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https://www.readbyqxmd.com/read/29348865/targeting-t-cell-malignancies-using-anti-cd4-car-nk-92-cells
#1
Kevin G Pinz, Elizabeth Yakaboski, Alexander Jares, Hua Liu, Amelia E Firor, Kevin H Chen, Masayuki Wada, Huda Salman, William Tse, Nabil Hagag, Fengshuo Lan, Elaine Lai-Han Leung, Xun Jiang, Yupo Ma
Peripheral T-cell lymphomas (PTCLs) are a group of very aggressive non-Hodgkin's lymphomas (NHLs) with poor prognoses and account for a majority of T-cell malignancies. Overall, the standard of care for patients with T-cell malignancies is poorly established, and there is an urgent clinical need for a new approach. As demonstrated in B-cell malignancies, chimeric antigen receptor (CAR) immunotherapy provides great hope as a curative treatment regimen. Because PTCLs develop from mature T-cells, these NHLs are commonly CD4+, and CD4 is highly and uniformly expressed...
December 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29339014/development-of-gpc3-specific-chimeric-antigen-receptor-engineered-natural-killer-cells-for-the-treatment-of-hepatocellular-carcinoma
#2
Min Yu, Hong Luo, Mingliang Fan, Xiuqi Wu, Bizhi Shi, Shengmeng Di, Ying Liu, Zeyan Pan, Hua Jiang, Zonghai Li
Chimeric antigen receptor (CAR)-modified natural killer (NK) cells represent a promising immunotherapeutic modality for cancer treatment. However, their potential utilities have not been explored in hepatocellular carcinoma (HCC). Glypian-3 (GPC3) is a rational immunotherapeutic target for HCC. In this study, we developed GPC3-specific NK cells and explored their potential in the treatment of HCC. The NK-92/9.28.z cell line was established by engineering NK-92, a highly cytotoxic NK cell line with second-generation GPC3-specific CAR...
December 19, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29334771/development-of-anti-human-mesothelin-targeted-chimeric-antigen-receptor-car-messenger-rna-mrna-transfected-peripheral-blood-lymphocytes-carma-hmeso-for-ovarian-cancer-therapy
#3
Chien-Fu Hung, Xuequn Xu, Linhong Li, Ying Ma, Qiu Jin, Angelia Viley, Cornell Allen, Pachai Natarajan, Rama Shivakumar, Madhusudan V Peshwa, Leisha A Emens
CD19-targeted chimeric antigen receptor (CAR) engineered T/natural kill (NK)-cell therapies can result in durable clinical responses in B-cell malignancies. However, CAR-based immunotherapies have been much less successful in solid cancers, in part due to 'on-target off-tumor' toxicity related to expression of target tumor antigens on normal tissue. Based on preliminary observations of safety and clinical activity in proof-of-concept clinical trials, tumor antigen-specific messenger RNA (mRNA) CAR transfection into selected, activated, and expanded T/NK-cells may permit prospective control of 'on-target off-tumor toxicity'...
January 15, 2018: Human Gene Therapy
https://www.readbyqxmd.com/read/29320890/chimeric-antigen-receptors-in-different-cell-types-new-vehicles-join-the-race
#4
Dennis C Harrer, Jan Dörrie, Niels Schaft
Adoptive cellular therapy has evolved into a powerful force in the battle against cancer, holding promise for curative responses in patients with advanced and refractory tumors. Autologous T cells, reprogrammed to target malignant cells via the expression of a chimeric antigen receptor (CAR) represent the frontrunner in this approach. Tremendous clinical regressions have been achieved using CAR-T cells against a variety of cancers both in numerous preclinical studies and in several clinical trials, most notably against ALL, and resulted in a very recent FDA-approval of the first CAR-T-cell therapy...
January 10, 2018: Human Gene Therapy
https://www.readbyqxmd.com/read/29316666/fusion-proteins-of-nkg2d-nkg2dl-in-cancer-immunotherapy
#5
REVIEW
Hui Ding, Xi Yang, Yanzhang Wei
NKG2D (natural killer group 2, member D) is an important activating receptor in natural killer (NK) cells and some T cells. NKG2D ligands (NKG2DLs) are specifically expressed on most tumor cells. The engagement of these ligands on tumor cells to NKG2D on NK cells will induce cell-mediated cytotoxicity and have target cells destroyed. This gives NKG2D/NKG2DLs great potential in cancer therapeutic application. The creation of NKG2D/NKG2DL-based multi-functional fusion proteins is becoming one of the most promising strategies in immunotherapy for cancer...
January 7, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29241547/car-t-cells-releasing-il-18-convert-to-t-bethigh-foxo1low-effectors-that-exhibit-augmented-activity-against-advanced-solid-tumors
#6
Markus Chmielewski, Hinrich Abken
Adoptive therapy with chimeric antigen receptor (CAR)-redirected T cells has achieved remarkable efficacy in the treatment of hematopoietic malignancies. However, eradicating large solid tumors in advanced stages of the disease remains challenging. We explored augmentation of the anti-tumor immune reaction by establishing an acute inflammatory reaction. Systematic screening indicates that IL-18 polarizes CAR T cells toward T-bethigh FoxO1low effectors with an acute inflammatory response. CAR T cells engineered with inducible IL-18 release exhibited superior activity against large pancreatic and lung tumors that were refractory to CAR T cells without cytokines...
December 12, 2017: Cell Reports
https://www.readbyqxmd.com/read/29103317/anticancer-cellular-immunotherapies-derived-from-umbilical-cord-blood
#7
Katalin Balassa, Vanderson Rocha
Introduction The lack of highly effective drugs in many malignancies has prompted scientific interest in the development of alternative treatment strategies. Cellular immunotherapy involving the adoptive transfer of immune cells that potently recognize and eliminate malignantly transformed cells has become a promising new tool in the anticancer armory. Studies suggest that the unique biological properties of umbilical cord blood (UCB) cells could precipitate enhanced anticancer activity; hence, UCB could be an optimal source for immunotherapy with the potential to provide products with "off-the-shelf" availability...
November 6, 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/29089311/slamf7-car-t-cells-eliminate-myeloma-and-confer-selective-fratricide-of-slamf7-normal-lymphocytes
#8
Tea Gogishvili, Sophia Danhof, Sabrina Prommersberger, Julian Rydzek, Martin Schreder, Christian Brede, Hermann Einsele, Michael Hudecek
SLAMF7 is under intense investigation as a target for immunotherapy in multiple myeloma. Here, we redirected the specificity of T-cells to SLAMF7 through expression of a chimeric antigen receptor (CAR) derived from the huLuc63 antibody (Elotuzumab), and demonstrate that SLAMF7-CAR T-cells prepared from patients and healthy donors confer potent antimyeloma reactivity. We confirmed uniform, high-level expression of SLAMF7 on malignant plasma cells in previously untreated and in relapsed/refractory (R/R) myeloma patients who had received prior treatment with proteasome-inhibitors and immunomodulatory agents (IMiDs)...
October 31, 2017: Blood
https://www.readbyqxmd.com/read/29040754/development-of-unique-cytotoxic-chimeric-antigen-receptors-based-on-human-scfv-targeting-b7h6
#9
Casey K Hua, Albert T Gacerez, Charles L Sentman, Margaret E Ackerman
As a stress-inducible natural killer (NK) cell ligand, B7H6 plays a role in innate tumor immunosurveillance and is a fairly tumor selective marker expressed on a variety of solid and hematologic cancer cells. Here, we describe the isolation and characterization of a new family of single chain fragment variable (scFv) molecules targeting the human B7H6 ligand. Through directed evolution of a yeast surface displayed non-immune human-derived scFv library, eight candidates comprising a single family of clones differing by up to four amino acid mutations and exhibiting nM avidities for soluble B7H6-Ig were isolated...
October 1, 2017: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/29038795/immune-engineering-from-systems-immunology-to-engineering-immunity
#10
Ning Jiang
The smallpox vaccine represents the earliest attempt in engineering immunity. The recent success of chimeric antigen receptor T cells (CAR-T cells) in cancer once again demonstrates the clinical potential of immune engineering. Inspired by this success, diverse approaches have been used to boost various aspects of immunity: engineering dendritic cells (DCs), natural killer (NK) cells, T cells, antibodies, cytokines, small peptides, and others. With recent development of various high-throughput technologies (of which engineers, especially biomedical engineers/bioengineers contributed significantly), such as immune repertoire sequencing, and analytical methods, a systems level of understanding immunity (or the lack of it) beyond model animals has provided critical insights into the human immune system...
March 2017: Current Opinion in Biomedical Engineering
https://www.readbyqxmd.com/read/29029499/generation-and-characterization-of-erbb2-car-engineered-cytokine-induced-killer-cells-for-the-treatment-of-high-risk-soft-tissue-sarcoma-in-children
#11
Michael Merker, Verena Pfirrmann, Sarah Oelsner, Simone Fulda, Thomas Klingebiel, Winfried S Wels, Peter Bader, Eva Rettinger
Pediatric patients with recurrent, refractory or advanced soft tissue sarcoma (STS) who are simultaneously showing signs of cumulative treatment toxicity are in need of novel therapies. In this preclinical analysis, we identified ErbB2 as a targetable antigen on STS cells and used cytokine-induced killer (CIK) cells transduced with the lentiviral 2nd-generation chimeric antigen receptor (CAR) vector pS-5.28.z-IEW to target ErbB2-positive tumors. Solely CIK cell subsets with the CD3+ T cell phenotype showed up to 85% cell surface expression of the respective CAR...
September 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/28932644/romidepsin-alone-or-in-combination-with-anti-cd20-chimeric-antigen-receptor-expanded-natural-killer-cells-targeting-burkitt-lymphoma-in-vitro-and-in-immunodeficient-mice
#12
Yaya Chu, Ashlin Yahr, Brian Huang, Janet Ayello, Matthew Barth, Mitchell S Cairo
Facilitating the development of alternative targeted therapeutic strategies is urgently required to improve outcome or circumvent chemotherapy resistance in children, adolescents, and adults with recurrent/refractory de novo mature B-cell (CD20) non-Hodgkin lymphoma, including Burkitt lymphoma (BL). Romidepsin, a histone deacetylase inhibitor (HDACi), has been used to treat cutaneous T-cell lymphoma. We have demonstrated the significant anti-tumor effect of anti-CD20 chimeric antigen receptor (CAR) modified expanded peripheral blood natural killer (exPBNK) against rituximab-sensitive and -resistant BL...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28880014/chimeric-antigen-receptor-car-transduced-natural-killer-cells-in-tumor-immunotherapy
#13
REVIEW
Yuan Hu, Zhi-Gang Tian, Cai Zhang
Natural killer (NK) cells are potential effector cells in cell-based cancer immunotherapy, particularly in the control of hematological malignancies. The chimeric antigen receptor (CAR) is an artificially modified fusion protein that consists of an extracellular antigen recognition domain fused to an intracellular signaling domain. T cells genetically modified with a CAR have demonstrated remarkable success in the treatment of hematological cancers. Compared to T cells, CAR-transduced NK cells (CAR-NK) exhibit several advantages, such as safety in clinical use, the mechanisms by which they recognize cancer cells, and their abundance in clinical samples...
September 7, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28879551/clinical-grade-manufacturing-of-genetically-modified-car-expressing-nk-92-cells-for-the-treatment-of-erbb2-positive-malignancies
#14
Paulina Nowakowska, Annette Romanski, Nicole Miller, Marcus Odendahl, Halvard Bonig, Congcong Zhang, Erhard Seifried, Winfried S Wels, Torsten Tonn
BACKGROUND: The NK-92/5.28.z cell line (also referred to as HER2.taNK) represents a stable, lentiviral-transduced clone of ErbB2 (HER2)-specific, second-generation CAR-expressing derivative of clinically applicable NK-92 cells. This study addresses manufacturing-related issues and aimed to develop a GMP-compliant protocol for the generation of NK-92/5.28.z therapeutic doses starting from a well-characterized GMP-compliant master cell bank. MATERIALS AND METHODS: Commercially available GMP-grade culture media and supplements (fresh frozen plasma, platelet lysate) were evaluated for their ability to support expansion of NK-92/5...
September 6, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28878363/a-tcr-based-chimeric-antigen-receptor
#15
Even Walseng, Hakan Köksal, Ibrahim M Sektioglu, Anne Fåne, Gjertrud Skorstad, Gunnar Kvalheim, Gustav Gaudernack, Else Marit Inderberg, Sébastien Wälchli
Effector T cells equipped with engineered antigen receptors specific for cancer targets have proven to be very efficient. Two methods have emerged: the Chimeric Antigen Receptors (CARs) and T-cell Receptor (TCR) redirection. Although very potent, CAR recognition is limited to membrane antigens which represent around 1% of the total proteins expressed, whereas TCRs have the advantage of targeting any peptide resulting from cellular protein degradation. However, TCRs depend on heavy signalling machinery only present in T cells which restricts the type of eligible therapeutic cells...
September 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28877899/equipping-nk-cells-with-cars
#16
(no author information available yet)
Adding a chimeric antigen receptor (CAR) to natural killer (NK) cells is garnering interest as a therapeutic strategy because this immune cell type doesn't cause graft-versus-host disease, making its widespread, off-the-shelf use feasible. Based on promising preclinical data, a phase I/II trial of one such CAR NK-cell therapy is under way, targeting CD19 in hematologic malignancies.
October 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28857616/adoptive-cell-therapy-in-multiple-myeloma
#17
Sonia Vallet, Martin Pecherstorfer, Klaus Podar
Recent breakthrough advances in Multiple Myeloma (MM) immunotherapy have been achieved with the approval of the first two monoclonal antibodies, elotuzumab and daratumumab. Adoptive cell therapy (ACT) represents yet another, maybe the most powerful modality of immunotherapy, in which allogeneic or autologous effector cells are expanded and activated ex vivo followed by their re-infusion back into patients. Infused effector cells belong to two categories: naturally occurring, non-engineered cells (donor lymphocyte infusion, myeloma infiltrating lymphocytes, deltagamma T cells) or genetically- engineered antigen-specific cells (chimeric antigen receptor T or NK cells, TCR-engineered cells)...
September 6, 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/28838796/nk-cell-based-immunotherapy-for-cancer
#18
REVIEW
Fang Fang, Weihua Xiao, Zhigang Tian
Natural killer (NK) cells can induce an antigen-independent immune response against malignant cells. A growing number of scientific reports and clinical studies have shown promising anti-tumor effects when using NK cell-based immunotherapy. Currently, various approaches are being used to enhance the number and function of NK cells. One approach uses cytokines to selectively boost both the number as well as the efficacy of anti-tumor functions of NK cells. Another emerging approach focuses on checkpoint inhibitors targeting the NK cell receptor...
June 2017: Seminars in Immunology
https://www.readbyqxmd.com/read/28836469/improved-killing-of-ovarian-cancer-stem-cells-by-combining-a-novel-chimeric-antigen-receptor-based-immunotherapy-and-chemotherapy
#19
Rüdiger Klapdor, Shuo Wang, Ulrich Hacker, Hildegard Büning, Michael Morgan, Thilo Dörk, Peter Hillemanns, Axel Schambach
Ovarian cancer represents the most lethal gynecological cancer. Although cytoreductive chemotherapy and surgery lead to complete macroscopic tumor removal, most of the patients in advanced stages suffer from recurrent disease and subsequently die. This may be explained by the activity of cancer stem cells (CSC), which are a subpopulation of cells with an elevated chemoresistance and an increased capacity for self-renewal and metastatic spread. Specifically targeting these cells by adoptive immunotherapy represents a promising strategy to reduce the risk for recurrent disease...
October 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28810809/optimization-of-human-nk-cell-manufacturing-fully-automated-separation-improved-ex-vivo-expansion-using-il-21-with-autologous-feeder-cells-and-generation-of-anti-cd123-car-expressing-effector-cells
#20
Stephan Klöß, Olaf Oberschmidt, Michael Morgan, Julia Dahlke, Lubomir Arseniev, Volker Huppert, Markus Granzin, Tanja Gardlowski, Nadine Matthies, Stephanie Soltenborn, Axel Schambach, Ulrike Koehl
The administration of ex vivo expanded natural killer (NK) cells as potential antitumor effector cells appears to be suitable for effector cell-based immunotherapies in high-risk cancer patients. However, good manufacturing practice (GMP)-compliant manufacturing of clinical-grade NK cells at sufficiently high numbers represents a great challenge. Therefore, previous expansion protocols for those effector cells were improved and optimized by using newly developed culture medium, interleukin (IL)-21, and autologous feeder cells (FCs)...
October 2017: Human Gene Therapy
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