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chimeric receptor

Abdulbaset Mazarzaei, Mahtab Vafaei, Abdolmajid Ghasemian, Seyede Amene Mirforughi, Hassan Rajabi Vardanjani, Nada A S Alwan
Human immunodeficiency virus (HIV) is one of the critical infectious agents with thousands of newly infected people worldwide. High mutational capability and rapid diversification, inhibition of humoral and cellular immune responses, and thus inability for recognition of an immunogenic region in the viral envelope by the immune system are major challenges. Natural killer (NK) cells are multifunctional, playing a key role in the identification and elimination of HIV-infected cells. These cells identify and eliminate virus-infected cells in a multilateral manner, such as ligand stress, antibody-dependent cell cytotoxicity (ADCC), T follicular helper (Tfh), and the activation of most of the stimulatory receptors...
February 18, 2019: Journal of Cellular Physiology
José Manuel Marín Morales, Nadine Münch, Katja Peter, Daniel Freund, Uta Oelschlägel, Kristina Hölig, Thea Böhm, Anne-Christine Flach, Jörg Keßler, Ezio Bonifacio, Martin Bornhäuser, Anke Fuchs
Adoptive transfer of T regulatory cells (Treg) has been successfully exploited in the context of graft-versus-host disease, transplantation, and autoimmune disease. For the majority of applications, clinical administration of Treg requires laborious ex vivo expansion and typically involves open handling for culture feeds and repetitive sampling. Here we show results from our approach to translate manual Treg manufacturing to the fully closed automated CliniMACS Prodigy® system reducing contamination risk, hands-on time, and quality variation from human intervention...
2019: Frontiers in Immunology
Jiang Lv, Ruocong Zhao, Di Wu, Diwei Zheng, Zhiping Wu, Jingxuan Shi, Xinru Wei, Qiting Wu, Youguo Long, Simiao Lin, Suna Wang, Zhi Wang, Yang Li, Yantao Chen, Qing He, Suimin Chen, Huihui Yao, Zixia Liu, Zhaoyang Tang, Yao Yao, Duanqing Pei, Pentao Liu, Xuchao Zhang, Zhenfeng Zhang, Shuzhong Cui, Ren Chen, Peng Li
BACKGROUND: Gastric cancer (GC) is a common cancer in Asia and currently lacks a targeted therapy approach. Mesothelin (MSLN) has been reported to be expressed in GC tissue and could be targeted by chimeric antigen receptor (CAR) T cells. Mesothelin targeting CAR-T has been reported in mesothelioma, lung cancer, breast cancer, and pancreas cancer. However, the feasibility of using anti-MSLN CAR T cells to treat GC remains to be studied. METHODS: We verified MSLN expression in primary human GC tissues and GC cell lines and then redirected T cells with a CAR containing the MSLN scFv (single-chain variable fragment), CD3ζ, CD28, and DAP10 intracellular signaling domain (M28z10) to target MSLN...
February 18, 2019: Journal of Hematology & Oncology
Hella Luksch, W Alexander Stinson, Derek J Platt, Wei Qian, Gowri Kalugotla, Cathrine A Miner, Brock G Bennion, Alexander Gerbaulet, Angela Rösen-Wolff, Jonathan J Miner
BACKGROUND: Monogenic interferonopathies are thought to be mediated by type I interferon (IFN). For example, a gain-of-function mutation in STING (STING N153S) up-regulates type I IFN-stimulated genes (ISGs) and causes perivascular inflammatory lung disease in mice. The equivalent mutation in humans also causes lung disease, which is thought to require signaling through the cGAS-STING pathway and subsequent activation of IFN regulatory factors (IRF) 3/7, type I IFN, and ISGs. OBJECTIVE: We set out to define the roles of cGAS, IRF3, IRF7, the type I IFN receptor (IFNAR1), T cells, and B cells in spontaneous lung disease in STING N153S mice...
February 14, 2019: Journal of Allergy and Clinical Immunology
Giorgio Zenere, Omalla Allan Olwenyi, Siddappa N Byrareddy, Stephen E Braun
Natural killer (NK) cells are innate immune lymphocytes with a key role in host defense against HIV infection. Recent advances in chimeric antigen receptors (CARs) have made NK cells a prime target for expressing recombinant receptors capable of redirecting NK cytotoxic functions towards HIV-infected cells. In this review, we discuss the role of NK cells in HIV and the mechanisms of actions of HIV-targeting CAR strategies. Furthermore, we also review NK cells signal transduction and its application to CAR NK cell strategies to develop new combinations of CAR intracellular domains and to improve CAR NK signaling and cytotoxic functions...
February 13, 2019: Drug Discovery Today
Richard P Harrison, Ezequiel Zylberberg, Simon Ellison, Bruce L Levine
Cell and gene therapies have demonstrated excellent clinical results across a range of indications with chimeric antigen receptor (CAR)-T cell therapies among the first to reach market. Although these therapies are currently manufactured using patient-derived cells, therapies using healthy donor cells are in development, potentially offering avenues toward process improvement and patient access. An allogeneic model could significantly reduce aggregate cost of goods (COGs), potentially improving market penetration of these life-saving treatments...
February 12, 2019: Cytotherapy
Jiasheng Wang, Yongxian Hu, Shuye Yang, Guoqin Wei, Xin Zhao, Wenjun Wu, Yanlei Zhang, Yafei Zhang, Donghe Chen, Zhao Wu, Lei Xiao, Alex Hongsheng Chang, He Huang, Kui Zhao
BACKGROUND: CD19-targeting chimeric antigen receptor (CAR) T cell therapy has shown great efficacy in patients with relapsed/refractory non-Hodgkin lymphoma (NHL), but has been associated with serious adverse effects such as cytokine release syndrome (CRS). It has been speculated that NHL baseline disease burden might affect clinical outcome and CRS, but such assumption has not been explored in detail. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG), as measured by FDG PET-CT, are quantitative indicators of baseline tumor burden...
February 12, 2019: Biology of Blood and Marrow Transplantation
Ashutosh Kumar, Kusum Harjai, Sanjay Chhibber
Enterobacterial pathogens that have acquired antibiotic resistance genes are a leading cause of community and hospital acquired infections. In such a situation vaccination is considered as a better option to prevent such infections. In the current study reverse vaccinology approach has been used to select peptides from already known immunogenic proteins to design a chimeric construct. We selected Yersiniabactin receptor of Escherichia coli UMN026 and Flagellin of Stenotrophomonas maltophila. B-cell linear epitopes were predicted using Bepipred prediction tool...
February 12, 2019: Human Immunology
Emmanuelle Rial-Sebbag, Christian Chabannon
Car-T Cells are autologous or allogeneic lymphocytes cells, genetically engineered to express a transmembrane receptor called ?chimeric? because it consists of the assembly of different parts of molecules. These new techniques using biotechnologies (cellular engineering and genetic modifications) are developing in a complex legal context integrating the rules of the European Union (EU) and national rules, aiming to guarantee a high level of security for products and techniques but also for patients. This framework can be either considered as a guaranty for the use of new molecules in a highly secure environment or as an impediment, on the one hand regarding those who want to develop them because of a great complexity in identifying the adequate procedures and regarding the scientific prerequisites expected by the control agencies, and on the other hand by patients who have to wait many years for these innovations to be made available...
July 2018: Journal International de Bioéthique et D'éthique des Sciences
Ping Zhang, Jyothy Raju, Md Ashik Ullah, Raymond Au, Antiopi Varelias, Kate H Gartlan, Stuart D Olver, Luke D Samson, Elise Sturgeon, Nienke Zomerdijk, Judy Avery, Tessa Gargett, Michael P Brown, Lachlan J Coin, Devika Ganesamoorthy, Cheryl Hutchins, Gary R Pratt, Glen A Kennedy, A James Morton, Cameron I Curley, Geoffrey R Hill, Siok-Keen Tey
Purpose: Inducible caspase 9 ( iCasp9 ) is a cellular safety switch that can make T-cell therapy safer. The purpose of this phase I trial was to investigate the use of iCasp9 -transduced T-cell addback in adult patients undergoing haploidentical stem cell transplantation for high-risk hematologic malignancies. Patients and Methods: Patients undergoing myeloablative, CD34-selected haploidentical stem cell transplantation were treated with 0.5-1.0 × 106 /kg donor-derived iCasp9 -transduced T cells on day +25 or 26 post-transplant, with additional doses allowed for disease relapse, infection, or mixed chimerism...
February 14, 2019: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Juanjuan Zhao, Yongping Song, Delong Liu
The current treatment for pediatric acute lymphoblastic leukemia (ALL) is highly successful with high cure rate. However, the treatment of adult ALL remains a challenge, particularly for refractory and/or relapsed (R/R) ALL. The advent of new targeted agents, blinatumomab, inotuzumab ozogamycin, and chimeric antigen receptor (CAR) T cells, are changing the treatment paradigm for ALL. Tisagenlecleucel (kymriah, Novartis) is an autologous CD19-targeted CAR T cell product approved for treatment of R/R B cell ALL and lymphoma...
February 14, 2019: Journal of Hematology & Oncology
Ibrahim Aldoss, Stephen J Forman, Vinod Pullarkat
Acute lymphoblastic leukemia (ALL) in older adults presents a real challenge as a result of adverse disease biology and comorbidities that preclude delivering curative regimens. Conventional chemotherapy approaches have generally yielded unsatisfactory results in older patients with ALL as a result of excessive induction mortality, chemotherapy resistance of the leukemia, and the need to omit or dose reduce key drugs during the course of therapy because of adverse effects. Philadelphia chromosome-positive ALL represents about a quarter of newly diagnosed older adults, and the striking single-agent activity and excellent safety profile of tyrosine kinase inhibitors has allowed incorporation of these agents into therapy, significantly improving the outcome of older adults with Philadelphia chromosome-positive ALL...
February 2019: Journal of Oncology Practice
DaMarcus E Baymon, Edward W Boyer
PURPOSE OF REVIEW: Chimeric antigen receptor -(CAR) T-cell therapy has become a commonly used immunotherapy originally used in the treatment of B-cell leukemias but which are now applied broadly across tumor classes. Although high rates of remission are associated with CAR T-cell therapy, toxicities associated with these novel treatment regimens can be lethal if not recognized in a timely manner. RECENT FINDINGS: Cytokine release syndrome and neurotoxicity are the two most common toxicities associated with CAR T-cell therapy...
February 11, 2019: Current Opinion in Pediatrics
Ramakrishnan Gopalakrishnan, Hittu Matta, Sunju Choi, Venkatesh Natarajan, Ruben Prins, Songjie Gong, Arta Zenunovic, Nell Narasappa, Fatima Patel, Rekha Prakash, Vishan Chaudhary, Varun Sikri, Saurabh Deepak Chitnis, Andrei Kochegarov, Dan Wang, Magdalena Falat, Michael Kahn, Pooja Smruthi Keerthipati, Naman Sharma, Jyotirmayee Lenka, Tomas Meza Stieben, Jason Braun, Ankita Batra, Katelyn Purvis, Kenta Ito, Jae Han Lee, Alberto Jeronimo, Hannalei Mae Zamora, Allen Membreno, Queenie Qiu, Supriya Peshin, Lalith Namburu, Preet M Chaudhary
Chimeric Antigen Receptor-T (CAR-T) cell immunotherapy has produced dramatic responses in hematologic malignancies. One of the challenges in the field is the lack of a simple assay for the detection of CARs on the surface of immune effector cells. In this study, we describe a novel luciferase-based assay, termed Topanga Assay, for the detection of CAR expression. The assay utilizes a recombinant fusion protein, called Topanga reagent, generated by joining the extra-cellular domain of a CAR-target in frame with one of the marine luciferases or their engineered derivatives...
February 13, 2019: Scientific Reports
Fengtao You, Yinyan Wang, Licui Jiang, Xuejun Zhu, Dan Chen, Lei Yuan, Gangli An, Huimin Meng, Lin Yang
Chimeric antigen receptor (CAR) immunotherapy has recently shown promise in clinical trials for B-cell malignancies; however, designing CARs for T-cell based diseases remain a challenge since most target antigens are shared between normal and malignant cells, leading to CAR-T cell fratricide. CD7 is highly expressed in T-cell acute lymphoblastic leukemia (T-ALL), but it is not expressed in one small group of normal T lymphocytes. Here, we constructed monovalent CD7-CAR-NK-92MI and bivalent dCD7-CAR-NK-92MI cells using the CD7 nanobody VHH6 sequences from our laboratory...
2019: American Journal of Cancer Research
Maria C Ramello, Ismahène Benzaïd, Brent M Kuenzi, Maritza Lienlaf-Moreno, Wendy M Kandell, Daniel N Santiago, Mibel Pabón-Saldaña, Lancia Darville, Bin Fang, Uwe Rix, Sean Yoder, Anders Berglund, John M Koomen, Eric B Haura, Daniel Abate-Daga
Adoptive transfer of T cells that express a chimeric antigen receptor (CAR) is an approved immunotherapy that may be curative for some hematological cancers. To better understand the therapeutic mechanism of action, we systematically analyzed CAR signaling in human primary T cells by mass spectrometry. When we compared the interactomes and the signaling pathways activated by distinct CAR-T cells that shared the same antigen-binding domain but differed in their intracellular domains and their in vivo antitumor efficacy, we found that only second-generation CARs induced the expression of a constitutively phosphorylated form of CD3ζ that resembled the endogenous species...
February 12, 2019: Science Signaling
Hongwei Du, Koichi Hirabayashi, Sarah Ahn, Nancy Porterfield Kren, Stephanie Ann Montgomery, Xinhui Wang, Karthik Tiruthani, Bhalchandra Mirlekar, Daniel Michaud, Kevin Greene, Silvia Gabriela Herrera, Yang Xu, Chuang Sun, Yuhui Chen, Xingcong Ma, Cristina Rosa Ferrone, Yuliya Pylayeva-Gupta, Jen Jen Yeh, Rihe Liu, Barbara Savoldo, Soldano Ferrone, Gianpietro Dotti
The high expression across multiple tumor types and restricted expression in normal tissues make B7-H3 an attractive target for immunotherapy. We generated chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR-Ts) and found that B7-H3.CAR-Ts controlled the growth of pancreatic ductal adenocarcinoma, ovarian cancer and neuroblastoma in vitro and in orthotopic and metastatic xenograft mouse models, which included patient-derived xenograft. We also found that 4-1BB co-stimulation promotes lower PD-1 expression in B7-H3...
February 11, 2019: Cancer Cell
Bradley D Hunter, Caron A Jacobson
Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary new form of immunotherapy for the treatment of hematologic malignancies. The two primary toxicities associated with CAR T-cell therapy include cytokine release syndrome (CRS) and neurotoxicity (NT). CRS is generally self-limited but high-grade toxicities like hypotension and hypoxemia can be managed with agents that block the effects of IL-6, like tocilizumab, and/or corticosteroids. While CAR-T cell therapy-associated NT is a well-described clinical phenomenon, its pathophysiology remains inadequately understood; treatments and preventive strategies remain elusive...
February 11, 2019: Journal of the National Cancer Institute
Nicholas Aj Dawson, Caroline Lamarche, Romy E Hoeppli, Peter Bergqvist, Vivian Fung, Emma McIver, Qing Huang, Jana Gillies, Madeleine Speck, Paul C Orban, Jonathan W Bush, Majid Mojibian, Megan K Levings
Chimeric antigen receptor (CAR) technology can be used to engineer the antigen-specificity of regulatory T cells (Tregs) and improve their potency as an adoptive cell therapy in multiple disease models. As synthetic receptors, CARs carry the risk of immunogenicity, particularly when derived from non-human antibodies. Using an HLA-A*02:01-specific CAR (A2-CAR) encoding a single-chain Fv derived from a mouse antibody, we developed a panel of 20 humanized (h)A2-CARs. Systematic testing demonstrated variations in expression, ability to bind HLA-A*02:01, and stimulate human Treg suppression in vitro...
February 12, 2019: JCI Insight
Hong Xu, Ziqiang Zhu, Yiming Huang, Suzanne T Ildstad
BACKGROUND: Mobilization of hematopoietic stem cells (HSC) has become the preferred approach for HSC transplantation. AMD3100, a competitive inhibitor of C-X-C motif chemokine receptor-4 (CXCR4), has been found to be a rapid mobilizing agent. The present study evaluated approaches to optimize the product collected. METHODS: Mobilized peripheral blood mononuclear cells (mPBMC) from B6 mice were transplanted to recipient BALB/c mice conditioned with ablative or nonmyeloablative approaches...
February 4, 2019: Transplantation
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