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TCR gene therapy

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https://www.readbyqxmd.com/read/28428503/-cancer-immunotherapy-utilizing-t-cell-receptor-gene-engineering
#1
Hiroaki Ikeda
Immune-checkpoint inhibitors have shown their efficacy in the treatment of patients with many kinds of progressive/relapsed cancers. However, the efficacy remains as 10-40%of the patients in most type of cancers, suggesting that the development of new therapy for patients resistant to the therapy is an urgent unmet need. Adoptive therapy with tumor-specific T cells is a promising therapy that can be effective in patients who are not benefited from the immune-checkpoint inhibitors. The T cell therapy with genetic engineering in T cell receptor(TCR)is expected to be a universal therapy because this therapy can be applicable for patients with many kinds of cancers...
April 2017: Gan to Kagaku Ryoho. Cancer & Chemotherapy
https://www.readbyqxmd.com/read/28424240/the-histone-acetyltransferase-gcn5-positively-regulates-t-cell-activation
#2
Beixue Gao, Qingfei Kong, Yana Zhang, Chawon Yun, Sharon Y R Dent, Jianxun Song, Donna D Zhang, Yiming Wang, Xuemei Li, Deyu Fang
Histone acetyltransferases (HATs) regulate inducible transcription in multiple cellular processes and during inflammatory and immune response. However, the functions of general control nonrepressed-protein 5 (Gcn5), an evolutionarily conserved HAT from yeast to human, in immune regulation remain unappreciated. In this study, we conditionally deleted Gcn5 (encoded by the Kat2a gene) specifically in T lymphocytes by crossing floxed Gcn5 and Lck-Cre mice, and demonstrated that Gcn5 plays important roles in multiple stages of T cell functions including development, clonal expansion, and differentiation...
April 19, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28422742/multi-omics-study-revealing-the-complexity-and-spatial-heterogeneity-of-tumor-infiltrating-lymphocytes-in-primary-liver-carcinoma
#3
Lijun Shi, Yang Zhang, Lin Feng, Liming Wang, Weiqi Rong, Fan Wu, Jianxiong Wu, Kaitai Zhang, Shujun Cheng
Intratumoral heterogeneity has been revealed in primary liver carcinoma (PLC). However, spatial heterogeneity of tumor-infiltrating lymphocytes (TILs), which reflects one dimension of a tumor's spatial heterogeneity, and the relationship between TIL diversity, local immune response and mutation burden remain unexplored in PLC. Therefore, we performed immune repertoire sequencing, gene expression profiling analysis and whole-exome sequencing in parallel on five regions of each tumor and on matched adjacent normal tissues and peripheral blood from five PLC patients...
March 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/28393253/recombinant-adenovirus-of-sea-and-cd80-genes-driven-by-mmre-and-mouse-tert-promoter-induce-effective-antitumor-immune-responses-against-different-types-of-tumor-cells-in%C3%A2-vitro-and-in%C3%A2-vivo
#4
Shao-Yan Si, Jun-Li Liu, Jun-Lian Liu, Bing-Xin Xu, Jian-Zhong Li, Ya-Ya Qin, Shu-Jun Song
Staphylococcus enterotoxin A (SEA) is a powerful immunostimulant and can stimulate T cells bearing certain T-cell receptor β-chain variable regions when bound to major histocompatibility complex II molecules. SEA is widely used in research of antitumor therapy. The low affinity T-cell receptor (TCR) interaction with SEA in the absence of MHC class II antigens is sufficient for the induction of cytotoxicity but requires additional CD28/B7 signaling to result in proliferation of resting T cells. In this study, we constructed recombinant adenovirus (named as Ad-MMRE-mTERT-BIS) carrying membrane-expressing SEA (named as SEAtm) and CD80 driven by Myc-Max response elements (MMRE) and mouse telomerase reverse transcriptase (mTERT) promoter to reduce toxicity and to improve safety and efficiency...
April 6, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28348568/a-bacterial-artificial-chromosome-reporter-system-for-expression-of-the-human-foxp3-gene-in-mouse-regulatory-t-cells
#5
Masato Tsuda, Yukiko Tone, Chihiro Ogawa, Yoshiko Nagaoka, Makoto Katsumata, Andra Necula, Duncan Howie, Esteban Masuda, Herman Waldmann, Masahide Tone
The transcription factor FOXP3 plays key roles in the development and function of regulatory T cells (Treg) capable of preventing and correcting immunopathology. There has been much interest in exploiting Treg as adoptive cell therapy in man, but issues of lack of nominal antigen-specificity and stability of FoxP3 expression in the face of pro-inflammatory cytokines have been a concern. In order to enable fundamental studies of human FOXP3 (hFOXP3) gene regulation and to provide preclinical tools to guide the selection of drugs that might modulate hFOXP3 expression for therapeutic purposes, we generated hFOXP3/AmCyan bacterial artificial chromosome (BAC) transgenic mice and transfectants, wherein hFOXP3 expression was read out as AmCyan expression...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28346544/epigenetic-silencing-of-v-d-j-recombination-is-a-major-determinant-for-selective-differentiation-of-mucosal-associated-invariant-t-cells-from-induced-pluripotent-stem-cells
#6
Yutaka Saito, Chie Sugimoto, Toutai Mituyama, Hiroshi Wakao
Mucosal-associated invariant T cells (MAITs) are innate-like T cells that play a pivotal role in the host defense against infectious diseases, and are also implicated in autoimmune diseases, metabolic diseases, and cancer. Recent studies have shown that induced pluripotent stem cells (iPSCs) derived from MAITs selectively redifferentiate into MAITs without altering their antigen specificity. Such a selective differentiation is a prerequisite for the use of MAITs in cell therapy and/or regenerative medicine...
2017: PloS One
https://www.readbyqxmd.com/read/28345004/homology-directed-recombination-for-enhanced-engineering-of-chimeric-antigen-receptor-t-cells
#7
Malika Hale, Baeckseung Lee, Yuchi Honaker, Wai-Hang Leung, Alexandra E Grier, Holly M Jacobs, Karen Sommer, Jaya Sahni, Shaun W Jackson, Andrew M Scharenberg, Alexander Astrakhan, David J Rawlings
Gene editing by homology-directed recombination (HDR) can be used to couple delivery of a therapeutic gene cassette with targeted genomic modifications to generate engineered human T cells with clinically useful profiles. Here, we explore the functionality of therapeutic cassettes delivered by these means and test the flexibility of this approach to clinically relevant alleles. Because CCR5-negative T cells are resistant to HIV-1 infection, CCR5-negative anti-CD19 chimeric antigen receptor (CAR) T cells could be used to treat patients with HIV-associated B cell malignancies...
March 17, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28330372/car-t-cell-therapy-progress-and-prospects
#8
Olivia Wilkins, Allison M Keeler, Terence R Flotte
Lentivirus-mediated transduction of autologous T cells with a chimeric antigen receptor (CAR) to confer a desired epitope specificity as a targeted immunotherapy for cancer has been among the first human gene therapy techniques to demonstrate widespread therapeutic efficacy. Other approaches to using gene therapy to enhance antitumor immunity have been less specific and less effective. These have included amplification, marking, and cytokine transduction of tumor infiltrating lymphocytes, recombinant virus-based expression of tumor antigens as a tumor vaccine, and transduction of antigen-presenting cells with tumor antigens...
April 2017: Human Gene Therapy Methods
https://www.readbyqxmd.com/read/28323276/open-capsule-budesonide-for-refractory-celiac-disease
#9
Saurabh S Mukewar, Ayush Sharma, Alberto Rubio-Tapia, Tsung-Teh Wu, Bana Jabri, Joseph A Murray
OBJECTIVES: Refractory celiac disease (RCD) is a rare condition often associated with poor prognosis. Various immunosuppressive medications (IMs) have been used with modest success. We describe outcomes in patients treated with open-capsule budesonide (OB), including those for whom IM treatment failed. METHODS: We identified RCD patients treated with OB at Mayo Clinic, Rochester, Minnesota from 2003 to 2015. Demographic, serologic, and clinical variables were analyzed...
March 21, 2017: American Journal of Gastroenterology
https://www.readbyqxmd.com/read/28318808/t-cell-receptor-assessment-in-autoimmune-disease-requires-access-to-the-most-adjacent-immunologically-active-organ
#10
Bergithe E Oftedal, Brita Ardesjö Lundgren, David Hamm, Poh-Yi Gan, Stephen R Holdsworth, Christopher N Hahn, Andreas W Schreiber, Hamish S Scott
Next generation sequencing of T and B cell receptors is emerging as a valuable and effective method to diagnose and monitor hematopoietic malignancies. So far, this approach has not been fully explored in regard to autoimmune diseases. T cells develop in the thymus where they undergo positive and negative selection, and the autoimmune regulator (Aire) is central in the establishment of immunological tolerance. Loss of Aire leads to severe multiorgan autoimmune disease with infiltration of autoreactive T cells in affected organs...
March 15, 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/28259946/%C3%AE-%C3%AE-tcr-immunoglobulin-constant-region-domain-exchange-in-human-%C3%AE-%C3%AE-tcrs-improves-tcr-pairing-without-altering-tcr-gene-modified-t-cell-function
#11
Changli Tao, Hongwei Shao, Wenfeng Zhang, Huaben Bo, Fenglin Wu, Han Shen, Shulin Huang
The adoptive genetic transfer of T cell receptors (TCRs) has been shown to be overall feasible and offer clinical potential as a treatment for different types of cancer. However, this promising clinical approach is limited by the serious potential consequence that exogenous TCR mispairing with endogenous TCR chains may lead to the risk of self-reactivity. In the present study, domain‑exchange and three‑dimensional modeling strategies were used to create a set of chimeric TCR variants, which were used to exchange the partial or complete constant region of αβTCR with corresponding γδTCR domains...
April 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28245368/-clinical-and-immunophenotypic-properties-of-small-cell-variant-of-t-cell-prolymphocytic-leukemia
#12
Ya-Ping Yu, Li-Ping Wang, Ping Song, Jian-Gang Mei, Zhi-Ming An, Xiao-Gang Zhou, Feng Li, Yu-Mei Tang, Yong-Ping Zhai
OBJECTIVE: To investigate the clinical, morphologic and immunophenotypic properties of the patients with small cell variant of T-cell prolymphocytic leukaemia(T-PLL). METHODS: Peripheral blood and bone marrow cytomorphologic and immunophenotypic examination, and T-cell receptor(TCR) gene rearrangement detection were used to verify the diagnosis for 2 patients with lymphocytosis. Two patients were treated with combined chemotherapeutic protocol based on fludarabine...
February 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28237835/integration-of-a-cd19-car-into-the-tcr-alpha-chain-locus-streamlines-production-of-allogeneic-gene-edited-car-t-cells
#13
Daniel T MacLeod, Jeyaraj Antony, Aaron J Martin, Rachel J Moser, Armin Hekele, Keith J Wetzel, Audrey E Brown, Melissa A Triggiano, Jo Ann Hux, Christina D Pham, Victor V Bartsevich, Caitlin A Turner, Janel Lape, Samantha Kirkland, Clayton W Beard, Jeff Smith, Matthew L Hirsch, Michael G Nicholson, Derek Jantz, Bruce McCreedy
Adoptive cellular therapy using chimeric antigen receptor (CAR) T cell therapies have produced significant objective responses in patients with CD19(+) hematological malignancies, including durable complete responses. Although the majority of clinical trials to date have used autologous patient cells as the starting material to generate CAR T cells, this strategy poses significant manufacturing challenges and, for some patients, may not be feasible because of their advanced disease state or difficulty with manufacturing suitable numbers of CAR T cells...
April 5, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28228595/hepatitis-c-virus-specific-t-cell-receptor-mrna-engineered-human-t-cells-impact-of-antigen-specificity-on-functional-properties
#14
Anangi Balasiddaiah, Haleh Davanian, Soo Aleman, Anna Pasetto, Lars Frelin, Matti Sällberg, Volker Lohmann, Sarene Koh, Antonio Bertoletti, Margaret Chen
Therapy with genetically modified autologous T cells has shown great promise in cancer therapy. For an efficient control of hepatitis C virus (HCV) infection, cytotoxic T cells (CTL) are pivotal but persistence of activated T cells may lead to liver toxicity. Here, anti-HCV T cell receptors (TCRs) recognising the HCV non-structural (NS) NS3 or NS5 viral peptide target were examined by mRNA transfection of human peripheral blood lymphocytes (PBL) derived from healthy donors as well as chronically infected HCV patients...
February 22, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28211040/anti-cd3-treatment-up-regulates-programmed-cell-death-protein-1-expression-on-activated-effector-t-cells-and-severely-impairs-their-inflammatory-capacity
#15
Maja Wallberg, Asha Recino, Jenny Phillips, Duncan Howie, Margaux Vienne, Christopher Paluch, Miyuki Azuma, F Susan Wong, Herman Waldmann, Anne Cooke
T cells play a key role in the pathogenesis of type 1 diabetes, and targeting the CD3 component of the T-cell receptor complex provides one therapeutic approach. Anti-CD3 treatment can reverse overt disease in spontaneously diabetic non-obese diabetic mice, an effect proposed to, at least in part, be caused by a selective depletion of pathogenic cells. We have used a transfer model to further investigate the effects of anti-CD3 treatment on green fluorescent protein (GFP)(+) islet-specific effector T cells in vivo...
February 17, 2017: Immunology
https://www.readbyqxmd.com/read/28199983/a-versatile-system-for-rapid-multiplex-genome-edited-car-t-cell-generation
#16
Jiangtao Ren, Xuhua Zhang, Xiaojun Liu, Chongyun Fang, Shuguang Jiang, Carl H June, Yangbing Zhao
The therapeutic potential of CRISPR system has already been demonstrated in many instances and begun to overlap with the rapidly expanding field of cancer immunotherapy, especially on the production of genetically modified T cell receptor or chimeric antigen receptor (CAR) T cells. Efficient genomic disruption of multiple gene loci to generate universal donor cells, as well as potent effector T cells resistant to multiple inhibitory pathways such as PD-1 and CTLA4 is an attractive strategy for cell therapy...
March 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28177911/turn-to-tcrs-when-cars-fail
#17
Hans J Stauss
No abstract text is available yet for this article.
February 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/28117148/generation-of-human-islet-specific-regulatory-t-cells-by-tcr-gene-transfer
#18
Caroline M Hull, Lauren E Nickolay, Megan Estorninho, Max W Richardson, James L Riley, Mark Peakman, John Maher, Timothy I M Tree
Based on the success in animal models of type 1 diabetes (T1D), clinical trials of adoptive regulatory T cell (Treg) therapy are underway using ex vivo expanded polyclonal Tregs. However, pre-clinical data also demonstrate that islet-specific Tregs are more potent than polyclonal Tregs at reversing T1D. Translation of this approach into man will require methods to generate large populations of islet-specific Tregs which, to date, has proved to be a major hurdle. Here we demonstrate the feasibility of lentiviral-mediated T cell receptor (TCR) gene transfer to confer antigen specificity on polyclonal human Tregs...
January 20, 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/28114254/adoptive-cell-therapy-for-metastatic-melanoma
#19
Efrat Merhavi-Shoham, Orit Itzhaki, Gal Markel, Jacob Schachter, Michal J Besser
Adoptive cell therapy (ACT) of tumor-infiltrating lymphocytes (TILs) is a powerful form of immunotherapy by inducing durable complete responses that significantly extend the survival of melanoma patients. Mutation-derived neoantigens were recently identified as key factors for tumor recognition and rejection by TILs. The isolation of T-cell receptor (TCR) genes directed against neoantigens and their retransduction into peripheral T cells may provide a new form of ACT.Genetic modifications of T cells with chimeric antigen receptors (CARs) have demonstrated remarkable clinical results in hematologic malignancies, but are so far less effective in solid tumors...
January 2017: Cancer Journal
https://www.readbyqxmd.com/read/28073842/expression-of-cd14-il-10-and-tolerogenic-signature-in-dendritic-cells-inversely-correlate-with-response-to-tarp-vaccination-in-prostate-cancer-patients
#20
Luciano Castiello, Marianna Sabatino, Jiaqiang Ren, Masaki Terabe, Hanh Khuu, Lauren V Wood, Jay A Berzofsky, David F Stroncek
PURPOSE: Despite the vast number of clinical trials conducted so far, Dendritic cell (DC)-based cancer vaccines have mostly shown unsatisfactory results. Factors and manufacturing procedures essential for these therapeutics to induce effective anti-tumor immune responses have yet to be fully characterized. We here aimed to identify DC markers correlating with clinical and immunological response in a prostate carcinoma vaccination regimen. EXPERIMENTAL DESIGN: We performed an extensive characterization of DCs used to vaccinate 18 prostate carcinoma patients enrolled in a pilot trial of TCR gamma alternate reading frame protein (TARP) peptide vaccination (NCT00908258)...
January 10, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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