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TCR gene therapy

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https://www.readbyqxmd.com/read/29423084/similarity-and-difference-in-tumor-infiltrating-lymphocytes-in-original-tumor-tissues-and-those-of-in-vitro-expanded-populations-in-head-and-neck-cancer
#1
Lili Ren, Tatsuo Matsuda, Boya Deng, Kazuma Kiyotani, Taigo Kato, Jae-Hyun Park, Tanguy Y Seiwert, Everett E Vokes, Nishant Agrawal, Yusuke Nakamura
Though adoptive tumor-infiltrating lymphocyte (TIL) therapy has been explored in clinical trials for many years, there is little information for the clonotype composition between TILs in original tumor tissues and TILs that were in vitro expanded and infused to cancer patients. To investigate the similarity/difference in TILs in original tumor tissues and those of in vitro expanded populations in squamous cell carcinoma of head and neck (SCCHN) as well as their correlation with somatic mutations in cancer cells, we performed whole exome analysis, expression profile analysis of immune-related genes, and T cell receptor (TCR) analysis of original TILs and in vitro expanded TILs in 8 surgically-resected HPV-negative fresh tumors with SCCHN...
January 9, 2018: Oncotarget
https://www.readbyqxmd.com/read/29392424/minimal-residual-disease-mrd-detection-using-rearrangement-of-immunoglobulin-t-cell-receptor-genes-in-adult-patients-with-acute-lymphoblastic-leukemia-all
#2
Sepideh Shahkarami, Roya Mehrasa, Samareh Younesian, Marjan Yaghmaie, Bahram Chahardouli, Mohammad Vaezi, Nima Rezaei, Mohsen Nikbakht, Kamran Alimoghaddam, Ardeshir Ghavamzadeh, Javad Tavakkoly-Bazzaz, Seyed H Ghaffari
MRD detection with allele-specific oligonucleotide-quantitative polymerase chain reaction (ASO-qPCR) and using clone-specific immunoglobulin/T cell receptor rearrangements is considered as a powerful prognostic factor in acute lymphoblastic leukemia (ALL). In the present study, we evaluated an ASO-qPCR assay for MRD quantification in peripheral blood (PB) samples of adult patients with ALL. DNA was isolated from PB samples of patients with newly diagnosed ALL. They were first investigated by multiplex-PCR assay to identify V/J usage...
February 1, 2018: Annals of Hematology
https://www.readbyqxmd.com/read/29380009/clinical-translation-and-regulatory-aspects-of-car-tcr-based-adoptive-cell-therapies-the-german-cancer-consortium-approach
#3
REVIEW
Angela M Krackhardt, Brigitte Anliker, Martin Hildebrandt, Michael Bachmann, Stefan B Eichmüller, Dirk M Nettelbeck, Matthias Renner, Lutz Uharek, Gerald Willimsky, Michael Schmitt, Winfried S Wels, Martina Schüssler-Lenz
Adoptive transfer of T cells genetically modified by TCRs or CARs represents a highly attractive novel therapeutic strategy to treat malignant diseases. Various approaches for the development of such gene therapy medicinal products (GTMPs) have been initiated by scientists in recent years. To date, however, the number of clinical trials commenced in Germany and Europe is still low. Several hurdles may contribute to the delay in clinical translation of these therapeutic innovations including the significant complexity of manufacture and non-clinical testing of these novel medicinal products, the limited knowledge about the intricate regulatory requirements of the academic developers as well as limitations of funds for clinical testing...
January 29, 2018: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/29368612/enhanced-clinical-scale-manufacturing-of-tcr-transduced-t-cells-using-closed-culture-system-modules
#4
Jianjian Jin, Nikolaos Gkitsas, Vicki S Fellowes, Jiaqiang Ren, Steven A Feldman, Christian S Hinrichs, David F Stroncek, Steven L Highfill
BACKGROUND: Genetic engineering of T-cells to express specific T cell receptors (TCR) has emerged as a novel strategy to treat various malignancies. More widespread utilization of these types of therapies has been somewhat constrained by the lack of closed culture processes capable of expanding sufficient numbers of T-cells for clinical application. Here, we evaluate a process for robust clinical grade manufacturing of TCR gene engineered T-cells. METHODS: TCRs that target human papillomavirus E6 and E7 were independently tested...
January 24, 2018: Journal of Translational Medicine
https://www.readbyqxmd.com/read/29361059/t-cell-receptor-%C3%AE-recombinations-in-renal-cell-carcinoma-exome-files-correlate-with-an-intermediate-level-of-t-cell-exhaustion-biomarkers
#5
Anne T Mai, Wei Lue Tong, Yaping N Tu, George Blanck
Renal cell carcinoma exome-derived, V(D)J recombination reads had an elevated presence and variability, for both TcR-α and β, when compared to marginal tissue, reflecting an opportunity to assess tumor immunogenicity by comparison with marginal tissue T-cells. PD-1, PD-L2, CTLA4, and FOXP3, all of which are implicated in the evasion of an anti-tumor immune response, had a significantly higher expression for samples representing co-detection of productive TcR-⍺ and -β recombination reads. Samples representing tumors with productive TcR-α recombination reads but no detectable, productive TcR-β recombination reads, reflected a 20% survival advantage, and RNASeq data indicated an intermediate level of immune checkpoint gene expression for those samples...
January 18, 2018: International Immunology
https://www.readbyqxmd.com/read/29360818/a-novel-epstein-barr-virus-latent-membrane-protein-1-specific-t-cell-receptor-for-tcr-gene-therapy
#6
Hyun-Il Cho, Un-Hee Kim, A-Ri Shin, Ji-Na Won, Hyun-Joo Lee, Hyun-Jung Sohn, Tai-Gyu Kim
BACKGROUND: Adoptive transfer of genetically engineered T-cells to express antigen-specific T-cell receptor (TCR) is a feasible and effective therapeutic approach for numerous types of cancers, including Epstein-Barr virus (EBV)-associated malignancies. Here, we describe a TCR gene transfer regimen to rapidly and reliably generate T-cells specific to EBV-encoded latent membrane protein-1 (LMP1), which is a potential target for T-cell-based immunotherapy. METHODS: A novel TCR specific to LMP1 (LMP1-TCR) was isolated from HLA-A*0201 transgenic mice that were immunised with the minimal epitope LMP1166 (TLLVDLLWL), and LMP1-TCR-transduced peripheral blood lymphocytes were evaluated for functional specificities...
January 23, 2018: British Journal of Cancer
https://www.readbyqxmd.com/read/29360643/tumor-infiltrating-brafv600e-specific-cd4-t-cells-correlated-with-complete-clinical-response-in-melanoma
#7
Joshua R Veatch, Sylvia M Lee, Matthew Fitzgibbon, I-Ting Chow, Brenda Jesernig, Thomas Schmitt, Ying Ying Kong, Julia Kargl, A McGarry Houghton, John A Thompson, Martin McIntosh, William W Kwok, Stanley R Riddell
T cells specific for neoantigens encoded by mutated genes in cancers are increasingly recognized as mediators of tumor destruction after immune checkpoint inhibitor therapy or adoptive cell transfer. Unfortunately, most neoantigens result from random mutations and are patient specific, and some cancers contain few mutations to serve as potential antigens. We describe a patient with stage IV acral melanoma who obtained a complete response following adoptive transfer of tumor infiltrating lymphocytes (TIL). Tumor exome sequencing surprisingly revealed less than 30 somatic mutations, including oncogenic BRAF V600E...
January 23, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29327377/s%C3%A3-zary-syndrome-managed-with-histone-deacetylase-inhibitor-followed-by-anti-ccr4-monoclonal-antibody
#8
T Numata, T Nagatani, K Shirai, T Maeda, K Mae, M Nakasu, M Saito, T Usuda, R Tsuboi, Y Okubo
A 70-year-old man presented to our clinic with a 10-year history of recurrent pruritic erythema and plaques on his trunk and limbs. Based on the pathological findings and monoclonal rearrangement of the T-cell receptor (TCR)-Cβ1 gene, mycosis fungoides (T2N0M0B0 stage IB) was diagnosed. Despite combination therapy including histone deacetylase inhibitor (vorinostat), the symptoms slowly evolved into Sézary syndrome (SS; T4N1M0B2) over 4 years, with dense infiltrates due to atypical lymphocytes expressing CCR4 developing in the entire dermis...
January 12, 2018: Clinical and Experimental Dermatology
https://www.readbyqxmd.com/read/29245286/case-report-for-recurrent-and-new-onset-sle-patients-treated-by-high-dose-glucocorticoid-therapy-characteristics-of-peripheral-tcr-beta-chain-cdr3-repertoires
#9
Jiang Yu, Bin Shi, Long Ma, Chunmei Liu, Suhong Sun, Rui Ma, Yuehong Qiu, Xinsheng Yao
RATIONALE: High-dose glucocorticoid therapy has been widely applied in clinical practice in systemic lupus erythematosus (SLE)patients, but less is known about the changes of T cells, especially the T cell receptor (TCR) repertoires, during the treatment. The aim of this paper is to describe the changes of TCR that recurrent and new-onset SLE patients treated by high-dose glucocorticoid therapy. PATIENT CONCERNS: Drugs of clinical treatment of SLE mainly include glucocorticoid, immunosuppressive agents, nonsteroidal anti-inflammatory drugs and B cell targeted drugs, etc, but the clinical symptoms were in remission and recurrent of onset patients with SLE...
December 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/29212954/inhibition-of-akt-signaling-uncouples-t-cell-differentiation-from-expansion-for-receptor-engineered-adoptive-immunotherapy
#10
Christopher A Klebanoff, Joseph G Crompton, Anthony J Leonardi, Tori N Yamamoto, Smita S Chandran, Robert L Eil, Madhusudhanan Sukumar, Suman K Vodnala, Jinhui Hu, Yun Ji, David Clever, Mary A Black, Devikala Gurusamy, Michael J Kruhlak, Ping Jin, David F Stroncek, Luca Gattinoni, Steven A Feldman, Nicholas P Restifo
Adoptive immunotherapies using T cells genetically redirected with a chimeric antigen receptor (CAR) or T cell receptor (TCR) are entering mainstream clinical practice. Despite encouraging results, some patients do not respond to current therapies. In part, this phenomenon has been associated with infusion of reduced numbers of early memory T cells. Herein, we report that AKT signaling inhibition is compatible with CAR and TCR retroviral transduction of human T cells while promoting a CD62L-expressing central memory phenotype...
December 7, 2017: JCI Insight
https://www.readbyqxmd.com/read/29212908/naive-cd4-t-cells-carrying-a-tlr2-agonist-overcome-tgf-%C3%AE-mediated-tumor-immune-evasion
#11
Mohsen Ibrahim, Davide Scozzi, Kelsey A Toth, Donatella Ponti, Daniel Kreisel, Cecilia Menna, Elena De Falco, Antonio D'Andrilli, Erino A Rendina, Antonella Calogero, Alexander S Krupnick, Andrew E Gelman
TLR agonists are effective at treating superficial cancerous lesions, but their use internally for other types of tumors remains challenging because of toxicity. In this article, we report that murine and human naive CD4+ T cells that sequester Pam3Cys4 (CD4+ TPam3) become primed for Th1 differentiation. CD4+ TPam3 cells encoding the OVA-specific TCR OT2, when transferred into mice bearing established TGF-β-OVA-expressing thymomas, produce high amounts of IFN-γ and sensitize tumors to PD-1/programmed cell death ligand 1 blockade-induced rejection...
December 6, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29167392/tcr-engagement-negatively-affects-cd8-but-not-cd4-car-t-cell-expansion-and-leukemic-clearance
#12
Yinmeng Yang, M Eric Kohler, Christopher D Chien, Christopher T Sauter, Elad Jacoby, Chunhua Yan, Ying Hu, Kelsey Wanhainen, Haiying Qin, Terry J Fry
Chimeric antigen receptor (CAR)-expressing T cells induce durable remissions in patients with relapsed/refractory B cell malignancies. CARs are synthetic constructs that, when introduced into mature T cells, confer a second, non-major histocompatibility complex-restricted specificity in addition to the endogenous T cell receptor (TCR). The implications of TCR activation on CAR T cell efficacy has not been well defined. Using an immunocompetent, syngeneic murine model of CD19-targeted CAR T cell therapy for pre-B cell acute lymphoblastic leukemia in which the CAR is introduced into T cells with known TCR specificity, we demonstrate loss of CD8 CAR T cell efficacy associated with T cell exhaustion and apoptosis when TCR antigen is present...
November 22, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29143824/pd-1-is-a-haploinsufficient-suppressor-of-t-cell-lymphomagenesis
#13
Tim Wartewig, Zsuzsanna Kurgyis, Selina Keppler, Konstanze Pechloff, Erik Hameister, Rupert Öllinger, Roman Maresch, Thorsten Buch, Katja Steiger, Christof Winter, Roland Rad, Jürgen Ruland
T cell non-Hodgkin lymphomas are a heterogeneous group of highly aggressive malignancies with poor clinical outcomes. T cell lymphomas originate from peripheral T cells and are frequently characterized by genetic gain-of-function variants in T cell receptor (TCR) signalling molecules. Although these oncogenic alterations are thought to drive TCR pathways to induce chronic proliferation and cell survival programmes, it remains unclear whether T cells contain tumour suppressors that can counteract these events...
December 7, 2017: Nature
https://www.readbyqxmd.com/read/29142313/effects-of-exosome-on-the-activation-of-cd4-t-cells-in-rhesus-macaques-a-potential-application-for-hiv-latency-reactivation
#14
Xiaowu Hong, Blake Schouest, Huanbin Xu
Exosomes are small extracellular vesicles (EVs), released by a wide variety of cell types, carry donor origin-proteins, cytokines, and nucleic acids, transport these cargos to adjacent or distant specific recipient cells, and thereby regulate gene expression and activation of target cells. In this study, we isolated and identified exosomes in rhesus macaques, and investigated their effects on cell tropism and activation, especially their potential to reactivate HIV latency. The results indicated that plasma-derived exosomes preferentially fuse to TCR-activated T cells and autologous parent cells...
November 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29123516/avidity-and-bystander-suppressive-capacity-of-human-regulatory-t-cells-expressing-de-novo-autoreactive-t-cell-receptors-in-type-1-diabetes
#15
Wen-I Yeh, Howard R Seay, Brittney Newby, Amanda L Posgai, Filipa Botelho Moniz, Aaron Michels, Clayton E Mathews, Jeffrey A Bluestone, Todd M Brusko
The ability to alter antigen specificity by T-cell receptor (TCR) or chimeric antigen receptor (CAR) gene transfer has facilitated personalized cellular immune therapies in cancer. Inversely, this approach can be harnessed in autoimmune settings to attenuate inflammation by redirecting the specificity of regulatory T cells (Tregs). Herein, we demonstrate efficient protocols for lentiviral gene transfer of TCRs that recognize type 1 diabetes-related autoantigens with the goal of tissue-targeted induction of antigen-specific tolerance to halt β-cell destruction...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29073235/src-family-kinases-negatively-regulate-nfat-signaling-in-resting-human-t-cells
#16
Alan Baer, Winston Colon-Moran, Jinhua Xiang, Jack T Stapleton, Nirjal Bhattarai
T cell signaling is required for activation of both natural and therapeutic T cells including chimeric antigen receptor (CAR) T cells. Identification of novel factors and pathways regulating T cell signaling may aid in development of effective T cell therapies. In resting human T cells, the majority of Src-family of tyrosine kinases (SFKs) are inactive due to phosphorylation of a conserved carboxy-terminal tyrosine residue. Recently, a pool of enzymatically active SFKs has been identified in resting T cells; however, the significance of these is incompletely understood...
2017: PloS One
https://www.readbyqxmd.com/read/29066497/t-cell-localization-activation-and-clonal-expansion-in-human-pancreatic-ductal-adenocarcinoma
#17
Ingunn M Stromnes, Ayaka Hulbert, Robert H Pierce, Philip D Greenberg, Sunil R Hingorani
Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy resistant to most therapies, including immune checkpoint blockade. To elucidate mechanisms of immunotherapy resistance, we assessed immune parameters in resected human PDA. We demonstrate significant interpatient variability in T-cell number, localization, and phenotype. CD8+ T cells, Foxp3+ regulatory T cells, and PD-1+ and PD-L1+ cells were preferentially enriched in tertiary lymphoid structures that were found in most tumors compared with stroma and tumor cell nests...
November 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29040163/adipose-tissue-is-enriched-for-activated-and-late-differentiated-cd8-t-cells-and-shows-distinct-cd8-receptor-usage-compared-to-blood-in-hiv-infected-persons
#18
John R Koethe, Wyatt McDonnell, Arion Kennedy, Chike O Abana, Mark Pilkinton, Ian Setliff, Ivelin Georgiev, Louise Barnett, Cindy C Hager, Rita Smith, Spyros A Kalams, Alyssa Hasty, Simon Mallal
BACKGROUND: Adverse viral and medication effects on adipose tissue contribute to the development of metabolic disease in HIV-infected persons, but T cells also have a central role modulating local inflammation and adipocyte function. We sought to characterize potentially pro-inflammatory T cell populations in adipose tissue among persons on long-term antiretroviral therapy, and assess whether adipose tissue CD8 T cells represent an expanded, oligoclonal population. METHODS: We recruited 10 HIV-infected, overweight and obese adults on efavirenz, tenofovir, and emtricitabine for >4 years with consistent viral suppression...
October 14, 2017: Journal of Acquired Immune Deficiency Syndromes: JAIDS
https://www.readbyqxmd.com/read/29033130/tumor-and-microenvironment-evolution-during-immunotherapy-with-nivolumab
#19
Nadeem Riaz, Jonathan J Havel, Vladimir Makarov, Alexis Desrichard, Walter J Urba, Jennifer S Sims, F Stephen Hodi, Salvador Martín-Algarra, Rajarsi Mandal, William H Sharfman, Shailender Bhatia, Wen-Jen Hwu, Thomas F Gajewski, Craig L Slingluff, Diego Chowell, Sviatoslav M Kendall, Han Chang, Rachna Shah, Fengshen Kuo, Luc G T Morris, John-William Sidhom, Jonathan P Schneck, Christine E Horak, Nils Weinhold, Timothy A Chan
The mechanisms by which immune checkpoint blockade modulates tumor evolution during therapy are unclear. We assessed genomic changes in tumors from 68 patients with advanced melanoma, who progressed on ipilimumab or were ipilimumab-naive, before and after nivolumab initiation (CA209-038 study). Tumors were analyzed by whole-exome, transcriptome, and/or T cell receptor (TCR) sequencing. In responding patients, mutation and neoantigen load were reduced from baseline, and analysis of intratumoral heterogeneity during therapy demonstrated differential clonal evolution within tumors and putative selection against neoantigenic mutations on-therapy...
November 2, 2017: Cell
https://www.readbyqxmd.com/read/28977608/anti-tcr%C3%AE-mab-in-combination-with-neurogenin3-gene-therapy-reverses-established-overt-type-1-diabetes-in-female-nod-mice
#20
Aini Xie, Rongying Li, Tao Jiang, Hui Yan, Hedong Zhang, Yisheng Yang, Lina Yang, Vijay Yechoor, Lawrence Chan, Wenhao Chen
Insulin-producing β cells in patients with type 1 diabetes (T1D) are destroyed by T lymphocytes. We investigated whether targeting the T-cell receptor (TCR) with a monoclonal antibody (mAb) abrogates T-cell response against residual and newly formed islets in overtly diabetic nonobese diabetic (NOD) mice. NOD mice with blood glucose levels of 250 to 350 mg/dL or 350 to 450 mg/dL were considered as new-onset or established overt diabetes, respectively. These diabetic NOD mice were transiently treated with an anti-TCR β chain (TCRβ) mAb, H57-597, for 5 days...
October 1, 2017: Endocrinology
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