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TCR gene therapy

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https://www.readbyqxmd.com/read/29212954/inhibition-of-akt-signaling-uncouples-t-cell-differentiation-from-expansion-for-receptor-engineered-adoptive-immunotherapy
#1
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
#2
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
#3
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
#4
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...
November 15, 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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
https://www.readbyqxmd.com/read/28809608/treatment-of-patients-with-metastatic-cancer-using-a-major-histocompatibility-complex-class-ii-restricted-t-cell-receptor-targeting-the-cancer-germline-antigen-mage-a3
#12
Yong-Chen Lu, Linda L Parker, Tangying Lu, Zhili Zheng, Mary Ann Toomey, Donald E White, Xin Yao, Yong F Li, Paul F Robbins, Steven A Feldman, Pierre van der Bruggen, Christopher A Klebanoff, Stephanie L Goff, Richard M Sherry, Udai S Kammula, James C Yang, Steven A Rosenberg
Purpose Adoptive transfer of genetically modified T cells is being explored as a treatment for patients with metastatic cancer. Most current strategies use genes that encode major histocompatibility complex (MHC) class I-restricted T-cell receptors (TCRs) or chimeric antigen receptors to genetically modify CD8(+) T cells or bulk T cells for treatment. Here, we evaluated the safety and efficacy of an adoptive CD4(+) T-cell therapy using an MHC class II-restricted, HLA-DPB1*0401-restricted TCR that recognized the cancer germline antigen, MAGE-A3 (melanoma-associated antigen-A3)...
October 10, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28664195/partial-exhaustion-of-cd8-t-cells-and-clinical-response-to-teplizumab-in-new-onset-type-1-diabetes
#13
S Alice Long, Jerill Thorpe, Hannah A DeBerg, Vivian Gersuk, James Eddy, Kristina M Harris, Mario Ehlers, Kevan C Herold, Gerald T Nepom, Peter S Linsley
Biologic treatment of T1D typically results in transient stabilization of C-peptide levels (a surrogate for endogenous insulin secretion) in some patients, followed by progression at the same rate as in untreated control groups. Here, we used integrated systems biology and flow cytometry approaches with clinical trial blood samples to elucidate pathways associated with C-peptide stabilization in T1D subjects treated with the anti-CD3 monoclonal antibody teplizumab. We identified a population of CD8 T cells that accumulated in subjects with the best response to treatment (responders) and showed that these cells phenotypically resembled exhausted T cells by expressing high levels of the transcription factor EOMES, effector molecules, and multiple inhibitory receptors (IRs), including TIGIT and KLRG1...
November 2016: Science Immunology
https://www.readbyqxmd.com/read/28632753/mait-cells-launch-a-rapid-robust-and-distinct-hyperinflammatory-response-to-bacterial-superantigens-and-quickly-acquire-an-anergic-phenotype-that-impedes-their-cognate-antimicrobial-function-defining-a-novel-mechanism-of-superantigen-induced-immunopathology
#14
COMPARATIVE STUDY
Christopher R Shaler, Joshua Choi, Patrick T Rudak, Arash Memarnejadian, Peter A Szabo, Mauro E Tun-Abraham, Jamie Rossjohn, Alexandra J Corbett, James McCluskey, John K McCormick, Olivier Lantz, Roberto Hernandez-Alejandro, S M Mansour Haeryfar
Superantigens (SAgs) are potent exotoxins secreted by Staphylococcus aureus and Streptococcus pyogenes. They target a large fraction of T cell pools to set in motion a "cytokine storm" with severe and sometimes life-threatening consequences typically encountered in toxic shock syndrome (TSS). Given the rapidity with which TSS develops, designing timely and truly targeted therapies for this syndrome requires identification of key mediators of the cytokine storm's initial wave. Equally important, early host responses to SAgs can be accompanied or followed by a state of immunosuppression, which in turn jeopardizes the host's ability to combat and clear infections...
June 2017: PLoS Biology
https://www.readbyqxmd.com/read/28599078/nonlesional-atopic-dermatitis-skin-shares-similar-t-cell-clones-with-lesional-tissues
#15
P M Brunner, R O Emerson, C Tipton, S Garcet, S Khattri, I Coats, J G Krueger, E Guttman-Yassky
BACKGROUND: Atopic dermatitis (AD) is characterized by robust immune activation. Various T-cell subsets, including Th2/Th22 cells, are increased in lesional and nonlesional skin. However, there is conflicting literature on the diversity of the T-cell receptor (TCR) repertoire in lesional AD, and its relation to nonlesional skin remains unclear. METHODS: We performed high-throughput deep sequencing of the β-TCR repertoire in 29 lesional and 19 nonlesional AD biopsies, compared to six healthy control and six cutaneous T-cell lymphoma (CTCL) samples from previously published cohorts...
June 9, 2017: Allergy
https://www.readbyqxmd.com/read/28507809/t-cell-therapy-targeting-a-public-neoantigen-in-microsatellite-instable-colon-cancer-reduces-in-vivo-tumor-growth
#16
Else M Inderberg, Sébastien Wälchli, Marit R Myhre, Sissel Trachsel, Hilde Almåsbak, Gunnar Kvalheim, Gustav Gaudernack
T-cell receptor (TCR) transfer is an attractive strategy to increase the number of cancer-specific T cells in adoptive cell therapy. However, recent clinical and pre-clinical findings indicate that careful consideration of the target antigen is required to limit the risk of off-target toxicity. Directing T cells against mutated proteins such as frequently occurring frameshift mutations may thus be a safer alternative to tumor-associated self-antigens. Furthermore, such frameshift mutations result in novel polypeptides allowing selection of TCRs from the non-tolerant T-cell repertoire circumventing the problem of low affinity TCRs due to central tolerance...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28482391/-two-families-of-x-linked-lymphoproliferative-disease-type-1-characterized-by-agammaglobulinemia
#17
W Y Li, J S Chen, Q Zhao, R X Dai, Y P Wang, H Y Zhao, X M Chen, X H Xue, X Y Sun, X M Tang, Y Zhang, Y Ding, X D Zhao, Z Y Zhang
Objective: To investigate the clinical and immunological laboratory features, mutations in SH2D1A gene and SAP protein expression in four children of two families with X-linked lymphoproliferative disease type 1(XLP-1). Method: Four patients (Family A including Patient 1 and Patient 2, Family B including Patient 3 and Patient 4) and their maternal relatives were enrolled in this study. The clinical manifestation, EBV infection status and chest CT scan were analyzed. The absolute and relative numbers of lymphocyte subsets, T lymphocyte proliferative response, SAP protein expression were assessed by flow cytometry...
May 4, 2017: Zhonghua Er Ke za Zhi. Chinese Journal of Pediatrics
https://www.readbyqxmd.com/read/28448599/simulation-of-the-dynamics-of-primary-immunodeficiencies-in-cd4-t-cells
#18
Gabriel N Teku, Mauno Vihinen
Primary immunodeficiencies (PIDs) form a large and heterogeneous group of mainly rare disorders that affect the immune system. T-cell deficiencies account for about one-tenth of PIDs, most of them being monogenic. Apart from genetic and clinical information, lots of other data are available for PID proteins and genes, including functions and interactions. Thus, it is possible to perform systems biology studies on the effects of PIDs on T-cell physiology and response. To achieve this, we reconstructed a T-cell network model based on literature mining and TPPIN, a previously published core T-cell network, and performed semi-quantitative dynamic network simulations on both normal and T-cell PID failure modes...
2017: PloS One
https://www.readbyqxmd.com/read/28441778/gene-expression-analysis-before-and-after-treatment-with-adalimumab-in-patients-with-ankylosing-spondylitis-identifies-molecular-pathways-associated-with-response-to-therapy
#19
Marzia Dolcino, Elisa Tinazzi, Andrea Pelosi, Giuseppe Patuzzo, Francesca Moretta, Claudio Lunardi, Antonio Puccetti
The etiology of Ankylosing spondylitis (AS) is still unknown and the identification of the involved molecular pathogenetic pathways is a current challenge in the study of the disease. Adalimumab (ADA), an anti-tumor necrosis factor (TNF)-alpha agent, is used in the treatment of AS. We aimed at identifying pathogenetic pathways modified by ADA in patients with a good response to the treatment. Gene expression analysis of Peripheral Blood Cells (PBC) from six responders and four not responder patients was performed before and after treatment...
April 24, 2017: Genes
https://www.readbyqxmd.com/read/28428503/-cancer-immunotherapy-utilizing-t-cell-receptor-gene-engineering
#20
REVIEW
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
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