Madhav V Dhodapkar, Kavita Dhodapkar, Rituparna Das, Dan T Vogl, Brendan M Weiss, Adam D Cohen, Patricia A Mangan, Emily C Ayers, Selene Nunez-Cruz, Irina Kulikovskaya, Megan M Davis, Anne Lamontagne, Karen Dengel, Naseem Ds Kerr, Regina M Young, Donald L Siegel, Bruce L Levine, Michael C Milone, Marcela V Maus, Carl H June
BACKGROUND: Multiple myeloma is usually fatal due to serial relapses that become progressively refractory to therapy. CD19 is typically absent on the dominant multiple myeloma cell population but may be present on minor subsets with unique myeloma-propagating properties. To target myeloma-propagating cells, we clinically evaluated autologous T cells transduced with a chimeric antigen receptor (CAR) against CD19 (CTL019). METHODS: Subjects received CTL019 following salvage high-dose melphalan and autologous stem cell transplantation (ASCT)...
April 19, 2018: JCI Insight
https://www.readbyqxmd.com/read/29665944/-current-status-and-challenges-of-car-t-immunotherapy-in-hematologic-malignancies-review
#5
Xin Cheng, Ya-Jie Wang, Shuai Feng, Ya-Yun Wu, Tong-Hua Yang, Xun Lai
The chimeric antigen receptor (CAR) T cell therapy has gradually became a new trend in the treatment of refractory and relapsed hematologic malignancies by developing for 30 years. With the exciting development of genetic engineering, CAR-T technology has subjected to 4 generations of innovation. Structure of CAR-T started from a single signal molecule to 2 or more than 2 co-stimulatory molecules, and then coding the CAR gene or promoter. CAR-T can specifically recognize tumor antigens, and does not be restricted by major histocompatibility complex (MHC), thus making a breakthrough in clinical treatment...
April 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/29665919/-effect-and-clinical-significance-of-bortezomib-and-thalidomide-on-the-memory-t-cells-subsets-and-regulatory-t-cells-in-peripheral-blood-of-patients-with-multiple-myeloma
#6
Ling-Ling Shi, Han-Qing Li, Jian-Gang Mei, Xiao-Gang Zhou, Feng Li, Ping Song, Yong-Ping Zhai
OBJECTIVE: To investigate the effects of bortezomib(BTZ) and thalidomide(TM) on peripheral blood memory T-cells (Tm ) and regulatory T cells(Tregs) in patients with multiple myeloma(MM). METHODS: Eighty-six MM patients received 2 courses of chemotherapy were divided into effective (partial response at least) group (63 cases) and ineffective (no partial response) group (17 cases) according to therapeutic efficacy; these 80 patients were divided into BTZ group (38 cases) and TM group (42 cases) yet according to therapeutic regimens, 20 newly diagnosed MM patients were used as baseline group, 30 healthy volunteers were used as healthy control group...
April 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/29662618/ectopic-expression-of-transcription-factor-batf3-induces-b-cell-lymphomas-in-a-murine-b-cell-transplantation-model
#7
Christian Weiser, Mina V Petkova, Benjamin Rengstl, Claudia Döring, Dorothee von Laer, Sylvia Hartmann, Ralf Küppers, Martin-Leo Hansmann, Sebastian Newrzela
The mechanisms involved in malignant transformation of mature B and T lymphocytes are still poorly understood. In a previous study, we compared gene expression profiles of the tumor cells of Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) to their normal cellular counterparts and found the basic leucine zipper protein ATF-like 3 (BATF3) to be significantly upregulated in the tumor cells of both entities. To assess the oncogenic potential of BATF3 in lymphomagenesis and to dissect the molecular interactions of BATF3 in lymphoma cells, we retrovirally transduced murine mature T and B cells with a BATF3-encoding viral vector and transplanted each population into Rag1-deficient recipients...
March 23, 2018: Oncotarget
https://www.readbyqxmd.com/read/29661776/targeting-the-leukemia-antigen-pr1-with-immunotherapy-for-the-treatment-of-multiple-myeloma
#8
Gheath Alatrash, Alexander A Perakis, Celine Kerros, Haley L Peters, Pariya Sukhumalchandra, Mao Zhang, Haroon Jakher, Madhushree Zope, Rebecca S Patenia, Anna Sergeeva, Shuhua Yi, Ken H Young, Anne V Philips, Amanda C Herrmann, Haven R Garber, Na Qiao, Jinsheng Weng, Lisa S St John, Sijie Lu, Karen Clise-Dwyer, Elizabeth A Mittendorf, Qing Ma, Jeffrey J Molldrem
PURPOSE: PR1 is a human leukocyte antigen (HLA)-A2 nonameric peptide derived from neutrophil elastase (NE) and proteinase 3 (P3). We have previously shown that PR1 is cross-presented by solid tumors, leukemia, and antigen presenting cells, including B cells. We have also shown that cross-presentation of PR1 by solid tumors renders them susceptible to killing by PR1-targeting immunotherapies. Since multiple myeloma (MM) is derived from B cells, we investigated whether MM is also capable of PR1 cross-presentation and subsequently capable of being targeted using PR1 immunotherapies...
April 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29661456/severe-renal-allograft-rejection-resulting-from-lenalidomide-therapy-for-multiple-myeloma-case-report
#9
V Walavalkar, D B Adey, Z G Laszik, K-Y Jen
Lenalidomide, a thalidomide analogue, is an immunomodulatory drug currently used as a chemotherapeutic agent in treating certain hematologic malignancies, including multiple myeloma. The antineoplastic effect of lenalidomide may be due to its ability to modulate different components of the immune system as well as its antiangiogenic, antiproliferative, and direct cytotoxic activity. Given its immunomodulatory effects, lenalidomide may potentially elicit unintended immune activity against allografts in solid organ transplant recipients...
April 2018: Transplantation Proceedings
https://www.readbyqxmd.com/read/29655962/novel-targets-and-technologies-for-car-t-cells-in-multiple-myeloma-and-acute-myeloid-leukemia
#10
EDITORIAL
Sabrina Prommersberger, Hardikkumar Jetani, Sophia Danhof, Razieh Monjezi, Thomas Nerreter, Julia Beckmann, Herrmann Einsele, Michael Hudecek
No abstract text is available yet for this article.
April 11, 2018: Current Research in Translational Medicine
https://www.readbyqxmd.com/read/29622655/repurposing-tofacitinib-as-an-anti-myeloma-therapeutic-to-reverse-growth-promoting-effects-of-the-bone-marrow-microenvironment
#11
Christine Lam, Ian D Ferguson, Margarette C Mariano, Yu-Hsiu T Lin, Megan Murnane, Hui Liu, Geoffrey A Smith, Sandy W Wong, Jack Taunton, Jun O Liu, Constantine S Mitsiades, Byron C Hann, Blake T Aftab, Arun P Wiita
The myeloma bone marrow microenvironment promotes proliferation of malignant plasma cells and resistance to therapy. Activation of JAK/STAT signaling is thought to be a central component of these microenvironment-induced phenotypes. In a prior drug repurposing screen, we identified tofacitinib, a pan-JAK inhibitor FDA-approved for rheumatoid arthritis, as an agent that may reverse the tumor-stimulating effects of bone marrow mesenchymal stromal cells. Here, we validated in vitro, in stromal-responsive human myeloma cell lines, and in vivo, in orthotopic disseminated xenograft models of myeloma, that tofacitinib showed efficacy in myeloma models...
April 5, 2018: Haematologica
https://www.readbyqxmd.com/read/29619024/extracellular-ngfr-spacers-allow-efficient-tracking-and-enrichment-of-fully-functional-car-t-cells-co-expressing-a-suicide-gene
#12
Monica Casucci, Laura Falcone, Barbara Camisa, Margherita Norelli, Simona Porcellini, Anna Stornaiuolo, Fabio Ciceri, Catia Traversari, Claudio Bordignon, Chiara Bonini, Attilio Bondanza
Chimeric antigen receptor (CAR)-T cell immunotherapy is at the forefront of innovative cancer therapeutics. However, lack of standardization of cellular products within the same clinical trial and lack of harmonization between different trials have hindered the clear identification of efficacy and safety determinants that should be unveiled in order to advance the field. With the aim of facilitating the isolation and in vivo tracking of CAR-T cells, we here propose the inclusion within the CAR molecule of a novel extracellular spacer based on the low-affinity nerve-growth-factor receptor (NGFR)...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29616649/description-of-48-cases-of-multiple-myeloma-seen-in-the-hematology-laboratory-of-the-chu-joseph-ravoahangy-andrianavalona-antananarivo-madagascar
#13
M O M Harioly Nirina, A S Rasolonjatovo, B G Tsifanesy, Z H Rakotoarivelo, T M Raheritiana, A O Rakoto Alson, A Rasamindrakotroka
Monoclonal gammopathies are common abnormalities and their incidence increases with age. They are detected in roughly 3 % of people older over 50 years and up to 7 % of those over 70 years. Multiple myeloma (MM) is characterized by the proliferation of plasma cells within the bone marrow and excess secretion of monoclonal immunoglobulins. In Madagascar, late performance of biological examinations such as serum protein electrophoresis overestimates MM rates. We studied 54 patient records between March 2009 and January 2015 in the biology laboratory of the Joseph Ravoahangy Andrianavalona university hospital in Antananarivo (Madagascar)...
February 1, 2018: Médecine et Santé Tropicales
https://www.readbyqxmd.com/read/29582696/anti-cd38-and-anti-slamf7-the-future-of-myeloma-immunotherapy
#14
Elena Zamagni, Paola Tacchetti, Lucia Pantani, Michele Cavo
the high expression of a number of surface antigens on malignant plasma cells, the bone marrow micro-environment and immune effector T cells, makes these appealing targets for immune therapy with monoclonal antibodies (mAbs). Areas covered: Two mAbs, anti-CD38 daratumumab (Dara) and anti-SLAMF7 elotuzumab (Elo), have achieved recent regulatory approval for relapsed or refractory MM (RRMM) and are currently being explored as possible treatment options in novel combinations and different settings. This review discusses the current landscape and possible development of anti-CD38 and anti-SLAMF7 mAbs...
March 27, 2018: Expert Review of Hematology
https://www.readbyqxmd.com/read/29572232/il18-promotes-mdsc-mediated-immunosuppression-in-multiple-myeloma
#15
(no author information available yet)
IL18 drives bone marrow MDSC function to suppress T-cell activity and accelerate multiple myeloma.
March 23, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29562446/-infiltration-of-tumor-associated-macrophages-in-multiple-myeloma-and-its-clinical-significance
#16
Q L Gui, Y S Wang, S Huang, Y Wan, H P Wang, Z G Zhu, M M Li, H Y Zhu, Q S Tao, Y Y Shen, Q Zhang, H Qin
Objective: To investigate the clinical significance of tumor associated macrophages (TAM) in multiple myeloma (MM) and the relationship with angiogenesis and immunosuppression. Methods: Seventy cases of MM patients diagnosed from August 2015 to June 2017 were enrolled in the study as experimental group, 20 cases of benign hematological diseases (13 with iron deficiency anemia and 7 with megaloblastic anemia) patients as control group. Immunohistochemical method was used to detect the expression of CD163, CD34 and VEGF in bone marrow samples, and flow cytometry was used to detect the proportion of regulatory T cell (Treg cells), ELISA was used to detect the level of IL-10, and the clinical features were analyzed...
February 14, 2018: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/29559475/germline-mutations-in-lysine-specific-demethylase-1-lsd1-kdm1a-confer-susceptibility-to-multiple-myeloma
#17
Xiaomu Wei, M Nieves Calvo-Vidal, Siwei Chen, Gang Wu, Maria V Revuelta, Jian Sun, Jinghui Zhang, Michael F Walsh, Kim E Nichols, Vijai Joseph, Carrie Snyder, Celine M Vachon, James D McKay, Shu-Ping Wang, David S Jayabalan, Lauren M Jacobs, Dina Becirovic, Rosalie G Waller, Mykyta Artomov, Agnes Viale, Jayeshkumar Patel, Jude M Phillip, Selina Chen-Kiang, Karen Curtin, Mohamed Salama, Djordje Atanackovic, Ruben Niesvizky, Ola Landgren, Susan L Slager, Lucy A Godley, Jane Churpek, Judy E Garber, Kenneth C Anderson, Mark J Daly, Robert G Roeder, Charles Dumontet, Henry T Lynch, Charles G Mullighan, Nicola J Camp, Kenneth Offit, Robert J Klein, Haiyuan Yu, Leandro Cerchietti, Steven M Lipkin
Given the frequent and largely incurable occurrence of multiple myeloma (MM), identification of germline genetic mutations that predispose cells to MM may provide insight into disease etiology and the developmental mechanisms of its cell of origin, the plasma cell. Here we identified familial and early-onset MM kindreds with truncating mutations in lysine-specific demethylase 1 (LSD1/KDM1A), an epigenetic transcriptional repressor that primarily demethylates histone H3 on lysine 4 and regulates hematopoietic stem cell self-renewal...
March 20, 2018: Cancer Research
https://www.readbyqxmd.com/read/29558366/blocking-ifnra1-inhibits-multiple-myeloma-driven-treg-expansion-and-immunosuppression
#18
Yawara Kawano, Oksana Zavidij, Jihye Park, Michele Moschetta, Katsutoshi Kokubun, Tarek H Mouhieddine, Salomon Manier, Yuji Mishima, Naoka Murakami, Mark Bustoros, Romanos Sklavenitis Pistofidis, Mairead Reidy, Yu J Shen, Mahshid Rahmat, Pavlo Lukyanchykov, Esilida Sula Karreci, Shokichi Tsukamoto, Jiantao Shi, Satoshi Takagi, Daisy Huynh, Antonio Sacco, Yu-Tzu Tai, Marta Chesi, P Leif Bergsagel, Aldo M Roccaro, Jamil Azzi, Irene M Ghobrial
Despite significant advances in the treatment of multiple myeloma (MM), most patients succumb to disease progression. One of the major immunosuppressive mechanisms that is believed to play a role in myeloma progression, is the expansion of regulatory T-cells (Tregs). In this study, we demonstrate that myeloma cells drive Treg expansion and activation by secreting type-1 interferon (IFN). Blocking IFNAR1 (interferon alpha and beta receptor 1) on Tregs significantly decreases both, myeloma-associated Treg immunosuppressive function and myeloma progression...
March 20, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29556955/adult-stem-cells-and-medicine
#19
Sinem Civriz Bozdağ, Meltem Kurt Yüksel, Taner Demirer
Stem cells can be either totipotent, pluripotent, multipotent or unipotent. Totipotent cells have the capability to produce all cell types of the developing organism, including both embryonic and extraembryonic tissues. The Hematopoietic Stem Cells (HSC) are the first defined adult stem cells (ASC) that give rise to all blood cells and immune system. Use of HSCs for treatment of hematologic malignancies, which is also called bone marrow (BM) transplantation or peripheral blood stem cells (PBSC) transplantation is the pioneer of cellular therapy and translational research...
March 20, 2018: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29551594/dysregulated-il-18-is-a-key-driver-of-immunosuppression-and-a-possible-therapeutic-target-in-the-multiple-myeloma-microenvironment
#20
Kyohei Nakamura, Sahar Kassem, Alice Cleynen, Marie-Lorraine Chrétien, Camille Guillerey, Eva Maria Putz, Tobias Bald, Irmgard Förster, Slavica Vuckovic, Geoffrey R Hill, Seth L Masters, Marta Chesi, P Leif Bergsagel, Hervé Avet-Loiseau, Ludovic Martinet, Mark J Smyth
Tumor-promoting inflammation and avoiding immune destruction are hallmarks of cancer. Here, we demonstrate that the pro-inflammatory cytokine interleukin (IL)-18 is critically involved in these hallmarks in multiple myeloma (MM). Mice deficient for IL-18 were remarkably protected from Vk∗ MYC MM progression in a CD8+ T cell-dependent manner. The MM-niche-derived IL-18 drove generation of myeloid-derived suppressor cells (MDSCs), leading to accelerated disease progression. A global transcriptome analysis of the immune microenvironment in 73 MM patients strongly supported the negative impact of IL-18-driven MDSCs on T cell responses...
March 1, 2018: Cancer Cell
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