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Chimeric Antigen Receptor T cells

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https://www.readbyqxmd.com/read/29678834/from-pluripotent-stem-to-car-t-cells
#1
(no author information available yet)
Within the field of allogeneic chimeric antigen receptor T-cell therapy, La Jolla, CA-based Fate Therapeutics is exploring in vitro differentiation of induced pluripotent stem cells, rather than T cells harvested from donors, as their source material. Preclinical data on the company's off-the-shelf candidate, FT819, look promising so far.
April 20, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29678657/development-and-evaluation-of-an-optimal-human-single-chain-variable-fragment-derived-bcma-targeted-car-t-cell-vector
#2
Eric L Smith, Mette Staehr, Reed Masakayan, Ishan J Tatake, Terence J Purdon, Xiuyan Wang, Pei Wang, Hong Liu, Yiyang Xu, Sarah C Garrett-Thomson, Steven C Almo, Isabelle Riviere, Cheng Liu, Renier J Brentjens
B cell maturation antigen (BCMA) has recently been identified as an important multiple myeloma (MM)-specific target for chimeric antigen receptor (CAR) T cell therapy. In CAR T cell therapy targeting CD19 for lymphoma, host immune anti-murine CAR responses limited the efficacy of repeat dosing and possibly long-term persistence. This clinically relevant concern can be addressed by generating a CAR incorporating a human single-chain variable fragment (scFv). We screened a human B cell-derived scFv phage display library and identified a panel of BCMA-specific clones from which human CARs were engineered...
March 28, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29676233/chimeric-antigen-receptor-t-cell-based-immunotherapy-for-cancer
#3
Feng Li, Tengfei Zhang, Ling Cao, Yi Zhang
Cancer immunotherapy, a new weapon against cancers by harnessing the patient's own immune system, potentiates an extended remission and possibly a cure for cancer. T cells genetically engineered with chimeric antigen receptor (CAR) vectors can specifically target the surface antigen of cancer cells and kill them in an MHC-independent manner. CD19 is extensively expressed on cancerous cells in B cell malignancies. To target this antigen, CAR T cells have gained great success in treating patients with B cell leukemia and lymphoma...
April 19, 2018: Current Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/29669947/anti-cd19-car-t-cells-with-high-dose-melphalan-and-autologous-stem-cell-transplantation-for-refractory-multiple-myeloma
#4
Alfred L Garfall, Edward A Stadtmauer, Wei-Ting Hwang, Simon F Lacey, Jan Joseph Melenhorst, Maria Krevvata, Martin P Carroll, William H Matsui, Qiuju Wang, Madhav V Dhodapkar, Kavita Dhodapkar, Rituparna Das, Dan T Vogl, Brendan M Weiss, Adam D Cohen, Patricia A Mangan, Emily C Ayers, Selene Nunez-Cruz, Irina Kulikovskaya, Megan M Davis, Anne Lamontagne, Karen Dengel, Naseem Ds Kerr, Regina M Young, Donald L Siegel, Bruce L Levine, Michael C Milone, Marcela V Maus, Carl H June
BACKGROUND: Multiple myeloma is usually fatal due to serial relapses that become progressively refractory to therapy. CD19 is typically absent on the dominant multiple myeloma cell population but may be present on minor subsets with unique myeloma-propagating properties. To target myeloma-propagating cells, we clinically evaluated autologous T cells transduced with a chimeric antigen receptor (CAR) against CD19 (CTL019). METHODS: Subjects received CTL019 following salvage high-dose melphalan and autologous stem cell transplantation (ASCT)...
April 19, 2018: JCI Insight
https://www.readbyqxmd.com/read/29668614/arthritis-of-large-joints-shown-as-a-rare-clinical-feature-of-cytokine-release-syndrome-after-chimeric-antigen-receptor-t-cell-therapy-a-case-report
#5
Li-Xin Wang, Xiaoping Chen, Mingming Jia, Shengdian Wang, Jianliang Shen
RATIONALE: Chimeric antigen receptor (CAR)-T cell therapy is a novel type of therapy that is being used in an increasing number of patients with acute lymphoblastic leukemia (ALL). Cytokine release syndrome (CRS) is the most common complication following CAR-T treatment, but the current understanding of the clinical manifestations and pathogenesis of CRS is still limited. PATIENT CONCERNS: A 34-year-old male patient was diagnosed with ALL in June 2015. Complete remission (CR) was achieved after induction chemotherapy...
April 2018: Medicine (Baltimore)
https://www.readbyqxmd.com/read/29667553/car-t-cell-therapy-a-new-era-in-cancer-immunotherapy
#6
Miliotou N Androulla, Papadopoulou C Lefkothea
BACKGROUND: Cancer is one of the leading causes of death worldwide. Over the years, a number of conventional cytotoxic approaches for neoplastic diseases has been developed. However, due to their limited effectiveness in accordance with the heterogeneity of cancer cells, there is a constant search for therapeutic approaches with improved outcome, such as immunotherapy that utilizes and enhances the normal capacity of the patient's immune system. METHODS: Chimeric Antigen Receptor (CAR) T-cell therapy involves genetic modification of patient's autologous T-cells to express a CAR specific for a tumor antigen, following by ex vivo cell expansion and re-infusion back to the patient...
April 17, 2018: Current Pharmaceutical Biotechnology
https://www.readbyqxmd.com/read/29665944/-current-status-and-challenges-of-car-t-immunotherapy-in-hematologic-malignancies-review
#7
Xin Cheng, Ya-Jie Wang, Shuai Feng, Ya-Yun Wu, Tong-Hua Yang, Xun Lai
The chimeric antigen receptor (CAR) T cell therapy has gradually became a new trend in the treatment of refractory and relapsed hematologic malignancies by developing for 30 years. With the exciting development of genetic engineering, CAR-T technology has subjected to 4 generations of innovation. Structure of CAR-T started from a single signal molecule to 2 or more than 2 co-stimulatory molecules, and then coding the CAR gene or promoter. CAR-T can specifically recognize tumor antigens, and does not be restricted by major histocompatibility complex (MHC), thus making a breakthrough in clinical treatment...
April 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/29662667/genetically-enhanced-t-lymphocytes-and-the-intensive-care-unit
#8
REVIEW
Tiberiu Tat, Huming Li, Catalin-Sorin Constantinescu, Anca Onaciu, Sergiu Chira, Ciprian Osan, Sergiu Pasca, Bobe Petrushev, Vlad Moisoiu, Wilhelm-Thomas Micu, Cristian Berce, Sebastian Tranca, Delia Dima, Ioana Berindan-Neagoe, Jianliang Shen, Ciprian Tomuleasa, Liren Qian
Chimeric antigen receptor-modified T cells (CAR-T cells) and donor lymphocyte infusion (DLI) are important protocols in lymphocyte engineering. CAR-T cells have emerged as a new modality for cancer immunotherapy due to their potential efficacy against hematological malignancies. These genetically modified receptors contain an antigen-binding moiety, a hinge region, a transmembrane domain, and an intracellular costimulatory domain resulting in lymphocyte T cell activation subsequent to antigen binding. In present-day medicine, four generations of CAR-T cells are described depending on the intracellular signaling domain number of T cell receptors...
March 27, 2018: Oncotarget
https://www.readbyqxmd.com/read/29662316/metformin-inhibits-proliferation-and-cytotoxicity-and-induces-apoptosis-via-ampk-pathway-in-cd19-chimeric-antigen-receptor-modified-t-cells
#9
Qian Mu, Miao Jiang, Yuzhu Zhang, Fei Wu, Hui Li, Wen Zhang, Fang Wang, Jiang Liu, Liang Li, Dongshan Wang, Wenjuan Wang, Shiwu Li, Haibo Song, Dongqi Tang
Background: CD19-chimericantigen receptor (CAR) modified T cells (CD19-CAR T cells) have been well documented to possess potent anti-tumor properties against CD19-expressingleukemia cells. As a traditional medicine, metformin has been widely used to treat type II diabetes mellitus and more recently has become a candidate for the treatment of cancer. However, no report has revealed the direct effect of metformin on CD19-CAR T cell biological function and its underling mechanisms. Purpose: The purpose of this research was to explore the effect of metformin on CD19-CAR T cell biological function and the mechanisms involved...
2018: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29662203/potent-antitumor-efficacy-of-anti-gd2-car-t-cells-in-h3-k27m-diffuse-midline-gliomas
#10
Christopher W Mount, Robbie G Majzner, Shree Sundaresh, Evan P Arnold, Meena Kadapakkam, Samuel Haile, Louai Labanieh, Esther Hulleman, Pamelyn J Woo, Skyler P Rietberg, Hannes Vogel, Michelle Monje, Crystal L Mackall
Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMGs) with mutated histone H3 K27M (H3-K27M)1-5 are aggressive and universally fatal pediatric brain cancers 6 . Chimeric antigen receptor (CAR)-expressing T cells have mediated impressive clinical activity in B cell malignancies7-10 , and recent results suggest benefit in central nervous system malignancies11-13 . Here, we report that patient-derived H3-K27M-mutant glioma cell cultures exhibit uniform, high expression of the disialoganglioside GD2...
April 16, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29656320/the-role-of-mesothelin-as-a-diagnostic-and-therapeutic-target-in-pancreatic-ductal-adenocarcinoma-a-comprehensive-review
#11
Federico Nichetti, Antonio Marra, Francesca Corti, Alessandro Guidi, Alessandra Raimondi, Natalie Prinzi, Filippo de Braud, Sara Pusceddu
Mesothelin is a tumor differentiation antigen, which is highly expressed in several solid neoplasms, including pancreatic cancer. Its selective expression on malignant cells and on only a limited number of healthy tissues has made it an interesting candidate for investigation as a diagnostic and prognostic biomarker and as a therapeutic target. Based on a strong preclinical rationale, a number of therapeutic agents targeting mesothelin have entered clinical trials, including immunotoxins, monoclonal antibodies, antibody-drug conjugates, cancer vaccines, and adoptive T cell therapies with chimeric antigen receptors...
April 14, 2018: Targeted Oncology
https://www.readbyqxmd.com/read/29655961/chimeric-antigen-receptor-t-cell-therapy-for-non-hodgkin-lymphoma
#12
REVIEW
Armin Ghobadi
Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy. More than 20,000 people in United States, more than 37,000 people in Europe and more than 199,000 people worldwide die of NHL every year. Recent advances in immunotherapeutic approaches for cancer have resulted in development of new classes of very effective immunotherapeutic approaches including chimeric antigen receptor T (CAR-T) cell therapy that are designed to bypass cancer immune evasion. Here, we review recent advances in CAR-T cell therapy for NHL...
April 11, 2018: Current Research in Translational Medicine
https://www.readbyqxmd.com/read/29651744/prospects-of-chimeric-antigen-receptor-t-cell-therapy-in-ovarian-cancer
#13
REVIEW
Vishal Jindal, Ena Arora, Sorab Gupta, Amos Lal, Muhammad Masab, Rashmika Potdar
Despite advances in various chemotherapy regimens, current therapeutic options are limited for ovarian cancer patients. Immunotherapy provides a promising and novel treatment option for ovarian cancer. Recently, chimeric antigen receptor (CAR) T cell therapy has shown promising results in hematological tumors and current research is going on in various solid tumors like ovarian cancer. CAR T cells are genetically engineered T cells with major histocompatibility complex-independent, tumor-specific, immune-mediated cytolytic actions against cancer cells...
April 12, 2018: Medical Oncology
https://www.readbyqxmd.com/read/29644505/cardiotoxicity-of-immunotherapy-incidence-diagnosis-and-management
#14
REVIEW
Aarti Asnani
PURPOSE OF REVIEW: This review describes cardiotoxicity associated with adoptive T cell therapy and immune checkpoint blockade. RECENT FINDINGS: Cardiotoxicity is a rare but potentially fatal complication associated with novel immunotherapies. Both affinity-enhanced and chimeric antigen receptor T cells have been reported to cause hypotension, arrhythmia, and left ventricular dysfunction, typically in the setting of cytokine release syndrome. Immune checkpoint inhibitors are generally well-tolerated but have the potential to cause myocarditis, with clinical presentations ranging from asymptomatic cardiac biomarker elevation to heart failure, arrhythmia, and cardiogenic shock...
April 11, 2018: Current Oncology Reports
https://www.readbyqxmd.com/read/29628798/versatile-car-t-cells-for-cancer-immunotherapy
#15
REVIEW
Fuliang Chu, Jingjing Cao, Sattva S Neelalpu
Chimeric antigen receptor (CAR) T-cell therapy has been clinically proven to efficiently combat haematological malignancies. However, continuous efforts are required to increase the specificity of CAR T-cells against tumour versus normal tissues, and are essential to improve their antitumour activity in solid tumours. This review summarises the structure of major CAR designs, and strategies to overcome immunosuppressive tumour microenvironment, and reduce toxicities. Along with reviewing currently available techniques that allow the elimination of CAR T-cells after they fulfil their desired functions, using suicide genes, drug elimination strategies are also introduced...
March 2018: Contemporary Oncology Współczesna Onkologia
https://www.readbyqxmd.com/read/29625833/celyad-s-novel-car-t-cell-therapy-for-solid-malignancies
#16
Caroline Lonez, Alain Hendlisz, Leila Shaza, Philippe Aftimos, Michaël Vouche, Vincent Donckier, Jean-Pascal H Machiels, Marc Van Den Eynde, Jean-Luc Canon, Javier Carrasco, Kunle Odunsi, Solmaz Sahebjam, Sylvie Rottey, Nathalie Braun, Bikash Verma, David E Gilham, Frédéric F Lehmann
Celyad recently initiated several clinical trials with the CYAD-01 product, a natural killer group 2D (NKG2D)-based chimeric antigen receptor (CAR), in both solid and hematologic tumor types. This review discusses the unique properties of CYAD-01, expecting to provide a new paradigm to fight against solid tumors.
April 3, 2018: Current Research in Translational Medicine
https://www.readbyqxmd.com/read/29625831/insights-into-cytokine-release-syndrome-and-neurotoxicity-after-cd19-specific-car-t-cell-therapy
#17
REVIEW
Jordan Gauthier, Cameron J Turtle
T-cells engineered to express CD19-specific chimeric antigen receptors (CD19 CAR-T cells) can achieve high response rates in patients with refractory/relapsed (R/R) CD19+ hematologic malignancies. Nonetheless, the efficacy of CD19-specific CAR-T cell therapy can be offset by significant toxicities, such as cytokine release syndrome (CRS) and neurotoxicity. In this report of our presentation at the 2018 Second French International Symposium on CAR-T cells (CAR-T day), we describe the clinical presentations of CRS and neurotoxicity in a cohort of 133 adults treated with CD19 CAR-T cells at the Fred Hutchinson Cancer Research Center, and provide insights into the mechanisms contributing to these toxicities...
April 3, 2018: Current Research in Translational Medicine
https://www.readbyqxmd.com/read/29622795/antitumor-activity-of-cd56-chimeric-antigen-receptor-t-cells-in-neuroblastoma-and-sclc-models
#18
Denise L Crossland, Warren L Denning, Sonny Ang, Simon Olivares, Tiejuan Mi, Kirsten Switzer, Harjeet Singh, Helen Huls, Kate S Gold, Bonnie S Glisson, Laurence J Cooper, John V Heymach
The CD56 antigen (NCAM-1) is highly expressed on several malignancies with neuronal or neuroendocrine differentiation, including small-cell lung cancer and neuroblastoma, tumor types for which new therapeutic options are needed. We hypothesized that CD56-specific chimeric antigen receptor (CAR) T cells could target and eliminate CD56-positive malignancies. Sleeping Beauty transposon-generated CD56R-CAR T cells exhibited αβT-cell receptors, released antitumor cytokines upon co-culture with CD56+ tumor targets, demonstrated a lack of fratricide, and expression of cytolytic function in the presence of CD56+ stimulation...
April 6, 2018: Oncogene
https://www.readbyqxmd.com/read/29622697/fda-approval-summary-tocilizumab-for-treatment-of-chimeric-antigen-receptor-t-cell-induced-severe-or-life-threatening-cytokine-release-syndrome
#19
Robert Q Le, Liang Li, Weishi Yuan, Stacy S Shord, Lei Nie, Bahru A Habtemariam, Donna Przepiorka, Ann T Farrell, Richard Pazdur
On August 30, 2017, the U.S. Food and Drug Administration approved Actemra (tocilizumab, Genentech, Inc., South San Francisco, CA) for the treatment of severe or life-threatening chimeric antigen receptor (CAR) T cell-induced cytokine release syndrome (CRS) in adults and in pediatric patients 2 years of age and older. The approval was based on a retrospective analysis of data for patients who developed CRS after treatment with CTL019 and KTE-C19 on prospective clinical trials. Evaluable patients had been treated with intravenous tocilizumab 8 mg/kg (12 mg/kg for patients <30 kg) for severe or life-threatening CRS; only the first episode of CRS was included in the analysis...
April 5, 2018: Oncologist
https://www.readbyqxmd.com/read/29622475/myeloid-conditioning-with-c-kit-targeted-car-t-cells-enables-donor-stem-cell-engraftment
#20
Yasuyuki Arai, Uimook Choi, Cristina I Corsino, Sherry M Koontz, Masaki Tajima, Colin L Sweeney, Mary A Black, Steven A Feldman, Mary C Dinauer, Harry L Malech
We report a novel approach to bone marrow (BM) conditioning using c-kit-targeted chimeric antigen receptor T (c-kit CAR-T) cells in mice. Previous reports using anti-c-kit or anti-CD45 antibody linked to a toxin such as saporin have been promising. We developed a distinctly different approach using c-kit CAR-T cells. Initial studies demonstrated in vitro killing of hematopoietic stem cells by c-kit CAR-T cells but poor expansion in vivo and poor migration of CAR-T cells into BM. Pre-treatment of recipient mice with low-dose cyclophosphamide (125 mg/kg) together with CXCR4 transduction in the CAR-T cells enhanced trafficking to and expansion in BM (<1%-13...
March 10, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
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