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https://www.readbyqxmd.com/read/27898263/genetic-alterations-affecting-gtpases-and-t-cell-receptor-signaling-in-peripheral-t-cell-lymphomas
#1
Rebecca L Boddicker, Gina L Razidlo, Andrew L Feldman
Peripheral T-cell lymphomas (PTCLs) are rare, heterogeneous tumors with poor response to standard therapy and few targeted treatments available. The identification of mutations in the T-cell receptor (TCR) signaling pathway that either directly or indirectly affect Ras- and Rho-family GTPases is an emerging theme across PTCL subtypes. This review summarizes the role of GTPases in TCR signaling and highlights the constellation of mutations in this pathway among PTCLs. In particular, focus is given to the functional impact of the mutations and opportunities for targeted therapy...
November 29, 2016: Small GTPases
https://www.readbyqxmd.com/read/27872095/t-cells-redirected-to-a-minor-histocompatibility-antigen-instruct-intratumoral-tnf-%C3%AE-expression-and-empower-adoptive-cell-therapy-for-solid-tumors
#2
Teresa Manzo, Tabea Sturmheit, Veronica Basso, Elisabetta Petrozziello, Rodrigo Hess Michelini, Michela Riba, Massimo Freschi, Angela R Elia, Matteo Grioni, Flavio Curnis, Maria Pia Protti, Ton N Schumacher, Reno Debets, Melody A Swartz, Angelo Corti, Matteo Bellone, Anna Mondino
Donor-derived allogeneic T cells evoke potent graft versus tumor (GVT) effects likely due to the simultaneous recognition of tumor-specific and host-restricted minor histocompatibility (H) antigens. Here we investigated whether such effects could be reproduced in autologous settings by TCR-gene engineered lymphocytes. We report that T cells redirected either to a broadly expressed Y-encoded minor H antigen or to a tumor-associated antigen, although poorly effective if individually transferred, when simultaneously administered enabled acute autochthonous tumor debulking and resulted in durable clinical remission...
November 21, 2016: Cancer Research
https://www.readbyqxmd.com/read/27823582/domain-swapped-t-cell-receptors-improve-the-safety-of-tcr-gene-therapy
#3
Michael T Bethune, Marvin H Gee, Mario Bunse, Mark S Lee, Eric H Gschweng, Meghana S Pagadala, Jing Zhou, Donghui Cheng, James R Heath, Donald B Kohn, Michael S Kuhns, Wolfgang Uckert, David Baltimore
T cells engineered to express a tumor-specific αβ T cell receptor (TCR) mediate anti-tumor immunity. However, mispairing of the therapeutic αβ chains with endogenous αβ chains reduces therapeutic TCR surface expression and generates self-reactive TCRs. We report a general strategy to prevent TCR mispairing: swapping constant domains between the α and β chains of a therapeutic TCR. When paired, domain-swapped (ds)TCRs assemble with CD3, express on the cell surface, and mediate antigen-specific T cell responses...
November 8, 2016: ELife
https://www.readbyqxmd.com/read/27815355/multiplex-genome-editing-to-generate-universal-car-t-cells-resistant-to-pd1-inhibition
#4
Jiangtao Ren, Xiaojun Liu, Chongyun Fang, Shuguang Jiang, Carl H June, Yangbing Zhao
PURPOSE: Using gene-disrupted allogeneic T cells as universal effector cells provides an alternative to and potentially improves current chimeric antigen receptor (CAR) T cell therapy against cancers and infectious diseases. EXPERIMENTAL DESIGN: The CRISPR/Cas9 system has recently emerged as a simple and efficient way for multiplex genome engineering. By combining the lentiviral delivery of CAR and CRISPR RNA electroporation to co-introduce RNA encoding the Cas9 and gRNAs targeting endogenous TCR, beta-2 microglobulin (B2M) and PD1 simultaneously, to generate gene-disrupted allogeneic CAR T cells deficient of TCR, HLA class I molecule and PD1...
November 4, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27776339/generation-of-cd20-specific-tcrs-for-tcr-gene-therapy-of-cd20low-b-cell-malignancies-insusceptible-to-cd20-targeting-antibodies
#5
Lorenz Jahn, Dirk M van der Steen, Renate S Hagedoorn, Pleun Hombrink, Michel G D Kester, Marjolein P Schoonakker, Daniëlle de Ridder, Peter A van Veelen, J H Frederik Falkenburg, Mirjam H M Heemskerk
Immunotherapy of B-cell leukemia and lymphoma with CD20-targeting monoclonal antibodies (mAbs) has demonstrated clinical efficacy. However, the emergence of unresponsive disease due to low or absent cell surface CD20 urges the need to develop additional strategies. In contrast to mAbs, T-cells via their T-cell receptor (TCR) can recognize not only extracellular but also intracellular antigens in the context of HLA molecules. We hypothesized that T-cells equipped with high affinity CD20-targeting TCRs would be able to recognize B-cell malignancies even in the absence of extracellular CD20...
October 20, 2016: Oncotarget
https://www.readbyqxmd.com/read/27757299/intratumoral-expression-levels-of-pd-l1-gzma-and-hla-a-along-with-oligoclonal-t-cell-expansion-associate-with-response-to-nivolumab-in-metastatic-melanoma
#6
Hiroyuki Inoue, Jae-Hyun Park, Kazuma Kiyotani, Makda Zewde, Azusa Miyashita, Masatoshi Jinnin, Yukiko Kiniwa, Ryuhei Okuyama, Ryota Tanaka, Yasuhiro Fujisawa, Hiroshi Kato, Akimichi Morita, Jun Asai, Norito Katoh, Kenji Yokota, Masashi Akiyama, Hironobu Ihn, Satoshi Fukushima, Yusuke Nakamura
Immune checkpoint inhibitors blocking the interaction between programmed death-1 (PD-1) and PD-1 ligand-1 (PD-L1) are revolutionizing the cancer immunotherapies with durable clinical responses. Although high expression of PD-L1 in tumor tissues has been implicated to correlate with the better response to the anti-PD-1 therapies, this association has been controversial. In this study, to characterize immune microenvironment in tumors, we examined mRNA levels of immune-related genes and characterized T cell repertoire in the tumors of 13 melanoma patients before and after nivolumab treatment...
2016: Oncoimmunology
https://www.readbyqxmd.com/read/27750220/blocking-tcr-restimulation-induced-necroptosis-in-adoptively-transferred-t-cells-improves-tumor-control
#7
Pravin Kesarwani, Paramita Chakraborty, Radhika Gudi, Shilpak Chatterjee, Gina Scurti, Kyle Toth, Patt Simms, Mahvash Husain, Kent Armeson, Shahid Husain, Elizabeth Garrett-Mayer, Chethamarakshan Vasu, Michael I Nishimura, Shikhar Mehrotra
Advancements in adoptive cell transfer therapy (ACT) has led to the use of T cells engineered with tumor specific T cell receptors, which after rapid expansion can be obtained in sufficient numbers for treating patients. However, due to massive proliferation these cells are close to replicative senescence, exhibit exhausted phenotype, and also display increased susceptibility to activation induced cell death. We have previously shown that tumor reactive T cells undergo caspase-independent cell death upon TCR restimulation with cognate antigen, which involves reactive oxygen species and c-jun N-terminal kinase...
October 14, 2016: Oncotarget
https://www.readbyqxmd.com/read/27713165/generation-of-v-%C3%AE-13-%C3%AE-21-t-cell-specific-target-cml-cells-by-tcr-gene-transfer
#8
Xianfeng Zha, Ling Xu, Shaohua Chen, Lijian Yang, Yikai Zhang, Yuhong Lu, Zhi Yu, Bo Li, Xiuli Wu, Wenjie Zheng, Yangqiu Li
Adoptive immunotherapy with antigen-specific T cells can be effective for treating melanoma and chronic myeloid leukemia (CML). However, to obtain sufficient antigen-specific T cells for treatment, the T cells have to be cultured for several weeks in vitro, but in vitro T cell expansion is difficult to control. Alternatively, the transfer of T cell receptors (TCRs) with defined antigen specificity into recipient T cells may be a simple solution for generating antigen-specific T cells. The objective of this study was to identify CML-associated, antigen-specific TCR genes and generate CML-associated, antigen-specific T cells with T cell receptor (TCR) gene transfer...
October 4, 2016: Oncotarget
https://www.readbyqxmd.com/read/27649554/the-t-cell-receptor-repertoire-influences-the-tumor-microenvironment-and-is-associated-with-survival-in-aggressive-b-cell-lymphoma
#9
Colm Keane, Clare Gould, Kimberley Jones, David Hamm, Dipti Talaulikar, Jonathan Ellis, Frank Vari, Simone Birch, Erica Han, Peter Wood, Kim-Anh Le Cao, Michael R Green, Pauline Crooks, Sanjiv Jain, Joshua Tobin, Raymond J Steptoe, Maher K Gandhi
PURPOSE: To investigate the relationship between the intra-tumoral T-cell receptor (TCR) repertoire and the tumor microenvironment (TME) in de novo Diffuse Large B-cell Lymphoma (DLBCL), and the TCR's impact on survival. EXPERIMENTAL DESIGN: We performed high-throughput unbiased TCRBeta sequencing on a population based cohort of 92 DLBCL patients treated with conventional (i.e. non-checkpoint blockade) frontline 'R-CHOP' therapy. Key immune checkpoint genes within the TME were digitally quantified by nanoString{trade mark, serif}...
September 20, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27603913/cancer-testis-antigens-expression-regulation-tumor-invasion-and-use-in-immunotherapy-of-cancers
#10
Arash Salmaninejad, Mohammad Reza Zamani, Mehrnaz Pourvahedi, Zahra Golchehre, Ali Hosseini Bereshneh, Nima Rezaei
UNLABELLED: Cancer/testis antigens (CTAs) are named based on their expression pattern that is restricted in a number of normal and abnormal tissues. Tumor cells frequently express antigens whose expression is typically restricted to germ cells. Their unique expression pattern is guaranteed by precise epigenetic regulatory mechanisms. Because of their tumor-limited, high immunogenicity, and biased expression, discovery of these molecules provides unprecedented opportunities for further research and clinical development in the field of cancer diagnosis and immunotherapy...
October 2016: Immunological Investigations
https://www.readbyqxmd.com/read/27489285/mage-c2-specific-tcrs-combined-with-epigenetic-drug-enhanced-antigenicity-yield-robust-and-tumor-selective-t-cell-responses
#11
Andre Kunert, Mandy van Brakel, Sabine van Steenbergen-Langeveld, Marvin da Silva, Pierre G Coulie, Cor Lamers, Stefan Sleijfer, Reno Debets
Adoptive T cell therapy has shown significant clinical success for patients with advanced melanoma and other tumors. Further development of T cell therapy requires improved strategies to select effective, yet nonself-reactive, TCRs. In this study, we isolated 10 TCR sequences against four MAGE-C2 (MC2) epitopes from melanoma patients who showed clinical responses following vaccination that were accompanied by significant frequencies of anti-MC2 CD8 T cells in blood and tumor without apparent side effects. We introduced these TCRs into T cells, pretreated tumor cells of different histological origins with the epigenetic drugs azacytidine and valproate, and tested tumor and self-reactivities of these TCRs...
September 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27466285/lack-of-p53-augments-antitumor-functions-in-cytolytic-t-cells
#12
Anirban Banerjee, Krishnamurthy Thyagarajan, Shilpak Chatterjee, Paramita Chakraborty, Pravin Kesarwani, Myroslawa Soloshchenko, Mazen Al-Hommrani, Kristina Andrijauskaite, Kelly Moxley, Harinarayanan Janakiraman, Matthew J Scheffel, Kristi Helke, Kent Armenson, Viswanathan Palanisamy, Mark P Rubinstein, Elizabeth-Garrett Mayer, David J Cole, Chrystal M Paulos, Christina Voelkel-Johnson, Michael I Nishimura, Shikhar Mehrotra
Repetitive stimulation of T-cell receptor (TCR) with cognate antigen results in robust proliferation and expansion of the T cells, and also imprints them with replicative senescence signatures. Our previous studies have shown that life-span and antitumor function of T cells can be enhanced by inhibiting reactive oxygen species (ROS) or intervening with ROS-dependent JNK activation that leads to its activation-induced cell death. Because tumor suppressor protein p53 is also a redox active transcription factor that regulates cellular ROS generation that triggers downstream factor-mediating apoptosis, we determined if p53 levels could influence persistence and function of tumor-reactive T cells...
September 15, 2016: Cancer Research
https://www.readbyqxmd.com/read/27463149/tcr%C3%AE-4%C3%AE-1-engineered-%C3%AE-%C3%AE-t-cells-exhibit-effective-antitumor-activity
#13
Kangxia He, Hongqin You, Yuxia Li, Lianxian Cui, Jianmin Zhang, Wei He
T cell engineering with T cell receptors (TCRs) specific for tumors plays an important role in adoptive T-cell transfer (ATC) therapy for cancer. Here, we present a novel strategy to redirect peripheral blood-derived αβT cells against tumors via TCRγ4δ1 gene transduction. The broad-spectrum anti-tumor activity of TCRδ1 cells in innate immunity is dependent on CDR3δ1. TCRγ4δ1-engineered αβT cells were prepared by lentiviral transduction and characterized by analyzing in vitro and in vivo cytotoxicity to tumors, ability of proliferation and cytokine production, and their potential role in autoimmunity...
July 26, 2016: Molecular Medicine
https://www.readbyqxmd.com/read/27434830/viral-bronchiolitis-is-associated-with-altered-cytokine-gene-expression-and-lymphocyte-activation-status
#14
T Ronan Leahy, Ross McManus, Derek G Doherty, Robert Grealy, Michael J Carr, Dubhfeasa Slattery, Thomas Ryan
BACKGROUND: Disease severity in viral bronchiolitis is often difficult to predict at onset, and may be related to the host immune response. Recognizing the particular immunologic features of infants who develop severe disease might offer an opportunity for developing diagnostic tools to facilitate early intervention and improve outcomes. METHODS: We compared cytokine gene expression (by real-time reverse-transcriptase polymerase chain reaction), cytokine concentrations (by enzyme-linked immunosorbent assay) and the activation status of lymphocytes (by flow cytometry) in the peripheral blood of children hospitalized with moderate and severe viral bronchiolitis and a group of age-matched controls...
November 2016: Pediatric Infectious Disease Journal
https://www.readbyqxmd.com/read/27402301/indolent-t-cell-lymphoproliferative-disease-of-the-gastro-intestinal-tract-following-treatment-with-adalimumab-in-resistant-crohn-s-colitis
#15
Natalia Edison, Hila Belhanes-Peled, Yuval Eitan, Yifat Guthmann, Yelena Yeremenko, Mark Raffeld, Irit Elmalah, Philippe Trougouboff
We report a case of intestinal indolent T-cell lymphoproliferative disease (TCLPD) occurring after the initiation of Tumor Necrosis Factor-α (TNF-α) inhibitor therapy for resistant Crohn's disease. A prominent T-cell infiltrate positive for CD8, TIA-1, TCR-βF1 was associated with the foci of active inflammation. T-Cell Receptor (TCR) gene clonality studies (BIOMED-2) demonstrated monoclonality. After the TNF-α inhibitor treatment was withdrawn, the T-cell infiltrates regressed, but two years later, the same monoclonal T-cell infiltrate reappeared at the only site of active inflammation...
July 8, 2016: Human Pathology
https://www.readbyqxmd.com/read/27354337/tumor-and-neoantigen-reactive-t-cell-receptors-can-be-identified-based-on-their-frequency-in-fresh-tumor
#16
Anna Pasetto, Alena Gros, Paul F Robbins, Drew C Deniger, Todd D Prickett, Rodrigo Matus-Nicodemos, Daniel C Douek, Bryan Howie, Harlan Robins, Maria R Parkhurst, Jared Gartner, Katarzyna Trebska-McGowan, Jessica S Crystal, Steven A Rosenberg
Adoptive transfer of T cells with engineered T-cell receptor (TCR) genes that target tumor-specific antigens can mediate cancer regression. Accumulating evidence suggests that the clinical success of many immunotherapies is mediated by T cells targeting mutated neoantigens unique to the patient. We hypothesized that the most frequent TCR clonotypes infiltrating the tumor were reactive against tumor antigens. To test this hypothesis, we developed a multistep strategy that involved TCRB deep sequencing of the CD8(+)PD-1(+) T-cell subset, matching of TCRA-TCRB pairs by pairSEQ and single-cell RT-PCR, followed by testing of the TCRs for tumor-antigen specificity...
September 2, 2016: Cancer Immunology Research
https://www.readbyqxmd.com/read/27329987/a-tet-on-inducible-system-for-controlling-cd19-chimeric-antigen-receptor-expression-upon-drug-administration
#17
Reona Sakemura, Seitaro Terakura, Keisuke Watanabe, Jakrawadee Julamanee, Erina Takagi, Kotaro Miyao, Daisuke Koyama, Tatsunori Goto, Ryo Hanajiri, Tetsuya Nishida, Makoto Murata, Hitoshi Kiyoi
T cells genetically modified with a CD19 chimeric antigen receptor (CD19CAR) are remarkably effective against B-cell malignancies in clinical trials. However, major concerns remain regarding toxicities, such as hypogammaglobulinemia, due to B-cell aplasia or severe cytokine release syndrome after overactivation of CAR T cells. To resolve these adverse events, we aimed to develop an inducible CAR system by using a tetracycline regulation system that would be activated only in the presence of doxycycline (Dox)...
August 2016: Cancer Immunology Research
https://www.readbyqxmd.com/read/27297792/integrated-mate-pair-and-rna-sequencing-identifies-novel-targetable-gene-fusions-in-peripheral-t-cell-lymphoma
#18
Rebecca L Boddicker, Gina L Razidlo, Surendra Dasari, Yu Zeng, Guangzhen Hu, Ryan A Knudson, Patricia T Greipp, Jaime I Davila, Sarah H Johnson, Julie C Porcher, James B Smadbeck, Bruce W Eckloff, Daniel D Billadeau, Paul J Kurtin, Mark A McNiven, Brian K Link, Stephen M Ansell, James R Cerhan, Yan W Asmann, George Vasmatzis, Andrew L Feldman
Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous group of T-cell malignancies that generally demonstrate aggressive clinical behavior, often are refractory to standard therapy, and remain significantly understudied. The most common World Health Organization subtype is PTCL, not otherwise specified (NOS), essentially a "wastebasket" category because of inadequate understanding to assign cases to a more specific diagnostic entity. Identification of novel fusion genes has contributed significantly to improving the classification, biologic understanding, and therapeutic targeting of PTCLs...
September 1, 2016: Blood
https://www.readbyqxmd.com/read/27249753/immunotherapy-beyond-anti-pd-1-and-anti-pd-l1-therapies
#19
Scott J Antonia, Johan F Vansteenkiste, Edmund Moon
Advanced-stage non-small cell lung cancer (NSCLC) and small cell lung cancer are cancers in which chemotherapy produces a survival benefit, although it is small. We now know that anti-PD-1/PD-L1 has substantial clinical activity in both of these diseases, with an overall response rate (ORR) of 15%-20%. These responses are frequently rapid and durable, increase median overall survival (OS) compared with chemotherapy, and produce long-term survivors. Despite these very significant results, many patients do not benefit from anti-PD-1/PD-L1...
2016: American Society of Clinical Oncology Educational Book
https://www.readbyqxmd.com/read/27216195/clonotypic-diversification-of-intratumoral-t-cells-following-sipuleucel-t-treatment-in-prostate-cancer-subjects
#20
Nadeem Sheikh, Jason Cham, Li Zhang, Todd DeVries, Simon Letarte, Jeff Pufnock, David Hamm, James Trager, Lawrence Fong
Sipuleucel-T is an autologous cellular therapy for asymptomatic, or minimally symptomatic, metastatic castrate-resistant prostate cancer, designed to stimulate an immune response against prostate cancer. In a recent clinical trial (NCT00715104), we found that neoadjuvant sipuleucel-T increased the number of activated T cells within the tumor microenvironment. The current analysis examined whether sipuleucel-T altered adaptive T-cell responses by expanding pre-existing T cells or by recruiting new T cells to prostate tissue...
July 1, 2016: Cancer Research
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