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https://www.readbyqxmd.com/read/29350486/inflammatory-response-and-treatment-tolerance-of-long-term-infusion-of-the-anti-gd2-antibody-ch14-18-cho-in-combination-with-interleukin-2-in-patients-with-high-risk-neuroblastoma
#1
Kiraz Ceylan, Luciana J Jahns, Bjoern N Lode, Karoline Ehlert, Silke Kietz, Sascha Troschke-Meurer, Nikolai Siebert, Holger N Lode
BACKGROUND: The monoclonal anti-GD2 antibody ch14.18/CHO in combination with IL-2 is active and effective in high-risk neuroblastoma (NB) patients. Here, we investigated the inflammatory response and treatment tolerance of long-term infusion (LTI) of ch14.18/CHO (10 × 10 mg/m2 ; 24 hr) in combination with subcutaneous (s.c.) IL-2 in a single center program. METHODS: Fifty-three NB patients received up to six cycles of 100 mg/m2 ch14.18/CHO (d8-18, where d represents day(s)) as LTI combined with 6 × 106 IU/m2 s...
January 19, 2018: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/29327110/the-role-of-interleukin-2-all-trans-retinoic-acid-and-natural-killer-cells-surveillance-mechanisms-in-anti-gd2-antibody-therapy-in-neuroblastoma
#2
Rosa Nguyen, Jim Houston, Wing K Chan, David Finkelstein, Michael A Dyer
Although anti-disialoganglioside (GD2) antibodies are successfully used for neuroblastoma therapy, a third of patients with neuroblastoma experience treatment failure or serious toxicity. Various strategies have been employed in the clinic to improve antibody-dependent cell-mediated cytotoxicity (ADCC), such as the addition of interleukin (IL)-2 to enhance natural killer (NK) cell function, adoptive transfer of allogeneic NK cells to exploit immune surveillance, and retinoid-induced differentiation therapy...
January 11, 2018: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/29312553/development-of-novel-target-modules-for-retargeting-of-unicar-t-cells-to-gd2-positive-tumor-cells
#3
Nicola Mitwasi, Anja Feldmann, Ralf Bergmann, Nicole Berndt, Claudia Arndt, Stefanie Koristka, Alexandra Kegler, Justyna Jureczek, Anja Hoffmann, Armin Ehninger, Marc Cartellieri, Susann Albert, Claudia Rossig, Gerhard Ehninger, Jens Pietzsch, Jörg Steinbach, Michael Bachmann
As the expression of a tumor associated antigen (TAA) is commonly not restricted to tumor cells, adoptively transferred T cells modified to express a conventional chimeric antigen receptor (CAR) might not only destroy the tumor cells but also attack target-positive healthy tissues. Furthermore, CAR T cells in patients with large tumor bulks will unpredictably proliferate and put the patients at high risk of adverse side effects including cytokine storms and tumor lysis syndrome. To overcome these problems, we previously established a modular CAR technology termed UniCAR: UniCAR T cells can repeatedly be turned on and off via dosing of a target module (TM)...
December 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29310916/chimeric-antigen-receptor-engineered-human-gamma-delta-t-cells-enhanced-cytotoxicity-with-retention-of-cross-presentation
#4
Anna Capsomidis, Gabriel Benthall, Heleen H Van Acker, Jonathan Fisher, Anne M Kramer, Zarah Abeln, Yvonne Majani, Talia Gileadi, Rebecca Wallace, Kenth Gustafsson, Barry Flutter, John Anderson
Gamma delta T (γδT) lymphocytes are primed for rapid function, including cytotoxicity toward cancer cells, and are a component of the immediate stress response. Following activation, they can function as professional antigen-presenting cells. Chimeric antigen receptors (CARs) work by focusing T cell function on defined cell surface tumor antigens and provide essential costimulation for robust activation. Given the natural tropism of γδT cells for the tumor microenvironment, we hypothesized that their transduction with CARs might enhance cytotoxicity while retaining their ability to migrate to tumor and act as antigen-presenting cells to prolong the intratumoral immune response...
December 8, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29298689/anti-gd2-4-1bb-chimeric-antigen-receptor-t-cell-therapy-for-the-treatment-of-chinese-melanoma-patients
#5
Jiayi Yu, Xiaowen Wu, Junya Yan, Huan Yu, Longwen Xu, Zhihong Chi, Xinan Sheng, Lu Si, Chuanliang Cui, Jie Dai, Meng Ma, Tianxiao Xu, Yan Kong, Jun Guo
BACKGROUND: Chimeric antigen receptor (CAR)-engineered T cells have demonstrated promising clinical efficacy in patients with B cell lymphoma. However, the application of CAR-T cell therapy in the treatment of other solid tumors has been limited. We incorporated 4-1BB into the anti-GD2 CAR-T cells to test their cytotoxicity in melanoma in vitro and in vivo. Moreover, we reported the expression of ganglioside GD2 in non-Caucasian melanoma populations for the first time, thus providing a basis for future clinical research...
January 3, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29238760/dinutuximab-for-the-treatment-of-pediatric-patients-with-neuroblastoma
#6
K Greenwood, J H Foster
Dinutuximab is a monoclonal antibody targeted at disialoganglioside (GD2), a tumor-associated antigen widely expressed in human neuroblastoma cells. The incorporation of dinutuximab into standard treatment regimens for patients with high-risk neuroblastoma has changed the landscape of neuroblastoma therapy. Dinutuximab has shown to be effective in prolonging survival for patients receiving standard multimodal treatment regimens and has now become standard of care during the final phase of treatment. More recently, it has also shown promising efficacy and tolerability in patients with relapsed or progressive neuroblastoma...
September 2017: Drugs of Today
https://www.readbyqxmd.com/read/29233551/generation-of-adrenal-chromaffin-like-cells-from-human-pluripotent-stem%C3%A2-cells
#7
Kwaku Dad Abu-Bonsrah, Dongcheng Zhang, Andrew R Bjorksten, Mirella Dottori, Donald F Newgreen
Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography...
November 27, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/29228761/targeting-tumor-associated-carbohydrate-antigens-a-phase-i-study-of-a-carbohydrate-mimetic-peptide-vaccine-in-stage-iv-breast-cancer-subjects
#8
Laura F Hutchins, Issam Makhoul, Peter D Emanuel, Angela Pennisi, Eric R Siegel, Fariba Jousheghany, Xueyan Guo, Anastas D Pashov, Behjatolah Monzavi-Karbassi, Thomas Kieber-Emmons
Tumor-associated carbohydrate antigens (TACAs) support cell survival that could be interrupted by anti-TACA antibodies. Among TACAs that mediate cell survival signals are the neolactoseries antigen Lewis Y (LeY) and the ganglioside GD2. To induce sustained immunity against both LeY and GD2, we developed a carbohydrate mimicking peptide (CMP) as a surrogate pan-immunogen that mimics both. This CMP, referred to as P10s, is the N-terminal half of a peptide vaccine named P10s-PADRE, the C-terminal half of which (PADRE) is a Pan-T-cell epitope...
November 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29221154/expression-of-ganglioside-gd2-reprogram-the-lipid-metabolism-and-emt-phenotype-in-bladder-cancer
#9
Venkatrao Vantaku, Sri Ramya Donepudi, Chandrashekar R Ambati, Feng Jin, Vasanta Putluri, Khoa Nguyen, Kimal Rajapakshe, Cristian Coarfa, Venkata Lokesh Battula, Yair Lotan, Nagireddy Putluri
High-grade Bladder Cancer (BLCA) represents the most aggressive and treatment-resistant cancer that renders the patients with poor survival. However, only a few biomarkers have been identified for the detection and treatment of BLCA. Recent studies show that ganglioside GD2 can be used as cancer biomarker and/or therapeutic target for various cancers. Despite its potential relevance in cancer diagnosis and therapeutics, the role of GD2 is unknown in BLCA. Here, we report for the first time that high-grade BLCA tissues and cell lines have higher expression of GD2 compared to low-grade by high-resolution Mass Spectrometry...
November 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29221128/mycn-amplified-stage-2-3-neuroblastoma-excellent-survival-in-the-era-of-anti-gd2-immunotherapy
#10
Brian H Kushner, Michael P LaQuaglia, Shakeel Modak, Suzanne L Wolden, Ellen M Basu, Stephen S Roberts, Kim Kramer, Karima Yataghene, Irene Y Cheung, Nai-Kong V Cheung
High-risk neuroblastoma (HR-NB) includes MYCN-amplified stage 2/3, but reports covering anti-GD2 immunotherapy, which recently became standard for HR-NB, do not provide details on this subset. We now report on all 20 MYCN-amplified stage 2/3 patients who received induction chemotherapy at our center during the era of consolidation with anti-GD2 antibody 3F8/ granulocyte-macrophage colony-stimulating factor (GM-CSF) (2000-2015). Early in this period, consolidation included autologous stem-cell transplantation (ASCT)...
November 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29206280/directional-scatter-imaging-for-the-stereoscopic-tracking-of-fiducial-markers-in-a-single-kv-exposure
#11
Héctor Mauricio Garnica-Garza
PURPOSE: To demonstrate, via Monte Carlo simulation, that an image obtained from the patient-generated scattered radiation forced to impinge on the detector from a known direction by means of parallel-focused grids, can be used to complement the information conveyed by the primary image, such that accurate stereoscopic three-dimensional localization of fiducial markers can be achieved in a single kV x-ray exposure. METHODS: A voxelized Zubal phantom was used to model the process of fiducial marker localization...
December 5, 2017: Medical Physics
https://www.readbyqxmd.com/read/29196189/pd-l1-inflammation-non-coding-rnas-and-neuroblastoma-immuno-oncology-perspective
#12
REVIEW
Palanisamy Nallasamy, Srinivas Chava, Sumit S Verma, Shruti Mishra, Santhi Gorantla, Don W Coulter, Siddappa N Byrareddy, Surinder K Batra, Subash C Gupta, Kishore B Challagundla
Neuroblastoma is the most common pediatric solid tumor of neural crest origin. The current treatment options for neuroblastoma produce severe side effects. Programmed death-ligand 1 (PD-L1), chronic inflammation, and non-coding RNAs are known to play a significant role in the pathogenesis of neuroblastoma. Cancer cells and the surrounding cells in the tumor microenvironment express PD-L1. Programmed death-1 (PD-1) is a co-receptor expressed predominantly by T cells. The binding of PD-1 to its ligands, PD-L1 or PD-L2, is vital for the physiologic regulation of the immune system...
November 28, 2017: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/29189429/new-developments-in-immunotherapy-for-pediatric-solid-tumors
#13
Liora M Schultz, Robbie Majzner, Kara L Davis, Crystal Mackall
PURPOSE OF REVIEW: Building upon preclinical advances, we are uncovering immunotherapy strategies that are translating into improved outcomes in tumor subsets. Advanced pediatric solid tumors carry poor prognoses and resultant robust efforts to apply immunotherapy advances to pediatric solid tumors are in progress. Here, we discuss recent developments in the field using mAb and mAb-based therapies including checkpoint blockade and chimeric antigen receptors (CARs). RECENT FINDINGS: The pediatric solid tumor mAb experience targeting the diganglioside, GD2, for patients with neuroblastoma has been the most compelling to date...
November 20, 2017: Current Opinion in Pediatrics
https://www.readbyqxmd.com/read/29180536/high-affinity-gd2-specific-car-t-cells-induce-fatal-encephalitis-in-a-preclinical-neuroblastoma-model
#14
Sarah A Richman, Selene Nunez-Cruz, Babak Moghimi, Lucy Z Li, Zachary T Gershenson, Zissimos Mourelatos, David M Barrett, Stephan A Grupp, Michael C Milone
The GD2 ganglioside, which is abundant on the surface of neuroblastoma cells, is targeted by an FDA-approved therapeutic monoclonal antibody and is an attractive tumor-associated antigen for cellular immunotherapy. Chimeric antigen receptor (CAR)-modified T cells can have potent antitumor activity in B-cell malignancies, and trials to harness this cytolytic activity toward GD2 in neuroblastoma are underway. In an effort to enhance the antitumor activity of CAR T cells that target GD2, we generated variant CAR constructs predicted to improve the stability and the affinity of the GD2-binding, 14G2a-based, single-chain variable fragment (scFv) of the CAR, and compared their properties in vivo...
November 27, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29151270/asct2-defined-by-enzyme-mediated-activation-of-radical-sources-enhances-malignancy-of-gd2-plus-small-cell-lung-cancer
#15
Nobutoshi Esaki, Yuki Ohkawa, Noboru Hashimoto, Yuhsuke Tsuda, Yuhsuke Ohmi, Robiul H Bhuiyan, Norihiro Kotani, Koichi Honke, Atsushi Enomoto, Masahide Takahashi, Keiko Furukawa, Koichi Furukawa
Ganglioside GD2 is specifically expressed in small cell lung cancer (SCLC) cells, leading to enhancement of malignant phenotypes, such as cell proliferation and migration. However, how GD2 promotes malignant phenotypes in SCLC cells is not well known. In this study, to reveal mechanisms by which GD2 increases malignant phenotypes in SCLC cells, we performed enzyme-mediated activation of radical sources combined with mass spectrometry in GD2 positive (+) SCLC cells. Consequently, we identified ASC amino-acid transporter 2 (ASCT2), a major glutamine transporter, which coordinately works with GD2...
November 19, 2017: Cancer Science
https://www.readbyqxmd.com/read/29147617/phase-i-trial-of-anti-gd2-monoclonal-antibody-hu3f8-plus-gm-csf-impact-of-body-weight-immunogenicity-and-anti-gd2-response-on-pharmacokinetics-and-survival
#16
Irene Y Cheung, Brian H Kushner, Shakeel Modak, Ellen M Basu, Stephen S Roberts, Nai-Kong V Cheung
Fifty-seven stage 4 patients with refractory/relapsed neuroblastoma were enrolled in a phase I trial (Clinicaltrials.gov NCT01757626) using humanized anti-GD2 monoclonal antibody hu3F8 in combination with granulocyte-macrophage colony-stimulating factor. The influence of body weight and human anti-human antibody (HAHA) on the pharmacokinetics (PK) of hu3F8, and the effect of de novo anti-GD2 response on patient outcome were explored. Serum samples before hu3F8 infusion, and serially up to day 12 during treatment cycle #1, and at 5 min after each hu3F8 infusion for all subsequent cycles were collected...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/29139510/crystal-structures-and-magnetic-properties-of-two-series-of-phenoxo-o-bridged-dinuclear-ln2-ln-gd-tb-dy-complexes
#17
Marek Machata, Radovan Herchel, Ivan Nemec, Zdeněk Trávníček
Six dinuclear lanthanide compounds of the formulae [Ln2(3m-L4)2(L2)2(MeOH)2]·6MeOH (Ln = Gd - 1a, Tb - 1b, and Dy - 1c) and [Ln2(3m-L4)2(L2)2(DMF)2] (Ln = Gd - 2a, Tb - 2b, and Dy - 2c; DMF = N,N-dimethylformamide, H23m-L4 = (2-[(E)-(3-metoxysalicylidene)amino]phenol), and HL2 = 1,3-diphenyl-1,3-diketopropane) were prepared and characterized by elemental analysis, FTIR spectroscopy, thermogravimetric measurements, single-crystal X-ray structural analysis, and magnetometry, and Gd2 and Dy2 compounds by ab initio methods as well...
November 15, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/29132473/-progress-in-clinical-studies-of-chimeric-antigen-receptor-engineered-t-cells-for-treatment-of-childhood-cancer
#18
Ya-Ru Ni, Xiao-Jun Xu, Yong-Min Tang
Nowadays, the 5-year survival rate of childhood cancer patients can be more than 80%, but some patients with relapse and refractory cancers have shown no good response to traditional strategies. Chimeric antigen receptor engineered T (CAR-T) cell therapy is promising for these patients. CAR-T cells recognize the tumor-associated antigens in a non-major histocompatibility complex-restricted manner, so their anti-tumor ability is enhanced. There are four generations of CAR-T cells now. The complete remission rate of pediatric patients with relapse and refractory acute lymphoblastic leukemia can be as high as 90% when treated with CD19-targeting CAR-T cells...
November 2017: Zhongguo Dang Dai Er Ke za Zhi, Chinese Journal of Contemporary Pediatrics
https://www.readbyqxmd.com/read/29123953/pd-1-blockade-augments-anti-neuroblastoma-immune-response-induced-by-anti-gd2-antibody-ch14-18-cho
#19
Nikolai Siebert, Maxi Zumpe, Madlen Jüttner, Sascha Troschke-Meurer, Holger N Lode
Immunotherapy with anti-GD2 antibody (Ab) ch14.18/CHO is effective for treatment of high-risk neuroblastoma (NB) patients and is mainly based on GD2-specific Ab-dependent cellular cytotoxicity (ADCC). Strategies to further enhance the efficacy are important and currently explored in prospective clinical trials randomizing ch14.18/CHO ± IL-2. Recently, expression of programmed death 1 (PD-1) inhibitory receptor by effector cells and its ligand (PD-L1) by tumor cells has been shown. Here, we report for the first time effects of PD-1 blockade on ch14...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/29120699/tolerability-response-and-outcome-of-high-risk-neuroblastoma-patients-treated-with-long-term-infusion-of-anti-gd2-antibody-ch14-18-cho
#20
Ina Mueller, Karoline Ehlert, Stefanie Endres, Lena Pill, Nikolai Siebert, Silke Kietz, Penelope Brock, Alberto Garaventa, Dominique Valteau-Couanet, Evelyne Janzek, Norbert Hosten, Andreas Zinke, Winfried Barthlen, Emine Varol, Hans Loibner, Ruth Ladenstein, Holger N Lode
Immunotherapy with short term infusion (STI) of monoclonal anti-GD2 antibody (mAb) ch14.18 (4 × 25mg/m(2)/d; 8-20h) in combination with cytokines and 13-cis retinoic acid (RA) prolonged survival in high-risk neuroblastoma (NB) patients. Here, we investigated long-term infusion (LTI) of ch14.18 produced in Chinese hamster ovary cells (ch14.18/CHO; 10 × 10mg/m(2); 24h) in combination with subcutaneous (s.c.) interleukin-2 (IL-2) in a single center program and report clinical response, toxicity and survival...
November 9, 2017: MAbs
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