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https://www.readbyqxmd.com/read/30116611/molecular-approaches-to-safe-and-controlled-engineered-t-cell-therapy
#1
R S Kalinin, A V Petukhov, V D Knorre, M A Maschan, A V Stepanov, A G Gabibov
Chimeric antigen receptor-modified T-cell therapy (CAR-T therapy) is one of the fastest developing areas of immuno-oncology. Over the past decade, it has revolutionized the cell therapy modality and expedited its pace of development, from optimization of the structure of chimeric antigen receptors and animal model experiments to successful clinical application. The initial designs of the CAR configuration focused on increasing T-cell activation, cytotoxicity, and persistence. However, the first attempts to treat patients with CAR T cells have demonstrated the need for increased safety and controlled activation of genetically modified T cells...
April 2018: Acta Naturae
https://www.readbyqxmd.com/read/30112696/a-method-for-expansion-of-t-cells-from-cynomolgus-monkey-macaca-fascicularis
#2
Change Gao, Qian Song, Ming Zhang, Jian Li, Miao Yi, Jian Dong
T cells have been successfully applied to cancer immunotherapy. However, a challenge is an expansion of T cells from cynomolgus monkey, which is a valuable non-human primate model for T cell therapy transferring to the clinic. Here, we compared several strategies to expand cynomolgus monkey T cell and developed an appropriate method. Our study demonstrated that 100 ng/ml CD3 mAb + 1% PHA+ 1000 U/ml IL2 therapy significantly expanded peripheral blood CD3+ T cells without compromising T cell phenotype in vitro...
August 15, 2018: In Vitro Cellular & Developmental Biology. Animal
https://www.readbyqxmd.com/read/30111631/il-21-selectively-protects-cd62l-nkt-cells-and-enhances-their-effector-functions-for-adoptive-immunotherapy
#3
Ho Ngai, Gengwen Tian, Amy N Courtney, Soodeh B Ravari, Linjie Guo, Bin Liu, Jingling Jin, Elise T Shen, Erica J Di Pierro, Leonid S Metelitsa
T cells expressing CD19-specific chimeric Ag receptors (CARs) produce high remission rates in B cell lymphoma, but frequent disease recurrence and challenges in generating sufficient numbers of autologous CAR T cells necessitate the development of alternative therapeutic effectors. Vα24-invariant NKTs have intrinsic antitumor properties and are not alloreactive, allowing for off-the-shelf use of CAR-NKTs from healthy donors. We recently reported that CD62L+ NKTs persist longer and have more potent antilymphoma activity than CD62L- cells...
August 15, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/30111427/-establishment-of-trace-amount-bone-marrow-hematopoietic-stem-cells-of-adult-mouse-transplantation-system
#4
Wei Liu, Bing Liu
OBJECTIVE: To establish a transplantation system for a trace amount of adult mouse bone marrow hematopoietic stem cells (HSCs). METHODS: The HSCs from bone marrow cells of GFP adult mouse were seperated by using marker combination ESLAM (CD45+ CD201+ CD150+ CD48- ) The goal cell population acquired by flow cytometry sorting were injected into lethally irradiated recipient mouse plus protective cells. And the peripheral blood cells from recipient mice tail veins at different time points were acquired to observe the reconstruction level and lineage differentiation...
August 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/30111196/tisagenlecleucel-for-the-treatment-of-b-cell-acute-lymphoblastic-leukemia
#5
Allison Barz Leahy, Caitlin W Elgarten, Stephan A Grupp, Shannon L Maude, David T Teachey
Cure rates for pediatric and young adult patients with refractory or recurrently relapsed acute lymphoblastic leukemia are dismal. Survival from time of relapse is typically measured in weeks to months, and standard chemotherapy and currently approved targeted therapy achieve remission in less than a third of affected patients. To date, the only definitive curative therapy has been allogeneic hematopoietic stem cell transplant (HSCT). Advances in immunotherapy, with the introduction of chimeric antigen receptor T cell therapies and the development of tisagenlecleucel, have changed the landscape...
August 15, 2018: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/30110720/unleashing-the-therapeutic-potential-of-car-t-cell-therapy-using-gene-editing-technologies
#6
In-Young Jung, Jungmin Lee
Chimeric antigen receptor (CAR) T-cell therapy, an emerging immunotherapy, has demonstrated promising clinical results in hematological malignancies including B-cell malignancies. However, accessibility to this transformative medicine is highly limited due to the complex process of manufacturing, limited options for target antigens, and insufficient anti-tumor responses against solid tumors. Advances in gene-editing technologies, such as the development of Zinc Finger Nucleases (ZFNs), Transcription Activator-Like Effector Nucleases (TALENs), and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR/Cas9), have provided novel engineering strategies to address these limitations...
August 14, 2018: Molecules and Cells
https://www.readbyqxmd.com/read/30109179/the-application-of-car-t-cell-therapy-in-hematological-malignancies-advantages-and-challenges
#7
REVIEW
Zijun Zhao, Yu Chen, Ngiambudulu M Francisco, Yuanqing Zhang, Minhao Wu
Chimeric antigen receptor T cell (CAR-T cell) therapy is a novel adoptive immunotherapy where T lymphocytes are engineered with synthetic receptors known as chimeric antigen receptors (CAR). The CAR-T cell is an effector T cell that recognizes and eliminates specific cancer cells, independent of major histocompatibility complex molecules. The whole procedure of CAR-T cell production is not well understood. The CAR-T cell has been used predominantly in the treatment of hematological malignancies, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphoma, and multiple myeloma...
July 2018: Acta Pharmaceutica Sinica. B
https://www.readbyqxmd.com/read/30108584/immune-cell-hacking-challenges-and-clinical-approaches-to-create-smarter-generations-of-chimeric-antigen-receptor-t-cells
#8
REVIEW
Reza Elahi, Elnaz Khosh, Safa Tahmasebi, Abdolreza Esmaeilzadeh
T cells equipped with chimeric antigen receptors (CAR T cells) have recently provided promising advances as a novel immunotherapeutic approach for cancer treatment. CAR T cell therapy has shown stunning results especially in B-cell malignancies; however, it has shown less success against solid tumors, which is more supposed to be related to the specific characteristics of the tumor microenvironment. In this review, we discuss the structure of the CAR, current clinical advantages from finished and ongoing trials, adverse effects, challenges and controversies, new engineering methods of CAR, and clinical considerations that are associated with CAR T cell therapy both in hematological malignancies and solid tumors...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/30105642/induced-expression-of-endogenous-cxcr4-in-ipscs-by-targeted-cpg-demethylation-enhances-cell-migration-toward-the-ligand-cxcl12
#9
Can Jiang, Jun Guo, Huaiyan Cheng, Ying-Hong Feng
Poor homing of cells after transplantation is an unresolved common issue in cardiac cell therapies. To enhance stem cell homing, the ligand CXC motif chemokine 12 (CXCL12) and its specific receptor CXC receptor type 4 (CXCR4) have been employed as a system in this study to show that induced expression of the endogenous CXCR4 gene in mouse-induced pluripotent stem cells (iPSCs) improved the cell migration. Loci-specific epigenome editing in the form of CpG demethylation at CXCR4 promoter region of the mouse iPSCs was accomplished with CXCR4b-TAL-Tet1c, chimeric fusion proteins of the catalytic domain of ten-eleven translocation 1 (TET1) to the C-terminal end of the DNA binding domains of predesigned synthetic transcription activator-like effectors (TALEs) that recognize specific DNA sequences within the mouse CXCR4 promoter region...
August 13, 2018: Inflammation
https://www.readbyqxmd.com/read/30104668/biomaterial-assisted-targeted-modulation-of-immune-cells-in-cancer-treatment
#10
REVIEW
Hua Wang, David J Mooney
The past decade has witnessed the accelerating development of immunotherapies for cancer treatment. Immune checkpoint blockade therapies and chimeric antigen receptor (CAR)-T cell therapies have demonstrated clinical efficacy against a variety of cancers. However, issues including life-threatening off-target side effects, long processing times, limited patient responses and high cost still limit the clinical utility of cancer immunotherapies. Biomaterial carriers of these therapies, though, enable one to troubleshoot the delivery issues, amplify immunomodulatory effects, integrate the synergistic effect of different molecules and, more importantly, home and manipulate immune cells in vivo...
August 13, 2018: Nature Materials
https://www.readbyqxmd.com/read/30104252/cd19-alterations-emerging-after-cd19-directed-immunotherapy-cause-retention-of-the-misfolded-protein-in-the-endoplasmic-reticulum
#11
Asen Bagashev, Elena Sotillo, Chih-Hang Anthony Tang, Kathryn L Black, Jessica Perazzelli, Steven H Seeholzer, Yair Argon, David M Barrett, Stephan A Grupp, Chih-Chi Andrew Hu, Andrei Thomas-Tikhonenko
We have previously described a mechanism of acquired resistance of B-cell acute lymphoblastic leukemia to CD19-directed chimeric antigen receptor T-cell (CART) immunotherapy. It was based on in-frame insertions in or skipping of CD19 exon 2. To distinguish between epitope loss and defects in surface localization, we used retroviral transduction and genome editing to generate cell lines expressing CD19 exon 2 variants (CD19ex2vs) bearing VSV-G tags. These lines were negative by live-cell flow cytometry with an anti-VSV-G antibody and resistant to killing by VSV-G directed antibody-drug conjugates (ADC), suggestive of a defect in surface localization...
August 13, 2018: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/30103775/recombination-of-a-dual-car-modified-t-lymphocyte-to-accurately-eliminate-pancreatic-malignancy
#12
Erhao Zhang, Peiwei Yang, Jieyi Gu, Heming Wu, Xiaowei Chi, Chen Liu, Ying Wang, Jianpeng Xue, Weiyan Qi, Qingbo Sun, Shengnan Zhang, Jialiang Hu, Hanmei Xu
BACKGROUND: The therapeutic application of T cells endowing with chimeric antigen receptors (CARs) is faced with "on-target, off-tumor" toxicity against solid tumors, particularly in the treatment of the pancreatic cancer. To our best knowledge, the pancreatic cancer cell line AsPC-1 often highly expressed some distinct tumor-associated antigens, such as carcino-embryonic antigen (CEA) and mesothelin (MSLN). Therefore, in this research, we have characterized dual-receptor CAR-modified T cells (dCAR-T) that exert effective and safe cytotoxicity against AsPC-1 cells...
August 13, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/30103488/the-generation-of-car-transfected-natural-killer-t-cells-for-the-immunotherapy-of-melanoma
#13
Bianca Simon, Manuel Wiesinger, Johannes März, Kilian Wistuba-Hamprecht, Benjamin Weide, Beatrice Schuler-Thurner, Gerold Schuler, Jan Dörrie, Ugur Uslu
Natural killer T (NKT) cells represent a cell subpopulation that combines characteristics of natural killer (NK) cells and T cells. Through their endogenous T-cell receptors (TCRs), they reveal a pronounced intrinsic anti-tumor activity. Thus, a NKT cell transfected with a chimeric antigen receptor (CAR), which recognizes a tumor-specific surface antigen, could attack tumor cells antigen-specifically via the CAR and additionally through its endogenous TCR. NKT cells were isolated from peripheral blood mononuclear cells (PBMCs), expanded, and electroporated with mRNA encoding a chondroitin sulfate proteoglycan 4 (CSPG4)-specific CAR...
August 11, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/30103457/early-investigations-and-recent-advances-in-intraperitoneal-immunotherapy-for-peritoneal-metastasis
#14
REVIEW
Anusha Thadi, Marian Khalili, William F Morano, Scott D Richard, Steven C Katz, Wilbur B Bowne
Peritoneal metastasis (PM) is an advanced stage malignancy largely refractory to modern therapy. Intraperitoneal (IP) immunotherapy offers a novel approach for the control of regional disease of the peritoneal cavity by breaking immune tolerance. These strategies include heightening T-cell response and vaccine induction of anti-cancer memory against tumor-associated antigens. Early investigations with chimeric antigen receptor T cells (CAR-T cells), vaccine-based therapies, dendritic cells (DCs) in combination with pro-inflammatory cytokines and natural killer cells (NKs), adoptive cell transfer, and immune checkpoint inhibitors represent significant advances in the treatment of PM...
August 10, 2018: Vaccines
https://www.readbyqxmd.com/read/30102931/exploring-receptor-selectivity-of-the-chimeric-relaxin-family-peptide-r3-i5-by-incorporating-unnatural-amino-acids
#15
Jia-Hui Wang, Meng-Jun Hu, Lei Zhang, Xiao-Xia Shao, Cai-Hong Lv, Ya-Li Liu, Zeng-Guang Xu, Zhan-Yun Guo
Relaxin family peptides perform a variety of biological functions by activating four G protein-coupled receptors, namely RXFP1-4. Our recent study demonstrated that selectivity of the chimeric relaxin family peptide R3/I5 towards the homologous RXFP3 and RXFP4 can be modulated by replacement of the highly conserved nonchiral B23Gly or B24Gly with some natural L-amino acids. To investigate the mechanism of this modulating effect, in the present study we incorporated unnatural amino acids into the B23 or B24 position of a semi-synthetic R3/I5 that was prepared by a novel sortase-catalysed ligation approach using synthetic relaxin-3 B-chain and recombinant INSL5 A-chain...
August 10, 2018: Biochimie
https://www.readbyqxmd.com/read/30102361/producing-prot-cells-to-promote-immunotherapies
#16
Jastaranpreet Singh, Juan Carlos Zúñiga-Pflücker
T-lymphocytes are critical mediators of the adaptive immune system and they can be harnessed as therapeutic agents against pathogens and in cancer immunotherapy. T-cells can be isolated and expanded from patients and potentially generated in vitro using clinically relevant systems. An ultimate goal for T-cell immunotherapy is to establish a safe, universal effector cell type capable of transcending allogeneic and histocompatibility barriers. To this end, human pluripotent stem cells (PSCs) offer an advantage in generating a boundless supply of T-cells that can be readily genetically engineered...
August 9, 2018: International Immunology
https://www.readbyqxmd.com/read/30102295/targeted-delivery-of-a-pd-1-blocking-scfv-by-car-t-cells-enhances-anti-tumor-efficacy-in-vivo
#17
Sarwish Rafiq, Oladapo O Yeku, Hollie J Jackson, Terence J Purdon, Dayenne G van Leeuwen, Dylan J Drakes, Mei Song, Matthew M Miele, Zhuoning Li, Pei Wang, Su Yan, Jingyi Xiang, Xiaojing Ma, Venkatraman E Seshan, Ronald C Hendrickson, Cheng Liu, Renier J Brentjens
The efficacy of chimeric antigen receptor (CAR) T cell therapy against poorly responding tumors can be enhanced by administering the cells in combination with immune checkpoint blockade inhibitors. Alternatively, the CAR construct has been engineered to coexpress factors that boost CAR-T cell function in the tumor microenvironment. We modified CAR-T cells to secrete PD-1-blocking single-chain variable fragments (scFv). These scFv-secreting CAR-T cells acted in both a paracrine and autocrine manner to improve the anti-tumor activity of CAR-T cells and bystander tumor-specific T cells in clinically relevant syngeneic and xenogeneic mouse models of PD-L1+ hematologic and solid tumors...
August 13, 2018: Nature Biotechnology
https://www.readbyqxmd.com/read/30101189/chimeric-camel-human-heavy-chain-antibodies-protect-against-mers-cov-infection
#18
V Stalin Raj, Nisreen M A Okba, Javier Gutierrez-Alvarez, Dubravka Drabek, Brenda van Dieren, W Widagdo, Mart M Lamers, Ivy Widjaja, Raul Fernandez-Delgado, Isabel Sola, Albert Bensaid, Marion P Koopmans, Joaquim Segalés, Albert D M E Osterhaus, Berend Jan Bosch, Luis Enjuanes, Bart L Haagmans
Middle East respiratory syndrome coronavirus (MERS-CoV) continues to cause outbreaks in humans as a result of spillover events from dromedaries. In contrast to humans, MERS-CoV-exposed dromedaries develop only very mild infections and exceptionally potent virus-neutralizing antibody responses. These strong antibody responses may be caused by affinity maturation as a result of repeated exposure to the virus or by the fact that dromedaries-apart from conventional antibodies-have relatively unique, heavy chain-only antibodies (HCAbs)...
August 2018: Science Advances
https://www.readbyqxmd.com/read/30093975/extracellular-atp-is-a-danger-signal-activating-p2x7-receptor-in-a-lps-mediated-inflammation-ards-ali
#19
Sanja Cicko, Thomas Christian Köhler, Cemil Korcan Ayata, Tobias Müller, Nicolas Ehrat, Anja Meyer, Madelon Hossfeld, Andreas Zech, Francesco Di Virgilio, Marco Idzko
Acute respiratory distress syndrome (ARDS) is a life-threating lung condition resulting from a direct and indirect injury to the lungs [1, 2]. Pathophysiologically it is characterized by an acute alveolar damage, an increased permeability of the microvascular-barrier, leading to protein-rich pulmonary edema and subsequent impairment of arterial oxygenation and respiratory failure [1]. This study examined the role of extracellular ATP in recruiting inflammatory cells to the lung after induction of acute lung injury with lipopolysaccharide (LPS)...
July 17, 2018: Oncotarget
https://www.readbyqxmd.com/read/30092570/rapid-growth-and-early-metastasis-of-papillary-thyroid-carcinoma-in-an-adolescent-girl-with-graves-disease
#20
Kazuhiro Shimura, Hironori Shibata, Yusuke Mizuno, Naoko Amano, Ken Hoshino, Tatsuo Kuroda, Kaori Kameyama, Michiko Matsuse, Norisato Mitsutake, Kiminori Sugino, Jaeduk Yoshimura Noh, Tomonobu Hasegawa, Tomohiro Ishii
BACKGROUND: The risk factors for rapid growth and early metastasis of papillary thyroid carcinoma (PTC) and the role of coexisting Graves' disease in the clinical course of PTC remain uncertain in children. CASE DESCRIPTION: We report on a Japanese girl, whose PTC rapidly grew and metastasized within 4 years. Graves' disease was diagnosed by the presence of serum TSH receptor antibodies at 8 years of age when thyroid ultrasonography detected no nodules. After 4 years of effective treatment with thiamazole, multifocal nodules - up to 47 mm in diameter - were detected on thyroid ultrasonography...
August 9, 2018: Hormone Research in Pædiatrics
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