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https://www.readbyqxmd.com/read/29904021/overcoming-resistance-of-human-non-hodgkin-s-lymphoma-to-cd19-car-ctl-therapy-by-celecoxib-and-histone-deacetylase-inhibitors
#1
Antoni Xavier Torres-Collado, Ali R Jazirehi
Patients with B-cell non-Hodgkin’s lymphoma (B-NHL) who fail to respond to first-line treatment regimens or develop resistance, exhibit poor prognosis. This signifies the need to develop alternative treatment strategies. CD19-chimeric antigen receptor (CAR) T cell-redirected immunotherapy is an attractive and novel option, which has shown encouraging outcomes in phase I clinical trials of relapsed/refractory NHL. However, the underlying mechanisms of, and approaches to overcome, acquired anti-CD19CAR CD8⁺ T cells (CTL)-resistance in NHL remain elusive...
June 14, 2018: Cancers
https://www.readbyqxmd.com/read/29895668/preinfusion-polyfunctional-anti-cd19-chimeric-antigen-receptor-t-cells-associate-with-clinical-outcomes-in-nhl
#2
John Rossi, Patrick Paczkowski, Yueh-Wei Shen, Kevin Morse, Brianna Flynn, Alaina Kaiser, Colin Ng, Kyle Gallatin, Tom Cain, Rong Fan, Sean Mackay, James R Heath, Steven A Rosenberg, James N Kochenderfer, Jing Zhou, Adrian Bot
After treatment with chimeric antigen receptor (CAR) T cells, interleukin (IL)-15 elevation and CAR T-cell expansion are associated with non-Hodgkin lymphoma (NHL) outcomes. However, the association of preinfusion CAR product T-cell functionality with clinical outcomes has not been reported. A single-cell analysis of the preinfusion CD19 CAR product from patients with NHL demonstrated that CAR products contain polyfunctional T-cell subsets capable of deploying multiple immune programs represented by cytokines and chemokines including interferon-γ (IFN-γ), IL-17A, IL-8, and macrophage inflammatory protein 1-α...
June 12, 2018: Blood
https://www.readbyqxmd.com/read/29859774/media-evaluation-for-production-and-expansion-of-anti-cd19-chimeric-antigen-receptor-t-cells
#3
Rehab Alnabhan, Ahmed Gaballa, Lisa-Mari Mörk, Jonas Mattsson, Michael Uhlin, Isabelle Magalhaes
BACKGROUND: The use of CD19 chimeric antigen receptor (CAR) T cells to treat B-cell malignancies has proven beneficial. Several groups use serum to produce CD19 CAR T cells. Today, ready-to-use serum-free media that require no addition of serum are commercially available. Therefore, it becomes important to evaluate the production of CD19 CAR T cells with and without the addition of serum. METHODS: T cells from buffy coats were cultured in AIM-V and TexMACS (TM) supplemented with 5% human serum (A5% and TM5%, respectively), and in TM without serum...
May 30, 2018: Cytotherapy
https://www.readbyqxmd.com/read/29812997/t-cells-genetically-modified-to-express-an-anti-b-cell-maturation-antigen-chimeric-antigen-receptor-cause-remissions-of-poor-prognosis-relapsed-multiple-myeloma
#4
Jennifer N Brudno, Irina Maric, Steven D Hartman, Jeremy J Rose, Michael Wang, Norris Lam, Maryalice Stetler-Stevenson, Dalia Salem, Constance Yuan, Steven Pavletic, Jennifer A Kanakry, Syed Abbas Ali, Lekha Mikkilineni, Steven A Feldman, David F Stroncek, Brenna G Hansen, Judith Lawrence, Rashmika Patel, Frances Hakim, Ronald E Gress, James N Kochenderfer
Purpose Therapies with novel mechanisms of action are needed for multiple myeloma (MM). T cells can be genetically modified to express chimeric antigen receptors (CARs), which are artificial proteins that target T cells to antigens. B-cell maturation antigen (BCMA) is expressed by normal and malignant plasma cells but not normal essential cells. We conducted the first-in-humans clinical trial, to our knowledge, of T cells expressing a CAR targeting BCMA (CAR-BCMA). Patients and Methods Sixteen patients received 9 × 106 CAR-BCMA T cells/kg at the highest dose level of the trial; we are reporting results of these 16 patients...
May 29, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29769444/glioblastoma-targeted-cd4-car-t-cells-mediate-superior-antitumor-activity
#5
Dongrui Wang, Brenda Aguilar, Renate Starr, Darya Alizadeh, Alfonso Brito, Aniee Sarkissian, Julie R Ostberg, Stephen J Forman, Christine E Brown
Chimeric antigen receptor-modified (CAR-modified) T cells have shown promising therapeutic effects for hematological malignancies, yet limited and inconsistent efficacy against solid tumors. The refinement of CAR therapy requires an understanding of the optimal characteristics of the cellular products, including the appropriate composition of CD4+ and CD8+ subsets. Here, we investigated the differential antitumor effect of CD4+ and CD8+ CAR T cells targeting glioblastoma-associated (GBM-associated) antigen IL-13 receptor α2 (IL13Rα2)...
May 17, 2018: JCI Insight
https://www.readbyqxmd.com/read/29769201/in-vitro-priming-of-adoptively-transferred-t-cells-with-a-ror%C3%AE-agonist-confers-durable-memory-and-stemness-in-vivo
#6
Xiao Hu, Kinga Majchrzak, Xikui Liu, Megan M Wyatt, Chauncey Spooner, Jacques Moisan, Weiping Zou, Laura L Carter, Chrystal M Paulos
Adoptive T cell transfer therapy is an FDA-approved treatment for leukemia that relies on the ex vivo expansion and re-infusion of a patient's immune cells, which can be engineered with a chimeric antigen receptor (CAR) for more efficient tumor recognition. Type 17 T cells, controlled transcriptionally by RORγ, have been reported to mediate potent anti-tumor effects superior to those observed with conventionally expanded T cells. Here we demonstrate that addition of a synthetic, small molecule RORγ agonist during ex vivo expansion potentiates the anti-tumor activity of human Th17 and Tc17 cells redirected with a CAR...
May 16, 2018: Cancer Research
https://www.readbyqxmd.com/read/29769184/explaining-resistance-to-car-t-cells
#7
(no author information available yet)
A new study reveals several attributes of T cells from patients with chronic lymphocytic leukemia who respond to CAR T-cell therapy. The patients' T cells show increased expression of memory-related genes and high activity of STAT3, which promotes memory cell differentiation. The researchers also found that patients who underwent complete remission have certain CD8+ T cells.
May 16, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29720380/car-t-cells-surface-engineered-with-drug-encapsulated-nanoparticles-can-ameliorate-intratumoral-t-cell-hypofunction
#8
Natnaree Siriwon, Yu Jeong Kim, Elizabeth Louise Siegler, Xianhui Chen, Jennifer A Rohrs, Yarong Liu, Pin Wang
One limiting factor of CAR T-cell therapy for treatment of solid cancers is the suppressive tumor microenvironment, which inactivates the function of tumor infiltrating lymphocytes (TILs) through the production of immunosuppressive molecules such as adenosine. Adenosine inhibits the function of CD4+ and CD8+ T cells by binding to and activating the A2a adenosine receptor (A2aR) expressed on their surface. This suppression pathway can be blocked using the A2aR-specific small molecule antagonist SCH-58261 (SCH), but its applications have been limited owing to difficulties delivering this drug to immune cells within the tumor microenvironment (TME)...
May 2, 2018: Cancer Immunology Research
https://www.readbyqxmd.com/read/29713085/determinants-of-response-and-resistance-to-cd19-chimeric-antigen-receptor-car-t-cell-therapy-of-chronic-lymphocytic-leukemia
#9
Joseph A Fraietta, Simon F Lacey, Elena J Orlando, Iulian Pruteanu-Malinici, Mercy Gohil, Stefan Lundh, Alina C Boesteanu, Yan Wang, Roddy S O'Connor, Wei-Ting Hwang, Edward Pequignot, David E Ambrose, Changfeng Zhang, Nicholas Wilcox, Felipe Bedoya, Corin Dorfmeier, Fang Chen, Lifeng Tian, Harit Parakandi, Minnal Gupta, Regina M Young, F Brad Johnson, Irina Kulikovskaya, Li Liu, Jun Xu, Sadik H Kassim, Megan M Davis, Bruce L Levine, Noelle V Frey, Donald L Siegel, Alexander C Huang, E John Wherry, Hans Bitter, Jennifer L Brogdon, David L Porter, Carl H June, J Joseph Melenhorst
Tolerance to self-antigens prevents the elimination of cancer by the immune system1,2 . We used synthetic chimeric antigen receptors (CARs) to overcome immunological tolerance and mediate tumor rejection in patients with chronic lymphocytic leukemia (CLL). Remission was induced in a subset of subjects, but most did not respond. Comprehensive assessment of patient-derived CAR T cells to identify mechanisms of therapeutic success and failure has not been explored. We performed genomic, phenotypic and functional evaluations to identify determinants of response...
May 2018: Nature Medicine
https://www.readbyqxmd.com/read/29605883/induction-of-a-central-memory-and-stem-cell-memory-phenotype-in-functionally-active-cd4-and-cd8-car-t-cells-produced-in-an-automated-good-manufacturing-practice-system-for-the-treatment-of-cd19-acute-lymphoblastic-leukemia
#10
Franziska Blaeschke, Dana Stenger, Theresa Kaeuferle, Semjon Willier, Ramin Lotfi, Andrew Didier Kaiser, Mario Assenmacher, Michaela Döring, Judith Feucht, Tobias Feuchtinger
Relapsed/refractory B-precursor acute lymphoblastic leukemia (pre-B ALL) remains a major therapeutic challenge. Chimeric antigen receptor (CAR) T cells are promising treatment options. Central memory T cells (Tcm) and stem cell-like memory T cells (Tscm) are known to promote sustained proliferation and persistence after T-cell therapy, constituting essential preconditions for treatment efficacy. Therefore, we set up a protocol for anti-CD19 CAR T-cell generation aiming at high Tcm/Tscm numbers. 100 ml peripheral blood from pediatric pre-B ALL patients was processed including CD4+ /CD8+ -separation, T-cell activation with modified anti-CD3/-CD28 reagents and transduction with a 4-1BB-based second generation CAR lentiviral vector...
March 31, 2018: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/29599530/excessive-activated-t-cell-proliferation-after-anti-cd19-car-t-cell-therapy
#11
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/29562451/-an-experimental-study-of-cd4-targeted-chimeric-antigen-receptor-modified-t-cell-with-anti-lymphoma-activity
#12
G H Chen, H W Huang, Y Wang, H W Liu, L J Xu, X Ma, S L Xue, X F He, Y Wang, B Gu, C X Li, H Y Qiu, X W Tang, Z M Jin, M Miao, A N Sun, D P Wu
Objective: To study the specific killing effect of CD4 membrane protein targeted chimeric antigen receptor modified T (CAR-T) cell. Methods: The second generation CD4 targeted chimeric antigen receptor containing 4-1BB costimulation domain was insert into lentiviral vector through recombinant DNA technology. Lentivirus was prepared and packaged by 293T cells with four plasmids. Beads activated T cells were transduced with lentivirus and the transduction efficiency was checked with Protein L and flow cytometry...
February 14, 2018: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/29546043/overcoming-barriers-of-age-to-enhance-efficacy-of-cancer-immunotherapy-the-clout-of-the-extracellular-matrix
#13
REVIEW
Mark Owyong, Gizem Efe, Michael Owyong, Aamna J Abbasi, Vaishnavi Sitarama, Vicki Plaks
There is a growing list of cancer immunotherapeutics approved for use in a population with an increasing number of aged individuals. Cancer immunotherapy (CIT) mediates tumor destruction by activating anti-tumor immune responses that have been silenced through the oncogenic process. However, in an aging individual, immune deregulation is positively correlated with age. In this context, it is vital to examine the age-related changes in the tumor microenvironment (TME) and specifically, those directly affecting critical players to ensure CIT efficacy...
2018: Frontiers in Cell and Developmental Biology
https://www.readbyqxmd.com/read/29518467/cationic-polymers-for-non-viral-gene-delivery-to-human-t-cells
#14
Brynn R Olden, Yilong Cheng, Jonathan L Yu, Suzie H Pun
The clinical success of chimeric antigen receptor (CAR) T cell immunotherapy in treating multiple blood cancers has created a need for efficient methods of ex vivo gene delivery to primary human T cells for cell engineering. Here, we synthesize and evaluate a panel of cationic polymers for gene delivery to both cultured and primary human T cells. We show that a subset of comb- and sunflower-shaped pHEMA-g-pDMAEMA polymers can mediate transfection with efficiencies up to 50% in the Jurkat human T cell line with minimal concomitant toxicity (>90% viability)...
March 5, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/29503195/adoptive-transfer-of-il13r%C3%AE-2-specific-chimeric-antigen-receptor-t-cells-creates-a-pro-inflammatory-environment-in-glioblastoma
#15
Katarzyna C Pituch, Jason Miska, Giedre Krenciute, Wojciech K Panek, Gina Li, Tania Rodriguez-Cruz, Meijing Wu, Yu Han, Maciej S Lesniak, Stephen Gottschalk, Irina V Balyasnikova
In order to fully harness the potential of immunotherapy with chimeric antigen receptor (CAR)-modified T cells, pre-clinical studies must be conducted in immunocompetent animal models that closely mimic the immunosuppressive malignant glioma (MG) microenvironment. Thus, the goal of this project was to study the in vivo fate of T cells expressing CARs specific for the MG antigen IL13Rα2 (IL13Rα2-CARs) in immunocompetent MG models. Murine T cells expressing IL13Rα2-CARs with a CD28.ζ (IL13Rα2-CAR.CD28...
April 4, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29472720/car-t-cells-targeting-flt3-have-potent-activity-against-flt3-itd-aml-and-act-synergistically-with-the-flt3-inhibitor-crenolanib
#16
Hardikkumar Jetani, Irene Garcia-Cadenas, Thomas Nerreter, Simone Thomas, Julian Rydzek, Javier Briones Meijide, Halvard Bonig, Wolfgang Herr, Jordi Sierra, Hermann Einsele, Michael Hudecek
FMS-like tyrosine kinase 3 (FLT3) is a transmembrane protein expressed on normal hematopoietic stem and progenitor cells (HSC) and retained on malignant blasts in acute myeloid leukemia (AML). We engineered CD8+ and CD4+ T-cells expressing a FLT3-specific chimeric antigen receptor (CAR) and demonstrate they confer potent reactivity against AML cell lines and primary AML blasts that express either wild-type FLT3 or FLT3 with internal tandem duplication (FLT3-ITD). We also show that treatment with the FLT3-inhibitor crenolanib leads to increased surface expression of FLT3 specifically on FLT3-ITD+ AML cells and consecutively, enhanced recognition by FLT3-CAR T-cells in vitro and in vivo...
May 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29467399/assessment-of-novel-vaccination-regimens-using-viral-vectored-liver-stage-malaria-vaccines-encoding-me-trap
#17
Carly M Bliss, Georgina Bowyer, Nicholas A Anagnostou, Tom Havelock, Claudia M Snudden, Huw Davies, Simone C de Cassan, Amy Grobbelaar, Alison M Lawrie, Navin Venkatraman, Ian D Poulton, Rachel Roberts, Pooja B Mange, Prateek Choudhary, Saul N Faust, Stefano Colloca, Sarah C Gilbert, Alfredo Nicosia, Adrian V S Hill, Katie J Ewer
Heterologous prime-boost vaccination with viral vectors simian adenovirus 63 (ChAd63) and Modified Vaccinia Ankara (MVA) induces potent T cell and antibody responses in humans. The 8-week regimen demonstrates significant efficacy against malaria when expressing the pre-erythrocytic malaria antigen Thrombospondin-Related Adhesion Protein fused to a multiple epitope string (ME-TRAP). We tested these vaccines in 7 new 4- and 8- week interval schedules to evaluate safety and immunogenicity of multiple ChAd63 ME-TRAP priming vaccinations (denoted A), multiple MVA ME-TRAP boosts (denoted M) and alternating vectors...
February 21, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29391351/t-cell-homing-therapy-for-reducing-regulatory-t-cells-and-preserving-effector-t-cell-function-in-large-solid-tumors
#18
Jiemiao Hu, Chuang Sun, Chantale Bernatchez, Xueqing Xia, Patrick Hwu, Gianpietro Dotti, Shulin Li
PURPOSE: Infused autologous tumor-infiltrating lymphocytes (TILs) and tumor-targeted chimeric antigen receptor (CAR)-T cells typically surround malignant lesions or penetrate small tumor nodules, but fail to penetrate large solid tumors, significantly compromising their antitumor impact. Strategies to overcome this primary challenge are largely required. EXPERIMENTAL DESIGN: We tested the effects of IL-12 plus doxorubicin on T cell penetration and efficacy in solid tumors in a murine lung cancer model, a murine breast carcinoma lung metastasis model and two human xenograft tumor models bearing large tumors (>10 mm)...
February 1, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29346301/braf-and-mek-inhibitors-influence-the-function-of-reprogrammed-t-cells-consequences-for-adoptive-t-cell-therapy
#19
Jan Dörrie, Lek Babalija, Stefanie Hoyer, Kerstin F Gerer, Gerold Schuler, Lucie Heinzerling, Niels Schaft
BRAF and MEK inhibitors (BRAFi/MEKi), the standard treatment for patients with BRAFV600 mutated melanoma, are currently explored in combination with various immunotherapies, notably checkpoint inhibitors and adoptive transfer of receptor-transfected T cells. Since two BRAFi/MEKi combinations with similar efficacy are approved, potential differences in their effects on immune cells would enable a rational choice for triple therapies. Therefore, we characterized the influence of the clinically approved BRAFi/MEKi combinations dabrafenib (Dabra) and trametinib (Tram) vs...
January 18, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29321369/enhancing-car-t-cell-persistence-through-icos-and-4-1bb-costimulation
#20
Sonia Guedan, Avery D Posey, Carolyn Shaw, Anna Wing, Tong Da, Prachi R Patel, Shannon E McGettigan, Victoria Casado-Medrano, Omkar U Kawalekar, Mireia Uribe-Herranz, Decheng Song, J Joseph Melenhorst, Simon F Lacey, John Scholler, Brian Keith, Regina M Young, Carl H June
Successful tumor eradication by chimeric antigen receptor-expressing (CAR-expressing) T lymphocytes depends on CAR T cell persistence and effector function. We hypothesized that CD4+ and CD8+ T cells may exhibit distinct persistence and effector phenotypes, depending on the identity of specific intracellular signaling domains (ICDs) used to generate the CAR. First, we demonstrate that the ICOS ICD dramatically enhanced the in vivo persistence of CAR-expressing CD4+ T cells that, in turn, increased the persistence of CD8+ T cells expressing either CD28- or 4-1BB-based CARs...
January 11, 2018: JCI Insight
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