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Chimeric Antigen Receptor T cells

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https://www.readbyqxmd.com/read/29467769/cd137-cd154-expression-as-a-regulatory-t-cell-treg-specific-activation-signature-for-identification-and-sorting-of-stable-human-tregs-from-in-vitro-expansion-cultures
#1
Anna Nowak, Dominik Lock, Petra Bacher, Thordis Hohnstein, Katrin Vogt, Judith Gottfreund, Pascal Giehr, Julia K Polansky, Birgit Sawitzki, Andrew Kaiser, Jörn Walter, Alexander Scheffold
Regulatory T cells (Tregs) are an attractive therapeutic tool for several different immune pathologies. Therapeutic Treg application often requires prolonged in vitro culture to generate sufficient Treg numbers or to optimize their functionality, e.g., via genetic engineering of their antigen receptors. However, purity of clinical Treg expansion cultures is highly variable, and currently, it is impossible to identify and separate stable Tregs from contaminating effector T cells, either ex vivo or after prior expansion...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29463744/mhc-mismatched-mixed-chimerism-restores-peripheral-tolerance-of-noncross-reactive-autoreactive-t-cells-in-nod-mice
#2
Mingfeng Zhang, Jeremy J Racine, Qing Lin, Yuqing Liu, Shanshan Tang, Qi Qin, Tong Qi, Arthur D Riggs, Defu Zeng
Autoimmune type 1 diabetes (T1D) and other autoimmune diseases are associated with particular MHC haplotypes and expansion of autoreactive T cells. Induction of MHC-mismatched but not -matched mixed chimerism by hematopoietic cell transplantation effectively reverses autoimmunity in diabetic nonobese diabetic (NOD) mice, even those with established diabetes. As expected, MHC-mismatched mixed chimerism mediates deletion in the thymus of host-type autoreactive T cells that have T-cell receptor (TCR) recognizing (cross-reacting with) donor-type antigen presenting cells (APCs), which have come to reside in the thymus...
February 20, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29462761/a-guide-to-manufacturing-car-t-cell-therapies
#3
REVIEW
Philipp Vormittag, Rebecca Gunn, Sara Ghorashian, Farlan S Veraitch
In recent years, chimeric antigen receptor (CAR) modified T cells have been used as a treatment for haematological malignancies in several phase I and II trials and with Kymriah of Novartis and Yescarta of KITE Pharma, the first CAR T cell therapy products have been approved. Promising clinical outcomes have yet been tempered by the fact that many therapies may be prohibitively expensive to manufacture. The process is not yet defined, far from being standardised and often requires extensive manual handling steps...
February 17, 2018: Current Opinion in Biotechnology
https://www.readbyqxmd.com/read/29459866/current-status-of-gene-engineering-cell-therapeutics
#4
REVIEW
Aurore Saudemont, Laurent Jespers, Timothy Clay
Ex vivo manipulations of autologous patient's cells or gene-engineered cell therapeutics have allowed the development of cell and gene therapy approaches to treat otherwise incurable diseases. These modalities of personalized medicine have already shown great promises including product commercialization for some rare diseases. The transfer of a chimeric antigen receptor or T cell receptor genes into autologous T cells has led to very promising outcomes for some cancers, and particularly for hematological malignancies...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29458388/a-novel-generation-1928zt2-car-t-cells-induce-remission-in-extramedullary-relapse-of-acute-lymphoblastic-leukemia
#5
Jianyu Weng, Peilong Lai, Le Qin, Yunxin Lai, Zhiwu Jiang, Chenwei Luo, Xin Huang, Suijing Wu, Dan Shao, Chengxin Deng, Lisi Huang, Zesheng Lu, Maohua Zhou, Lingji Zeng, Dongmei Chen, Yulian Wang, Xiaomei Chen, Suxia Geng, Weinkove Robert, Zhaoyang Tang, Chang He, Peng Li, Xin Du
BACKGROUND: Anti-CD19 chimeric antigen receptor (CAR) T cells have shown promise in the treatment of B cell acute lymphocytic leukemia (B-ALL). However, its efficacy in B-ALL patients with extramedullary involvement is limited due to poor responses and neurotoxicity. Here, we utilized a third generation of CAR T cell vector, which contains the Toll/interleukin-1 receptor (ITR) domain of Toll-like receptor 2 (TLR2), to generate 1928zT2 T cells targeting CD19, and evaluated the efficacy of 1928zT2 T cells in relapse or refractory B-ALL patients with extramedullary involvement...
February 20, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29453518/chimeric-antigen-receptors-with-human-scfvs-preferentially-induce-t-cell-anti-tumor-activity-against-tumors-with-high-b7h6-expression
#6
Albert T Gacerez, Casey K Hua, Margaret E Ackerman, Charles L Sentman
B7H6 is emerging as a promising tumor antigen that is known to be expressed on a wide array of tumors and is reported to stimulate anti-tumor responses from the immune system. As such, B7H6 presents a good target for tumor-specific immunotherapies. B7H6-specific chimeric antigen receptors (CAR) based on a murine antibody showed successful targeting and elimination of tumors expressing B7H6. However, mouse single chain variable fragments (scFvs) have the potential to induce host anti-CAR responses that may limit efficacy, so human scFvs specific for B7H6 were selected by yeast surface display...
February 16, 2018: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/29453239/a-next-generation-chimeric-antigen-receptor-induces-jak-stat-signaling
#7
(no author information available yet)
CAR-T cells designed to activate JAK-STAT signaling show enhanced persistence and antitumor activity.
February 16, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29451276/tisagenlecleucel-an-approved-anti-cd19-chimeric-antigen-receptor-t-cell-therapy-for-the-treatment-of-leukemia
#8
Y Liu, X Chen, W Han, Y Zhang
On August 30, 2017, the U.S. Food and Drug Administration (FDA) approved Novartis' tisagenlecleucel (CTL-019, Kymriah), which is a synthetic bioimmune product of anti-CD19 chimeric antigen receptor (CAR) T cells, for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). This was a milestone in tumor immunology on account of the significant antitumor effect of tisagenlecleucel for the treatment of relapsed/refractory B-ALL patients. Conventional standard therapies for B-ALL have high failure rates, thus developing new therapies is crucial for patients with B-ALL...
November 2017: Drugs of Today
https://www.readbyqxmd.com/read/29448937/engineering-chimeric-antigen-receptor-t-cells-for-cancer-treatment
#9
REVIEW
Baixin Ye, Creed M Stary, Xuejun Li, Qingping Gao, Chunsheng Kang, Xiaoxing Xiong
Intratumor heterogeneity of tumor clones and an immunosuppressive microenvironment in cancer ecosystems contribute to inherent difficulties for tumor treatment. Recently, chimeric antigen receptor (CAR) T-cell therapy has been successfully applied in the treatment of B-cell malignancies, underscoring its great potential in antitumor therapy. However, functional challenges of CAR-T cell therapy, especially in solid tumors, remain. Here, we describe cancer-immunity phenotypes from a clonal-stromal-immune perspective and elucidate mechanisms of T-cell exhaustion that contribute to tumor immune evasion...
February 15, 2018: Molecular Cancer
https://www.readbyqxmd.com/read/29446998/considerations-for-clinical-review-of-cellular-therapy-products-perspectives-of-the-china-food-and-drug-administration-center-for-drug-evaluation
#10
Yantong Liu, Chenyang Zhao, Liucun Gao, Huan Yang, Ruyi He, Chenyan Gao
With increasing numbers of technical developments and clinical studies, pioneering cellular/gene therapies are now available that could cure life-threatening disease. Cellular/gene therapy products are broad-ranging and complicated, and thereby bring challenges for clinical review by regulatory agencies. This review discusses principles for the clinical review of cellular therapy products, including protection of clinical trial populations, pharmacodynamics, pharmacokinetics, dose evaluation, clinical efficacy, clinical safety, and risk-management plans...
February 2018: Human Gene Therapy
https://www.readbyqxmd.com/read/29443792/pleural-cavity-cytokine-release-syndrome-in-cd19-directed-chimeric-antigen-receptor-modified-t-cell-therapy-a-case-report
#11
Lijuan Ding, Yongxian Hu, Kui Zhao, Guoqing Wei, Wenjun Wu, Zhao Wu, Lei Xiao, He Huang
RATIONALE: Cytokine release syndrome (CRS) is a common and potentially fatal complication of CAR-T cell therapy. However, compartment CRS is relatively rare in hematological malignancies, as well as in solid tumors. The pathogenesis and prognosis of compartment CRS are unclear and there is no standardized treatment yet. In this case report, we will introduce a patient developing pleural cavity CRS after CART19s infusion. PATIENT CONCERNS: A 28-year-old woman was admitted for evaluation of mediastinal mass...
February 2018: Medicine (Baltimore)
https://www.readbyqxmd.com/read/29440406/chimeric-antigen-receptor-t-cells-form-nonclassical-and-potent-immune-synapses-driving-rapid-cytotoxicity
#12
A J Davenport, R S Cross, K A Watson, Y Liao, W Shi, H M Prince, P A Beavis, J A Trapani, M H Kershaw, D S Ritchie, P K Darcy, P J Neeson, M R Jenkins
Chimeric antigen receptor T (CAR-T) cells are effective serial killers with a faster off-rate from dying tumor cells than CAR-T cells binding target cells through their T cell receptor (TCR). Here we explored the functional consequences of CAR-mediated signaling using a dual-specific CAR-T cell, where the same cell was triggered via TCR (tcrCTL) or CAR (carCTL). The carCTL immune synapse lacked distinct LFA-1 adhesion rings and was less reliant on LFA to form stable conjugates with target cells. carCTL receptors associated with the synapse were found to be disrupted and formed a convoluted multifocal pattern of Lck microclusters...
February 12, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29436394/optimized-rnp-transfection-for-highly-efficient-crispr-cas9-mediated-gene-knockout-in-primary-t-cells
#13
Akiko Seki, Sascha Rutz
CRISPR (clustered, regularly interspaced, short palindromic repeats)/Cas9 (CRISPR-associated protein 9) has become the tool of choice for generating gene knockouts across a variety of species. The ability for efficient gene editing in primary T cells not only represents a valuable research tool to study gene function but also holds great promise for T cell-based immunotherapies, such as next-generation chimeric antigen receptor (CAR) T cells. Previous attempts to apply CRIPSR/Cas9 for gene editing in primary T cells have resulted in highly variable knockout efficiency and required T cell receptor (TCR) stimulation, thus largely precluding the study of genes involved in T cell activation or differentiation...
February 7, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29434963/a-rare-e14a3-bcr-abl-fusion-transcript-in-acute-lymphoblastic-leukemia-patient-treated-with-car-modified-t-cell-therapy
#14
Haodong Cai, Li Yang, Kefeng Shen, Wei Zhang, Jie Xiong, Meilan Zhang, Xia Mao, Ying Wang, Min Xiao
E14a3 breakpoint cluster region (BCR)/ABL proto-oncogene 1, non-receptor tyrosine kinase (ABL) fusion transcript is rare in Philadelphia chromosome positive disease, particularly in acute lymphoblastic leukemia (ALL). Recently an e14a3 fusion transcript was detected by multiple laboratory examinations, and the patient was suffering from ALL. Except for the BCR/ABL fusion gene, in the present study the patient additionally had an IKAROS family zinc finger 1 deletion which, has been confirmed as a significant adverse prognosis factor...
February 2018: Oncology Letters
https://www.readbyqxmd.com/read/29434335/toxicity-management-after-chimeric-antigen-receptor-t-cell-therapy-one-size-does-not-fit-all
#15
David T Teachey, Michael R Bishop, David G Maloney, Stephan A Grupp
No abstract text is available yet for this article.
February 13, 2018: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/29434334/toxicity-management-after-chimeric-antigen-receptor-t-cell-therapy-one-size-does-not-fit-all
#16
Sattva S Neelapu, Sudhakar Tummala, Partow Kebriaei, William Wierda, Frederick L Locke, Yi Lin, Nitin Jain, Naval Daver, Alison M Gulbis, Sherry Adkins, Katayoun Rezvani, Patrick Hwu, Elizabeth J Shpall
No abstract text is available yet for this article.
February 13, 2018: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/29433552/chimeric-antigen-receptor-t-cell-car-t-immunotherapy-for-solid-tumors-lessons-learned-and-strategies-for-moving-forward
#17
REVIEW
Jian Li, Wenwen Li, Kejia Huang, Yang Zhang, Gary Kupfer, Qi Zhao
Recently, the US Food and Drug Administration (FDA) approved the first chimeric antigen receptor T cell (CAR-T) therapy for the treatment CD19-positive B cell acute lymphoblastic leukemia. While CAR-T has achieved remarkable success in the treatment of hematopoietic malignancies, whether it can benefit solid tumor patients to the same extent is still uncertain. Even though hundreds of clinical trials are undergoing exploring a variety of tumor-associated antigens (TAA), no such antigen with comparable properties like CD19 has yet been identified regarding solid tumors CAR-T immunotherapy...
February 13, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29431047/car-t-cells-for-cancer-therapy
#18
Niaz Muhammad, Qinwen Mao, Haibin Xia
Chimeric antigen receptor (CAR) T-cells are redirected T-cells that can recognize cancer antigens in a major histocompatibility complex (MHC)-independent fashion. A typical CAR is comprised of two main functional domains: an extracellular antigen recognition domain, called a single-chain variable fragment (scFv), and an intracellular signaling domain. Based on the number of intracellular signaling molecules, CARs are categorized into four generations. CAR T-cell therapy has become a promising treatment for hematologic malignancies...
February 12, 2018: Biotechnology & Genetic Engineering Reviews
https://www.readbyqxmd.com/read/29427174/adverse-effects-associated-with-clinical-applications-of-car-engineered-t-cells
#19
REVIEW
Zohreh Sadat Badieyan, Sayed Shahabuddin Hoseini
Cancer has been ranked as the second leading cause of death in the United States. To reduce cancer mortality, immunotherapy is gaining momentum among other therapeutic modalities, due to its impressive results in clinical trials. The genetically engineered T cells expressing chimeric antigen receptors (CARs) are emerging as a new approach in cancer immunotherapy, with the most successful outcomes in the refractory/relapse hematologic malignancies. However, the widespread clinical applications are limited by adverse effects some of which are life-threatening...
February 9, 2018: Archivum Immunologiae et Therapiae Experimentalis
https://www.readbyqxmd.com/read/29425516/reprint-of-building-a-safer-and-faster-car-seatbelts-airbags-and-crispr
#20
REVIEW
Miguel-Angel Perales, Partow Kebriaei, Leslie S Kean, Michel Sadelain
Therapeutic T cell engineering has recently garnered widespread interest because of the success of CD19 chimeric antigen receptor (CAR) therapy. CARs are synthetic receptors for antigen that redirect the specificity and reprogram the function of the T cells in which they are genetically introduced. CARs targeting CD19, a cell surface molecule found in most leukemias and lymphomas, have yielded high remission rates in patients with chemorefractory, relapsed disease, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma...
March 2018: Biology of Blood and Marrow Transplantation
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