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CAR T-Cells

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https://www.readbyqxmd.com/read/29348865/targeting-t-cell-malignancies-using-anti-cd4-car-nk-92-cells
#1
Kevin G Pinz, Elizabeth Yakaboski, Alexander Jares, Hua Liu, Amelia E Firor, Kevin H Chen, Masayuki Wada, Huda Salman, William Tse, Nabil Hagag, Fengshuo Lan, Elaine Lai-Han Leung, Xun Jiang, Yupo Ma
Peripheral T-cell lymphomas (PTCLs) are a group of very aggressive non-Hodgkin's lymphomas (NHLs) with poor prognoses and account for a majority of T-cell malignancies. Overall, the standard of care for patients with T-cell malignancies is poorly established, and there is an urgent clinical need for a new approach. As demonstrated in B-cell malignancies, chimeric antigen receptor (CAR) immunotherapy provides great hope as a curative treatment regimen. Because PTCLs develop from mature T-cells, these NHLs are commonly CD4+, and CD4 is highly and uniformly expressed...
December 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29346301/braf-and-mek-inhibitors-influence-the-function-of-reprogrammed-t-cells-consequences-for-adoptive-t-cell-therapy
#2
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/29343642/mechanogenetics-for-the-remote-and-noninvasive-control-of-cancer-immunotherapy
#3
Yijia Pan, Sangpil Yoon, Jie Sun, Ziliang Huang, Changyang Lee, Molly Allen, Yiqian Wu, Ya-Ju Chang, Michel Sadelain, K Kirk Shung, Shu Chien, Yingxiao Wang
While cell-based immunotherapy, especially chimeric antigen receptor (CAR)-expressing T cells, is becoming a paradigm-shifting therapeutic approach for cancer treatment, there is a lack of general methods to remotely and noninvasively regulate genetics in live mammalian cells and animals for cancer immunotherapy within confined local tissue space. To address this limitation, we have identified a mechanically sensitive Piezo1 ion channel (mechanosensor) that is activatable by ultrasound stimulation and integrated it with engineered genetic circuits (genetic transducer) in live HEK293T cells to convert the ultrasound-activated Piezo1 into transcriptional activities...
January 17, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29340102/the-impact-of-antibiotic-usage-on-the-efficacy-of-chemoimmunotherapy-is-contingent-on-the-source-of-tumor-reactive-t-cells
#4
Michal P Kuczma, Zhi-Chun Ding, Tao Li, Tsadik Habtetsion, Tingting Chen, Zhonglin Hao, Locke Bryan, Nagendra Singh, James N Kochenderfer, Gang Zhou
In recent years the combined use of chemotherapy and immunotherapy, collectively termed chemoimmunotherapy, has emerged as a promising treatment option for patients with cancer. Antibiotics are commonly used to reduce infection-related complications in patients undergoing chemotherapy. Intriguingly, accumulating evidence has implicated gut microbiota as a critical determinant of host antitumor immune responses, raising the question as to whether the use of broad-spectrum antibiotics would invariably diminish tumor response to chemoimmunotherapies...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29334841/tocilizumab-in-the-treatment-of-myocardial-infarction
#5
Matthew B Carroll
Tocilizumab (TCZ) is an important biologic response modifier that Rheumatologists routinely employ in the treatment of several systemic autoimmune diseases. TCZ binds to interleukin (IL)-6 receptors, inhibits cellular activation, and mitigates inflammation by IL-6. In mid-2017 TCZ was approved by the U.S. Food and Drug Administration for its first non-rheumatologic condition, the treatment of chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome in patients 2 years of age or older...
January 16, 2018: Modern Rheumatology
https://www.readbyqxmd.com/read/29334771/development-of-anti-human-mesothelin-targeted-chimeric-antigen-receptor-car-messenger-rna-mrna-transfected-peripheral-blood-lymphocytes-carma-hmeso-for-ovarian-cancer-therapy
#6
Chien-Fu Hung, Xuequn Xu, Linhong Li, Ying Ma, Qiu Jin, Angelia Viley, Cornell Allen, Pachai Natarajan, Rama Shivakumar, Madhusudan V Peshwa, Leisha A Emens
CD19-targeted chimeric antigen receptor (CAR) engineered T/natural kill (NK)-cell therapies can result in durable clinical responses in B-cell malignancies. However, CAR-based immunotherapies have been much less successful in solid cancers, in part due to 'on-target off-tumor' toxicity related to expression of target tumor antigens on normal tissue. Based on preliminary observations of safety and clinical activity in proof-of-concept clinical trials, tumor antigen-specific messenger RNA (mRNA) CAR transfection into selected, activated, and expanded T/NK-cells may permit prospective control of 'on-target off-tumor toxicity'...
January 15, 2018: Human Gene Therapy
https://www.readbyqxmd.com/read/29334370/scaffolds-that-mimic-antigen-presenting-cells-enable-ex-vivo-expansion-of-primary-t-cells
#7
Alexander S Cheung, David K Y Zhang, Sandeep T Koshy, David J Mooney
Therapeutic ex vivo T-cell expansion is limited by low rates and T-cell products of limited functionality. Here we describe a system that mimics natural antigen-presenting cells (APCs) and consists of a fluid lipid bilayer supported by mesoporous silica micro-rods. The lipid bilayer presents membrane-bound cues for T-cell receptor stimulation and costimulation, while the micro-rods enable sustained release of soluble paracrine cues. Using anti-CD3, anti-CD28, and interleukin-2, we show that the APC-mimetic scaffolds (APC-ms) promote two- to tenfold greater polyclonal expansion of primary mouse and human T cells compared with commercial expansion beads (Dynabeads)...
January 15, 2018: Nature Biotechnology
https://www.readbyqxmd.com/read/29329591/prospects-for-chimeric-antigen-receptor-modified-t-cell-therapy-for-solid-tumors
#8
REVIEW
Erhao Zhang, Jieyi Gu, Hanmei Xu
The potential for adoptive cell immunotherapy as a treatment against cancers has been demonstrated by the remarkable response in some patients with hematological malignancies using autologous T cells endowed with chimeric antigen receptors (CARs) specific for CD19. Clinical efficacy of CAR-T cell therapy for the treatment of solid tumors, however, is rare due to physical and biochemical factors. This review focuses on different aspects of multiple mechanisms of immunosuppression in solid tumors. We characterize the current state of CAR-modified T cell therapy and summarize the various strategies to combat the immunosuppressive microenvironment of solid tumors, with the aim of promoting T cell cytotoxicity and enhancing tumor cell eradication...
January 12, 2018: Molecular Cancer
https://www.readbyqxmd.com/read/29327909/more-on-anti-cd19-car-t-cells-in-cns-diffuse-large-b-cell-lymphoma
#9
Jeremy S Abramson, Yi-Bin Chen
No abstract text is available yet for this article.
November 23, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/29327908/more-on-anti-cd19-car-t-cells-in-cns-diffuse-large-b-cell-lymphoma
#10
Pierre Tiberghien, Eric Deconinck, Oliver Adotevi
No abstract text is available yet for this article.
November 23, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/29321369/enhancing-car-t-cell-persistence-through-icos-and-4-1bb-costimulation
#11
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
https://www.readbyqxmd.com/read/29320890/chimeric-antigen-receptors-in-different-cell-types-new-vehicles-join-the-race
#12
Dennis C Harrer, Jan Dörrie, Niels Schaft
Adoptive cellular therapy has evolved into a powerful force in the battle against cancer, holding promise for curative responses in patients with advanced and refractory tumors. Autologous T cells, reprogrammed to target malignant cells via the expression of a chimeric antigen receptor (CAR) represent the frontrunner in this approach. Tremendous clinical regressions have been achieved using CAR-T cells against a variety of cancers both in numerous preclinical studies and in several clinical trials, most notably against ALL, and resulted in a very recent FDA-approval of the first CAR-T-cell therapy...
January 10, 2018: Human Gene Therapy
https://www.readbyqxmd.com/read/29318647/realizing-effectiveness-across-continents-with-hydroxyurea-enrollment-and-baseline-characteristics-of-the-multicenter-reach-study-in-sub-saharan-africa
#13
Patrick T McGann, Thomas N Williams, Peter Olupot-Olupot, George A Tomlinson, Adam Lane, José Luís Reis da Fonseca, Robert Kitenge, George Mochamah, Ham Wabwire, Susan Stuber, Thad A Howard, Kathryn McElhinney, Banu Aygun, Teresa Latham, Brígida Santos, Léon Tshilolo, Russell E Ware
Despite its well-described safety and efficacy in the treatment of sickle cell anemia (SCA) in high-income settings, hydroxyurea remains largely unavailable in sub-Saharan Africa, where more than 75% of annual SCA births occur and many comorbidities exist. Realizing Effectiveness Across Continents with Hydroxyurea (REACH, ClinicalTrials.gov NCT01966731) is a prospective, Phase I/II open-label trial of hydroxyurea designed to evaluate the feasibility, safety, and benefits of hydroxyurea treatment for children with SCA in four sub-Saharan African countries...
January 10, 2018: American Journal of Hematology
https://www.readbyqxmd.com/read/29317339/from-clinical-proof-of-concept-to-commercialization-of-car-t-cells
#14
Boris Calmels, Bechara Mfarrej, Christian Chabannon
The development of CAR T cells currently represents an exciting opportunity to convert the already published clinical successes observed in clinical trials into commercially available efficient therapies. However, the path toward successful commercialization is still hindered by many hurdles. Here, we review such issues as: the need for structured collaborations between hospital collection and clinical facilities and industry manufacturing facilities to streamline the supply chain; necessity for uniform and efficient medical procedures to cope with severe toxicities associated with CAR T cells; and absolute need to define an economical and sustainable model for manufacturers and payers...
January 6, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29316944/car-t-cells-targeting-cll-1-as-an-approach-to-treat-acute-myeloid-leukemia
#15
Jinghua Wang, Siyu Chen, Wei Xiao, Wende Li, Liang Wang, Shuo Yang, Weida Wang, Liping Xu, Shuangye Liao, Wenjian Liu, Yang Wang, Nawei Liu, Jianeng Zhang, Xiaojun Xia, Tiebang Kang, Gong Chen, Xiuyu Cai, Han Yang, Xing Zhang, Yue Lu, Penghui Zhou
BACKGROUND: Acute myeloid leukemia (AML) is one of the most common types of adult acute leukemia. Standard chemotherapies can induce complete remission in selected patients; however, a majority of patients eventually relapse and succumb to the disease. Thus, the development of novel therapeutics for AML is urgently needed. Human C-type lectin-like molecule-1 (CLL-1) is a type II transmembrane glycoprotein, and its expression is restricted to myeloid cells and the majority of AML blasts...
January 10, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29316666/fusion-proteins-of-nkg2d-nkg2dl-in-cancer-immunotherapy
#16
REVIEW
Hui Ding, Xi Yang, Yanzhang Wei
NKG2D (natural killer group 2, member D) is an important activating receptor in natural killer (NK) cells and some T cells. NKG2D ligands (NKG2DLs) are specifically expressed on most tumor cells. The engagement of these ligands on tumor cells to NKG2D on NK cells will induce cell-mediated cytotoxicity and have target cells destroyed. This gives NKG2D/NKG2DLs great potential in cancer therapeutic application. The creation of NKG2D/NKG2DL-based multi-functional fusion proteins is becoming one of the most promising strategies in immunotherapy for cancer...
January 7, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29315094/cd19-chimeric-antigen-receptor-t-cells-from-patients-with-chronic-lymphocytic-leukemia-display-an-elevated-ifn-%C3%AE-production-profile
#17
Isabelle Magalhaes, Ingrid Kalland, James N Kochenderfer, Anders Österborg, Michael Uhlin, Jonas Mattsson
CD19 chimeric antigen receptor (CAR) T cell immunotherapy has demonstrated dramatic results for the treatment of B cell malignancies such as chronic lymphocytic leukemia (CLL). As T cell defects are common in patients with CLL, we compared the T cells from these patients with healthy donors (HDs), and subsequently the CD19 CAR T cells produced from patients and HDs. Despite initial differences when comparing the phenotype of circulating T cells in patients with CLL and HDs, the CD19 CAR T cells manufactured from patients' or HDs' cells showed a similar phenotype (effector memory or terminally differentiated), both were specifically activated by and killed CD19 target cells, and secreted cytokines (ie, IL-2, TNF, and IFN-γ)...
January 8, 2018: Journal of Immunotherapy
https://www.readbyqxmd.com/read/29312553/development-of-novel-target-modules-for-retargeting-of-unicar-t-cells-to-gd2-positive-tumor-cells
#18
Nicola Mitwasi, Anja Feldmann, Ralf Bergmann, Nicole Berndt, Claudia Arndt, Stefanie Koristka, Alexandra Kegler, Justyna Jureczek, Anja Hoffmann, Armin Ehninger, Marc Cartellieri, Susann Albert, Claudia Rossig, Gerhard Ehninger, Jens Pietzsch, Jörg Steinbach, Michael Bachmann
As the expression of a tumor associated antigen (TAA) is commonly not restricted to tumor cells, adoptively transferred T cells modified to express a conventional chimeric antigen receptor (CAR) might not only destroy the tumor cells but also attack target-positive healthy tissues. Furthermore, CAR T cells in patients with large tumor bulks will unpredictably proliferate and put the patients at high risk of adverse side effects including cytokine storms and tumor lysis syndrome. To overcome these problems, we previously established a modular CAR technology termed UniCAR: UniCAR T cells can repeatedly be turned on and off via dosing of a target module (TM)...
December 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29311388/chimeric-antigen-receptor-t-cell-therapy-challenges-to-bench-to-bedside-efficacy
#19
REVIEW
Shivani Srivastava, Stanley R Riddell
Immunotherapy with T cells genetically modified to express chimeric Ag receptors (CARs) that target tumor-associated molecules have impressive efficacy in hematological malignancies. The field has now embraced the challenge of applying this approach to treat common epithelial malignancies, which make up the majority of cancer cases but evade immunologic attack by a variety of subversive mechanisms. In this study, we review the principles that have guided CAR T cell design and the extraordinary clinical results being achieved in B cell malignancies targeting CD19 with a single infusion of engineered T cells...
January 15, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29310916/chimeric-antigen-receptor-engineered-human-gamma-delta-t-cells-enhanced-cytotoxicity-with-retention-of-cross-presentation
#20
Anna Capsomidis, Gabriel Benthall, Heleen H Van Acker, Jonathan Fisher, Anne M Kramer, Zarah Abeln, Yvonne Majani, Talia Gileadi, Rebecca Wallace, Kenth Gustafsson, Barry Flutter, John Anderson
Gamma delta T (γδT) lymphocytes are primed for rapid function, including cytotoxicity toward cancer cells, and are a component of the immediate stress response. Following activation, they can function as professional antigen-presenting cells. Chimeric antigen receptors (CARs) work by focusing T cell function on defined cell surface tumor antigens and provide essential costimulation for robust activation. Given the natural tropism of γδT cells for the tumor microenvironment, we hypothesized that their transduction with CARs might enhance cytotoxicity while retaining their ability to migrate to tumor and act as antigen-presenting cells to prolong the intratumoral immune response...
December 8, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
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