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https://www.readbyqxmd.com/read/28202953/fully-human-cd19-specific-chimeric-antigen-receptors-for-t-cell-therapy
#1
D Sommermeyer, T Hill, S M Shamah, A I Salter, Y Chen, K M Mohler, S R Riddell
Impressive results have been achieved by adoptively transferring T-cells expressing CD19-specific CARs with binding domains from murine mAbs to treat B-cell malignancies. T-cell mediated immune responses specific for peptides from the murine scFv antigen-binding domain of the CAR can develop in patients and result in premature elimination of CAR-T-cells increasing the risk of tumor relapse. As fully human scFv might reduce immunogenicity, we generated CD19-specific human scFvs with similar binding characteristics as the murine FMC63-derived scFv using human Ab/DNA-libraries...
February 16, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28199983/a-versatile-system-for-rapid-multiplex-genome-edited-car-t-cell-generation
#2
Jiangtao Ren, Xuhua Zhang, Xiaojun Liu, Chongyun Fang, Shuguang Jiang, Carl H June, Yangbing Zhao
The therapeutic potential of CRISPR system has already been demonstrated in many instances and begun to overlap with the rapidly expanding field of cancer immunotherapy, especially on the production of genetically modified T cell receptor or chimeric antigen receptor (CAR) T cells. Efficient genomic disruption of multiple gene loci to generate universal donor cells, as well as potent effector T cells resistant to multiple inhibitory pathways such as PD-1 and CTLA4 is an attractive strategy for cell therapy...
February 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28193774/universal-car-t-cells-successfully-treat-leukemia
#3
(no author information available yet)
Two infants with relapsed, refractory B-cell acute lymphoblastic leukemia went into complete remission after being treated with CD19-targeting CAR T cells derived from an unmatched donor. The study is the first to demonstrate that a universal form of CAR T-cell therapy can be safely utilized.
February 13, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28186088/current-status-of-immunotherapy-for-gastrointestinal-stromal-tumor
#4
REVIEW
Y Tan, J C Trent, B A Wilky, D A Kerr, A E Rosenberg
Gastrointestinal stromal tumors (GIST) contain tumor-infiltrating immune cells and their presence provides an opportunity and rationale for developing effective forms of immunotherapy. The types of tumor-infiltrating inflammatory cells and relevant immune checkpoint inhibitors are the focus of active investigation. The most numerous tumor-infiltrating inflammatory cells are tumor-associated macrophages (TAMs) and CD3+ T cells. Studies have shown that patients with GISTs that harbor increased numbers of CD3+ T cells have better outcomes...
February 10, 2017: Cancer Gene Therapy
https://www.readbyqxmd.com/read/28162024/immunotherapeutic-strategies-for-the-treatment-of-renal-cell-carcinoma-where-will-we-go
#5
Inês Anselmo da Costa, Steffen Rausch, Stephan Kruck, Tilman Todenhöfer, Arnulf Stenzl, Jens Bedke
Historically, renal cell carcinoma (RCC) is considered a chemotherapy-resistant tumor. The cornerstone of systemic therapy included mammalian target of rapamycin (mTOR) inhibitors, endothelial growth factor receptor (VEGFR) and tyrosine kinase inhibitors (TKIs). Currently, a new era is enteres with promising immunotherapeutic treatments, which are becoming commercially available. Areas covered: We provide a comprehensive review using PubMed and ClinicalTrials.gov about the following immunotherapies in RCC: i) vaccine therapy, ii) adoptive T Cell Transfer and CAR T cells, iii) nonspecific immunotherapy-IL-2 (new formulations), iv) Checkpoint inhibitors, v) other checkpoint-molecules...
February 4, 2017: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/28153859/high-response-to-anti-cd19-car-therapy-in-dlbcl
#6
(no author information available yet)
According to an interim analysis of phase II data from a study of the anti-CD19 chimeric antigen receptor T-cell therapy KTE-C19, 76% of 51 patients with diffuse large B-cell lymphoma responded to the treatment; 47% had a complete response. After 3 months, 33% continued to experience a complete response.
February 2, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28143740/engineering-hiv-resistant-anti-hiv-chimeric-antigen-receptor-t-cells
#7
Malika Hale, Taylor Mesojednik, Guillermo S Romano Ibarra, Jaya Sahni, Alison Bernard, Karen Sommer, Andrew M Scharenberg, David J Rawlings, Thor A Wagner
The treatment or cure of HIV infection by cell and gene therapy has been a goal for decades. Recent advances in both gene editing and chimeric antigen receptor (CAR) technology have created new therapeutic possibilities for a variety of diseases. Broadly neutralizing monoclonal antibodies (bNAbs) with specificity for the HIV envelope glycoprotein provide a promising means of targeting HIV-infected cells. Here we show that primary human T cells engineered to express anti-HIV CARs based on bNAbs (HIVCAR) show specific activation and killing of HIV-infected versus uninfected cells in the absence of HIV replication...
January 28, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28129132/expanding-accessibility-to-cd19-car-t-cells-commercializing-a-boutique-therapy
#8
Premal Lulla, Carlos A Ramos
No abstract text is available yet for this article.
January 4, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28129122/phase-1-results-of-zuma-1-a-multicenter-study-of-kte-c19-anti-cd19-car-t-cell-therapy-in-refractory-aggressive-lymphoma
#9
Frederick L Locke, Sattva S Neelapu, Nancy L Bartlett, Tanya Siddiqi, Julio C Chavez, Chitra M Hosing, Armin Ghobadi, Lihua E Budde, Adrian Bot, John M Rossi, Yizhou Jiang, Allen X Xue, Meg Elias, Jeff Aycock, Jeff Wiezorek, William Y Go
Outcomes for patients with refractory diffuse large B cell lymphoma (DLBCL) are poor. In the multicenter ZUMA-1 phase 1 study, we evaluated KTE-C19, an autologous CD3ζ/CD28-based chimeric antigen receptor (CAR) T cell therapy, in patients with refractory DLBCL. Patients received low-dose conditioning chemotherapy with concurrent cyclophosphamide (500 mg/m(2)) and fludarabine (30 mg/m(2)) for 3 days followed by KTE-C19 at a target dose of 2 × 10(6) CAR T cells/kg. The incidence of dose-limiting toxicity (DLT) was the primary endpoint...
January 4, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28129121/masked-chimeric-antigen-receptor-for-tumor-specific-activation
#10
Xiaolu Han, Paul D Bryson, Yifan Zhao, Gunce E Cinay, Si Li, Yunfei Guo, Natnaree Siriwon, Pin Wang
Adoptive cellular therapy based on chimeric antigen receptor (CAR)-engineered T (CAR-T) cells is a powerful form of cancer immunotherapy. CAR-T cells can be redirected to specifically recognize tumor-associated antigens (TAAs) and induce high levels of antitumor activity. However, they may also display "on-target off-tumor" toxicities, resulting from low-level expression of TAAs in healthy tissues. These adverse effects have raised considerable safety concerns and limited the clinical application of this otherwise promising therapeutic modality...
January 4, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28128714/donor-origin-car-t-cells-graft-versus-malignancy-effect-without-gvhd-a-systematic-review
#11
Faiz Anwer, Al-Aman Shaukat, Umar Zahid, Muhammad Husnain, Ali McBride, Daniel Persky, Melissa Lim, Nida Hasan, Irbaz Bin Riaz
CD19, CD20 chimeric antigen receptor T (CAR T) cell therapy has shown promising results for the treatment of relapsed or refractory hematological malignancies. Best results have been reported in acute lymphoblastic leukemia patients with a complete response rate above 80%. Patients who received donor-derived CAR T cells for the relapsed malignancy after stem cell transplantation (allogenic hematopoietic stem cell transplant) were identified from the published trials. A total of 72 patients from seven studies were treated with donor-derived CAR T cells...
January 2017: Immunotherapy
https://www.readbyqxmd.com/read/28125795/superior-therapeutic-index-in-lymphoma-therapy-cd30-cd34-hematopoietic-stem-cells-resist-a-chimeric-antigen-receptor-t-cell-attack
#12
Andreas A Hombach, André Görgens, Markus Chmielewski, Florian Murke, Janine Kimpel, Bernd Giebel, Hinrich Abken
Recent clinical trials with chimeric antigen receptor (CAR) redirected T cells targeting CD19 revealed particular efficacy in the treatment of leukemia/lymphoma, however, were accompanied by a lasting depletion of healthy B cells. We here explored CD30 as an alternative target, which is validated in lymphoma therapy and expressed by a broad variety of Hodgkin's and non-Hodgkin's lymphomas. As a safty concern, however, CD30 is also expressed by lymphocytes and hematopoietic stem and progenitor cells (HSPCs) during activation...
August 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28116322/genetically-modified-t-cell-based-adoptive-immunotherapy-in-hematological-malignancies
#13
REVIEW
Baixin Ye, Creed M Stary, Qingping Gao, Qiongyu Wang, Zhi Zeng, Zhihong Jian, Lijuan Gu, Xiaoxing Xiong
A significant proportion of hematological malignancies remain limited in treatment options. Immune system modulation serves as a promising therapeutic approach to eliminate malignant cells. Cytotoxic T lymphocytes (CTLs) play a central role in antitumor immunity; unfortunately, nonspecific approaches for targeted recognition of tumor cells by CTLs to mediate tumor immune evasion in hematological malignancies imply multiple mechanisms, which may or may not be clinically relevant. Recently, genetically modified T-cell-based adoptive immunotherapy approaches, including chimeric antigen receptor (CAR) T-cell therapy and engineered T-cell receptor (TCR) T-cell therapy, promise to overcome immune evasion by redirecting the specificity of CTLs to tumor cells...
2017: Journal of Immunology Research
https://www.readbyqxmd.com/read/28114254/adoptive-cell-therapy-for-metastatic-melanoma
#14
Efrat Merhavi-Shoham, Orit Itzhaki, Gal Markel, Jacob Schachter, Michal J Besser
Adoptive cell therapy (ACT) of tumor-infiltrating lymphocytes (TILs) is a powerful form of immunotherapy by inducing durable complete responses that significantly extend the survival of melanoma patients. Mutation-derived neoantigens were recently identified as key factors for tumor recognition and rejection by TILs. The isolation of T-cell receptor (TCR) genes directed against neoantigens and their retransduction into peripheral T cells may provide a new form of ACT.Genetic modifications of T cells with chimeric antigen receptors (CARs) have demonstrated remarkable clinical results in hematologic malignancies, but are so far less effective in solid tumors...
January 2017: Cancer Journal
https://www.readbyqxmd.com/read/28110394/chimeric-antigen-receptor-car-t-cells-lessons-learned-from-targeting-of-cd19-in-b-cell-malignancies
#15
Kevin A Hay, Cameron J Turtle
Adoptive immunotherapy with chimeric antigen receptor-modified (CAR)-T cells is a rapidly growing therapeutic approach to treating patients with refractory cancer, with over 100 clinical trials in various malignancies in progress. The enthusiasm for CAR-T cells has been driven by the clinical success of CD19-targeted CAR-T cell therapy in B-cell acute lymphoblastic leukemia, and the promising data in B-cell non-Hodgkin's lymphoma and chronic lymphocytic leukemia. Despite the success of targeting CD19 with CAR-T cells in early clinical studies, many challenges remain to improve outcomes, reduce toxicity, and determine the appropriate settings for CAR-T cell immunotherapy...
January 21, 2017: Drugs
https://www.readbyqxmd.com/read/28108463/targeting-glioblastoma-with-car-t-cells
#16
(no author information available yet)
CAR T cells targeting IL13Rα2 proved effective against recurrent multifocal leptomeningeal glioblastoma, according to a case report. Direct delivery of the therapy into the cerebrospinal fluid was well tolerated, completely eliminating the patient's brain and spinal tumors for 7.5 months, during which the patient resumed his normal activities.
January 20, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28106050/an-oxygen-sensitive-self-decision-making-engineered-car-t-cell
#17
Alexandre Juillerat, Alan Marechal, Jean Marie Filhol, Yannick Valogne, Julien Valton, Aymeric Duclert, Philippe Duchateau, Laurent Poirot
A key to the success of chimeric antigen receptor (CAR) T-cell based therapies greatly rely on the capacity to identify and target antigens with expression restrained to tumor cells. Here we present a strategy to generate CAR T-cells that are only effective locally (tumor tissue), potentially also increasing the choice of targetable antigens. By fusing an oxygen sensitive subdomain of HIF1α to a CAR scaffold, we generated CAR T-cells that are responsive to a hypoxic environment, a hallmark of certain tumors...
January 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28100832/reporter-gene-imaging-of-targeted-t-cell-immunotherapy-in-recurrent-glioma
#18
Khun Visith Keu, Timothy H Witney, Shahriar Yaghoubi, Jarrett Rosenberg, Anita Kurien, Rachel Magnusson, John Williams, Frezghi Habte, Jamie R Wagner, Stephen Forman, Christine Brown, Martin Allen-Auerbach, Johannes Czernin, Winson Tang, Michael C Jensen, Behnam Badie, Sanjiv S Gambhir
High-grade gliomas are aggressive cancers that often become rapidly fatal. Immunotherapy using CD8(+) cytotoxic T lymphocytes (CTLs), engineered to express both herpes simplex virus type 1 thymidine kinase (HSV1-TK) and interleukin-13 (IL-13) zetakine chimeric antigen receptor (CAR), is a treatment strategy with considerable potential. To optimize this and related immunotherapies, it would be helpful to monitor CTL viability and trafficking to glioma cells. We show that noninvasive positron emission tomography (PET) imaging with 9-[4-[(18)F]fluoro-3-(hydroxymethyl)butyl]guanine ([(18)F]FHBG) can track HSV1-tk reporter gene expression present in CAR-engineered CTLs...
January 18, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28094575/treatment-approaches-of-hard-to-treat-non-hodgkin-lymphomas
#19
Lakshminarayanan Nandagopal, Amitkumar Mehta
Even after recent advancements with monoclonal antibodies, antibody drug conjugates and immune therapies, relapsed and refractory lymphomas remain challenging to treat; and the definition and treatment approaches of hard-to-treat lymphomas (HTL) continue to evolve. Areas covered: In this review, we will address HTL encompassing diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL) and peripheral T cell lymphomas (PTCL). DLBCL, which comprises 30-40% of non-Hodgkin lymphomas is a highly aggressive and heterogeneous malignancy, with primary refractory or relapsed disease remaining a therapeutic challenge...
January 17, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28089834/recent-clinical-trials-utilizing-chimeric-antigen-receptor-t-cells-therapies-against-solid-tumors
#20
Shuanglin Han, Olivier Latchoumanin, Guang Wu, Gang Zhou, Lionel Hebbard, Jacob George, Liang Qiao
Chimeric antigen receptors (CARs) are a series of manufactured receptors that have the capacity of binding to specific antigens expressed on surface of tumor cells. A CAR normally has an extracellular antigen recognition domain derived from single variable chain of a monoclonal antibody, a transmembrane domain and an intracellular T cell activation domain. During the last decade, CAR-T cells were demonstrated to possess great therapeutic effects on hematological malignancies. However, strategies using CAR-T cells to treat solid tumors have been hindered by considerable obstacles including "on tissue off target" effects and cytokine storm syndrome...
April 1, 2017: Cancer Letters
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