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TCR gene therapy

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https://www.readbyqxmd.com/read/29669936/engineered-t-cells-targeting-e7-mediate-regression-of-human-papillomavirus-cancers-in-a-murine-model
#1
Benjamin Y Jin, Tracy E Campbell, Lindsey M Draper, Sanja Stevanović, Bianca Weissbrich, Zhiya Yu, Nicholas P Restifo, Steven A Rosenberg, Cornelia L Trimble, Christian S Hinrichs
T cell receptor (TCR) T cell therapy is a promising cancer treatment modality. However, its successful development for epithelial cancers may depend on the identification of high-avidity TCRs directed against tumor-restricted target antigens. The human papillomavirus (HPV) E7 antigen is an attractive therapeutic target that is constitutively expressed by HPV+ cancers but not by healthy tissues. It is unknown if genetically engineered TCR T cells that target E7 can mediate regression of HPV+ cancers. We identified an HPV-16 E7-specific, HLA-A*02:01-restricted TCR from a uterine cervix biopsy from a woman with cervical intraepithelial neoplasia...
April 19, 2018: JCI Insight
https://www.readbyqxmd.com/read/29669806/targeting-merkel-cell-carcinoma-by-engineered-t-cells-specific-to-t-antigens-of-merkel-cell-polyomavirus
#2
Ioannis Gavvovidis, Matthias Leisegang, Gerald Willimsky, Natalie J Miller, Paul Nghiem, Thomas Blankenstein
PURPOSE: The causative agent of most cases of Merkel cell carcinoma (MCC) has been identified as the Merkel cell polyomavirus (MCV). MCV-encoded T-antigens (Tags) are essential not only for virus-mediated tumorigenesis but also for maintaining MCC cell lines in vitro. MCV Tags are thus an appealing target for viral oncoprotein-directed T cell therapy for MCC. With this study, we aimed to isolate and characterize Tag-specific T cell receptors (TCR) for potential use in gene therapy clinical trials...
April 18, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29628306/tumor-resident-dendritic-cells-and-macrophages-modulate-the-accumulation-of-tcr-engineered-t-cells-in-melanoma
#3
Alastair Hotblack, Angelika Holler, Alice Piapi, Sophie Ward, Hans J Stauss, Clare L Bennett
Ongoing clinical trials explore T cell receptor (TCR) gene therapy as a treatment option for cancer, but responses in solid tumors are hampered by the immunosuppressive microenvironment. The production of TCR gene-engineered T cells requires full T cell activation in vitro, and it is currently unknown whether in vivo interactions with conventional dendritic cells (cDCs) regulate the accumulation and function of engineered T cells in tumors. Using the B16 melanoma model and the inducible depletion of CD11c+ cells in CD11c...
March 16, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29605708/long-terminal-repeat-crispr-car-coupled-universal-t-cells-mediate-potent-anti-leukemic-effects
#4
Christos Georgiadis, Roland Preece, Lauren Nickolay, Aniekan Etuk, Anastasia Petrova, Dariusz Ladon, Alexandra Danyi, Neil Humphryes-Kirilov, Ayokunmi Ajetunmobi, Daesik Kim, Jin-Soo Kim, Waseem Qasim
Gene editing can be used to overcome allo-recognition, which otherwise limits allogeneic T cell therapies. Initial proof-of-concept applications have included generation of such "universal" T cells expressing chimeric antigen receptors (CARs) against CD19 target antigens combined with transient expression of DNA-targeting nucleases to disrupt the T cell receptor alpha constant chain (TRAC). Although relatively efficient, transgene expression and editing effects were unlinked, yields variable, and resulting T cell populations heterogeneous, complicating dosing strategies...
March 6, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29599530/excessive-activated-t-cell-proliferation-after-anti-cd19-car-t-cell-therapy
#5
Wen-Ying Zhang, Yang Liu, Yao Wang, Jing Nie, Ye-Lei Guo, Chun-Meng Wang, Han-Ren Dai, Qing-Ming Yang, Zhi-Qiang Wu, Wei-Dong Han
Excessive activated T-cell proliferation was observed in vivo in one patient after an anti-CD19-chimeric antigen receptor (CAR) T-cell infusion. The patient, who had chemotherapy refractory and CD19+ diffuse large B-cell lymphoma (DLBCL), received an anti-CD19 CAR T-cell infusion following conditioning chemotherapy (fludarabine/cyclophosphamide). The lymphocyte count in the peripheral blood (PB) increased to 77 × 109 /L on day 13 post infusion, and the proportion of CD8+ actived T cells was 93.06% of the lymphocytes...
March 29, 2018: Gene Therapy
https://www.readbyqxmd.com/read/29593943/tumor-immunity-landscape-in-non-small-cell-lung-cancer
#6
Xiaoqing Yu, Xuefeng Wang
Even with the great advances in immunotherapy in recent years, the response rate to immune checkpoint inhibitor therapy for non-small cell lung cancer is only about 20%. We aimed to identify new features that would better predict which patients can benefit from an immune checkpoint blocker. This study is based on the publicly available gene expression data from The Cancer Genome Atlas lung cancer samples and the newly released mutation annotation data. We performed a comprehensive analysis by correlating patient cytolytic activity index, mutational signatures, and other immune characteristics in four stratified patient groups...
2018: PeerJ
https://www.readbyqxmd.com/read/29588318/rapid-construction-of-antitumor-t-cell-receptor-vectors-from-frozen-tumors-for-engineered-t-cell-therapy
#7
Takemasa Tsuji, Akira Yoneda, Junko Matsuzaki, Anthony Miliotto, Courtney Ryan, Richard C Koya, Kunle Odunsi
T cells genetically engineered with tumor antigen-specific T-cell receptor (TCR) genes have demonstrated therapeutic potential in patients with solid tumors. In order to achieve broader application, an efficient method to identify TCR genes for an array of tumor antigens and HLA restriction elements is required. Here, we have developed a method to construct a TCR-expression library from specimens, including frozen tumor biopsies, that contain antigen-specific T cells. TCR-expressing cassettes were constructed and cloned in a retroviral plasmid vector within 24 hours by unbiased PCR amplification of TCR α and β chain variable regions assembled with TCR constant regions...
March 27, 2018: Cancer Immunology Research
https://www.readbyqxmd.com/read/29559473/erap1-dependent-antigen-cross-presentation-determines-efficacy-of-adoptive-t-cell-therapy-in-mice
#8
Karin Schmidt, Christin Keller, Anja A Kühl, Ana Textor, Ulrike Seifert, Thomas Blankenstein, Gerald Willimsky, Peter-Michael Kloetzel
Cytotoxic T lymphocytes can reject established tumors if their target peptide is efficiently presented by major histocompatibility complex class I molecules (pMHC-I) on the surface of cancerous cells. Therapeutic success upon adoptive T cell transfer (ATT), however, requires additional cross-presentation of the same pMHC-I on non-cancerous cells. Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an enzyme that customizes the N-terminus of proteasome-generated peptides so they can be loaded onto MHC-I molecules in the endoplasmic reticulum (ER)...
March 20, 2018: Cancer Research
https://www.readbyqxmd.com/read/29528339/cell-based-molecularly-targeted-therapy-targeting-oncoproteins-with-t-cell-receptor-gene-therapy
#9
Christian S Hinrichs
As oncogenes drive carcinogenesis and promote cancer cell survival, they are highly attractive therapeutic targets, and oncogene-targeting small molecules have achieved some clinical success. While many oncogenes are presently considered to be "druggable," tumors often acquire treatment resistance, and patients are rarely cured in response to oncogene-specific treatment. In this issue of the JCI, Veatch and colleagues describe a patient with metastatic acral melanoma who experienced a complete tumor response following infusion of tumor-infiltrating T cells that targeted multiple tumor antigens, including a BRAFV600E driver mutation...
March 12, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29515077/-cancer-immunotherapy-using-gene-engineered-t-cells
#10
Shinichi Kageyama
Cancer immunotherapies using gene-engineered T cells comprise adoptive transfer of T-cell receptor (TCR) and chimeric antigen receptor (CAR) gene-transduced T cells. Although CD19-targeting CAR-T cell therapy is the most progressed, wherein B-cell malignancy is treated efficiently, it also induces cytokine release syndrome and neurotoxicity, which frequently leads to serious adverse events. Of note, TCR-T cell therapy has been primarily used to target melanoma, resulting in 30%-50% of tumor responses. In clinical trials that target NY-ESO-1-expressing synovial sarcoma, a high efficacy of 50%-60% has been obtained...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/29475880/identification-of-tumoricidal-tcrs-from-tumor-infiltrating-lymphocytes-by-single-cell-analysis
#11
Kiyomi Shitaoka, Hiroshi Hamana, Hiroyuki Kishi, Yoshihiro Hayakawa, Eiji Kobayashi, Kenta Sukegawa, Xiuhong Piao, Fulian Lyu, Takuya Nagata, Daisuke Sugiyama, Hiroyoshi Nishikawa, Atsushi Tanemura, Ichiro Katayama, Mutsunori Murahashi, Yasushi Takamatsu, Kenzaburo Tani, Tatsuhiko Ozawa, Atsushi Muraguchi
T-cell receptor (TCR) gene therapy is a promising next-generation antitumor treatment. We previously developed a single-T-cell analysis protocol that allows the rapid capture of paired TCRalpha and beta cDNAs. Here, we applied the protocol to analyze the TCR repertoire of tumor-infiltrating lymphocytes (TILs) of various cancer patients. We found clonally expanded populations of T cells that expressed the same clonotypic TCR in 50 to 70% of CD137+CD8+ TILs, indicating that they responded to certain antigens in the tumor environment...
February 23, 2018: Cancer Immunology Research
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
#12
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
#13
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...
April 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
#14
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
#15
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/tcr-%C3%AE-recombinations-in-renal-cell-carcinoma-exome-files-correlate-with-an-intermediate-level-of-t-cell-exhaustion-biomarkers
#16
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-α 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...
February 3, 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
#17
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...
February 20, 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
#18
Joshua R Veatch, Sylvia M Lee, Matthew Fitzgibbon, I-Ting Chow, Brenda Jesernig, Tom 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 achieved a complete response following adoptive transfer of tumor-infiltrating lymphocytes (TILs). Tumor exome sequencing surprisingly revealed fewer than 30 nonsynonymous somatic mutations, including oncogenic BRAFV600E...
April 2, 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
#19
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...
April 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
#20
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)
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