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Paulina J Paszkiewicz, Simon P Fräßle, Shivani Srivastava, Daniel Sommermeyer, Michael Hudecek, Ingo Drexler, Michel Sadelain, Lingfeng Liu, Michael C Jensen, Stanley R Riddell, Dirk H Busch
The adoptive transfer of T cells that have been genetically modified to express a CD19-specific chimeric antigen receptor (CAR) is effective for treating human B cell malignancies. However, the persistence of functional CD19 CAR T cells causes sustained depletion of endogenous CD19+ B cells and hypogammaglobulinemia. Thus, there is a need for a mechanism to ablate transferred T cells after tumor eradication is complete to allow recovery of normal B cells. Previously, we developed a truncated version of the epidermal growth factor receptor (EGFRt) that is coexpressed with the CAR on the T cell surface...
October 17, 2016: Journal of Clinical Investigation
Linan Wang, Ning Ma, Sachiko Okamoto, Yasunori Amaishi, Eiichi Sato, Naohiro Seo, Junichi Mineno, Kazutoh Takesako, Takuma Kato, Hiroshi Shiku
Carcinoembryonic antigen (CEA) is a cell surface antigen highly expressed in various cancer cell types and in healthy tissues. It has the potential to be a target for chimeric antigen receptor (CAR)-modified T-cell therapy; however, the safety of this approach in terms of on-target/off-tumor effects needs to be determined. To address this issue in a clinically relevant model, we used a mouse model in which the T cells expressing CEA-specific CAR were transferred into tumor-bearing CEA-transgenic (Tg) mice that physiologically expressed CEA as a self-antigen...
2016: Oncoimmunology
Noelle V Frey, David L Porter
Chimeric antigen receptors (CARs) are engineered molecules that can be introduced into T cells to enable them to target specific tumor antigens. CAR T cells targeting CD19 have shown promise in patients with relapsed and refractory B-cell neoplasms, including those with acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphomas. Notably, durable responses have been observed in patients who had not undergone consolidative stem cell transplant, a finding that correlates with reports of T-cell persistence and B-cell aplasia in studies of anti-CD19 treatment in vivo...
October 15, 2016: Oncology (Williston Park, NY)
Leonardo Solaini, Bambang T Atmaja, Prabhu Arumugam, Robert R Hutchins, Ajit T Abraham, Satyajit Bhattacharya, Hemant M Kocher
BACKGROUND: We aim to evaluate the prognostic value of preoperative and postoperative inflammatory systems in patients who had undergone surgery for colorectal liver metastases, focusing our analysis on the role of C-reactive protein-to-albumin ratio (CAR) and Glasgow prognostic score (GPS). METHODS: A total of 194 patients were enrolled onto this study. Demographics, tumor-related variables, preoperative and postoperative (day 1) inflammatory variables were analyzed as potential prognostic factors...
October 11, 2016: International Journal of Surgery
Preeti Sharma, David M Kranz
Adoptive T-cell therapies have shown exceptional promise in the treatment of cancer, especially B-cell malignancies. Two distinct strategies have been used to redirect the activity of ex vivo engineered T cells. In one case, the well-known ability of the T-cell receptor (TCR) to recognize a specific peptide bound to a major histocompatibility complex molecule has been exploited by introducing a TCR against a cancer-associated peptide/human leukocyte antigen complex. In the other strategy, synthetic constructs called chimeric antigen receptors (CARs) that contain antibody variable domains (single-chain fragments variable) and signaling domains have been introduced into T cells...
2016: F1000Research
Michele Moschetta, Yawara Kawano, Klaus Podar
Unprecedented advances in multiple myeloma (MM) therapy during the last 15 years are predominantly based on our increasing understanding of the pathophysiologic role of the bone marrow (BM) microenvironment. Indeed, new treatment paradigms, which incorporate thalidomide, immunomodulatory drugs (IMiDs), and proteasome inhibitors, target the tumor cell as well as its BM microenvironment. Ongoing translational research aims to understand in more detail how disordered BM-niche functions contribute to MM pathogenesis and to identify additional derived targeting agents...
2016: Cancer Treatment and Research
Michael Boice, Darin Salloum, Frederic Mourcin, Viraj Sanghvi, Rada Amin, Elisa Oricchio, Man Jiang, Anja Mottok, Nicolas Denis-Lagache, Giovanni Ciriello, Wayne Tam, Julie Teruya-Feldstein, Elisa de Stanchina, Wing C Chan, Sami N Malek, Daisuke Ennishi, Renier J Brentjens, Randy D Gascoyne, Michel Cogné, Karin Tarte, Hans-Guido Wendel
The HVEM (TNFRSF14) receptor gene is among the most frequently mutated genes in germinal center lymphomas. We report that loss of HVEM leads to cell-autonomous activation of B cell proliferation and drives the development of GC lymphomas in vivo. HVEM-deficient lymphoma B cells also induce a tumor-supportive microenvironment marked by exacerbated lymphoid stroma activation and increased recruitment of T follicular helper (TFH) cells. These changes result from the disruption of inhibitory cell-cell interactions between the HVEM and BTLA (B and T lymphocyte attenuator) receptors...
October 6, 2016: Cell
C J DeSelm, M Hamieh, M Sadelain
No abstract text is available yet for this article.
October 1, 2016: International Journal of Radiation Oncology, Biology, Physics
M A Cortez, A B Korngold, D R Valdecanas, H G Caruso, S Niknam, L Cooper, J W Welsh
No abstract text is available yet for this article.
October 1, 2016: International Journal of Radiation Oncology, Biology, Physics
B J Hughes, J Thomas, A M Lynch, S J Borghoff, S Green, T Mensing, S S Sarang, M J LeBaron
In a National Toxicology Program (NTP) chronic inhalation study with methyl isobutyl ketone (MIBK), increases in hepatocellular adenomas and hepatocellular adenomas and carcinomas (combined) were observed in male and female B6C3F1 mice at 1800 ppm. A DNA reactive Mode-of-Action (MOA) for this liver tumor response is not supported by the evidence as MIBK and its major metabolites lack genotoxicity in both in vitro and in vivo studies. Constitutive androstane receptor (CAR) nuclear receptor-mediated activation has been hypothesized as the MOA for MIBK-induced mouse liver tumorigenesis...
September 21, 2016: Regulatory Toxicology and Pharmacology: RTP
Eelco F M Wijdicks, Axel Karenberg
The history of Neurocinema includes neuroethics, and this theme was first used in 2 films released in the 1940s in both Germany and the United States. Ich Klage An (I Accuse) is about "terminal" multiple sclerosis in a young woman and the decision to determine one's own fate. The protagonist anticipates becoming "deaf, blind, and idiotic" and asks her husband to administer a toxic drug dose, which he does. The film disturbingly suggests that the diagnosis of multiple sclerosis is tantamount to a death sentence...
September 20, 2016: Neurology
Challice L Bonifant, Hollie J Jackson, Renier J Brentjens, Kevin J Curran
T cells can be genetically modified to target tumors through the expression of a chimeric antigen receptor (CAR). Most notably, CAR T cells have demonstrated clinical efficacy in hematologic malignancies with more modest responses when targeting solid tumors. However, CAR T cells also have the capacity to elicit expected and unexpected toxicities including: cytokine release syndrome, neurologic toxicity, "on target/off tumor" recognition, and anaphylaxis. Theoretical toxicities including clonal expansion secondary to insertional oncogenesis, graft versus host disease, and off-target antigen recognition have not been clinically evident...
2016: Molecular Therapy Oncolytics
Ahmed Z Gad, Shahenda El-Naggar, Nabil Ahmed
Over the last two decades, harnessing the power of the immune system has shown substantial promise. Specifically, the successes that chimeric antigen receptor (CAR) T cells achieved in the treatment of hematologic malignancies provided a concrete platform for further development in solid tumors. Considering that the latter contribute more than three quarters of cancer-related deaths in humans makes it clear that solid tumors represent the larger medical challenge, but also the larger developmental promise in the market...
November 2016: Cytotherapy
Shou-Hui Du, Zhendong Li, Can Chen, Wee-Kiat Tan, Zhixia Chi, Timothy Weixin Kwang, Xue-Hu Xu, Shu Wang
Gamma delta (γδ) T cells and cytokine-induced killer (CIK) cells, which are a heterogeneous population of T lymphocytes and natural killer T (NKT) cells, have been separately expanded ex vivo and shown to be capable of targeting and mediating cytotoxicity against various tumor cells in a major histocompatibility complex-unrestricted manner. However, the co-expansion and co-administration of these immune cells have not been explored. In this study we describe an efficient method to expand simultaneously both CIK and Vγ9Vδ2 T cells, termed as CIKZ cells, from human peripheral blood mononuclear cells (PBMCs) using Zometa, interferon-gamma (IFN-γ), interleukin 2 (IL-2), anti-CD3 antibody and engineered K562 feeder cells expressing CD64, CD137L and CD86...
2016: PloS One
Mark B Geyer, Renier J Brentjens
The past several years have been marked by extraordinary advances in clinical applications of immunotherapy. In particular, adoptive cellular therapy utilizing chimeric antigen receptor (CAR)-modified T cells targeted to CD19 has demonstrated substantial clinical efficacy in children and adults with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) and durable clinical benefit in a smaller subset of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or B-cell non-Hodgkin lymphoma (B-NHL)...
November 2016: Cytotherapy
Chunmeng Wang, Zhiqiang Wu, Yao Wang, Yelei Guo, Hanren Dai, Xiao-Hui Wang, Xiang Li, Ya-Jing Zhang, Wen-Ying Zhang, Mei-Xia Chen, Yan Zhang, Kai-Chao Feng, Yang Liu, Su-Xia Li, Qing-Ming Yang, Weidong Han
PURPOSE: Relapsed or refractory Hodgkin's lymphoma is a challenge for medical oncologists because of poor overall survival. We aimed to assess the feasibility, safety, and efficacy of CD30-targeting CAR T cells in patients with progressive relapsed or refractory HL. EXPERIMENTAL DESIGN: Patients with relapsed or refractory HL received a conditioning chemotherapy followed by the CART-30 cell infusion. The level of CAR transgenes in peripheral blood and biopsied tumor tissues was measured periodically according to an assigned protocol by quantitative Polymerase Chain Reaction...
August 31, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Joanne A Hammill, Arya Afsahi, Jonathan L Bramson, Christopher W Helsen
The adoptive transfer of a bolus of tumor-specific T lymphocytes into cancer patients is a promising therapeutic strategy. In one approach, tumor specificity is conferred upon T cells via engineering expression of exogenous receptors, such as chimeric antigen receptors (CARs). Here, we describe the generation and production of both murine and human CAR-engineered T lymphocytes using retroviruses.
2016: Methods in Molecular Biology
Adrienne H Long, Steven L Highfill, Yongzhi Cui, Jillian P Smith, Alec J Walker, Sneha Ramakrishna, Rana El-Etriby, Susana Galli, Maria G Tsokos, Rimas J Orentas, Crystal L Mackall
Genetically engineered T cells expressing CD19-specific chimeric antigen receptors (CAR) have shown impressive activity against B-cell malignancies, and preliminary results suggest that T cells expressing a first-generation disialoganglioside (GD2)-specific CAR can also provide clinical benefit in patients with neuroblastoma. We sought to assess the potential of GD2-CAR therapies to treat pediatric sarcomas. We observed that 18 of 18 (100%) of osteosarcomas, 2 of 15 (13%) of rhabdomyosarcomas, and 7 of 35 (20%) of Ewing sarcomas expressed GD2...
October 2016: Cancer Immunology Research
Radhika Thokala, Simon Olivares, Tiejuan Mi, Sourindra Maiti, Drew Deniger, Helen Huls, Hiroki Torikai, Harjeet Singh, Richard E Champlin, Tamara Laskowski, George McNamara, Laurence J N Cooper
Adoptive immunotherapy infusing T cells with engineered specificity for CD19 expressed on B- cell malignancies is generating enthusiasm to extend this approach to other hematological malignancies, such as acute myelogenous leukemia (AML). CD123, or interleukin 3 receptor alpha, is overexpressed on most AML and some lymphoid malignancies, such as acute lymphocytic leukemia (ALL), and has been an effective target for T cells expressing chimeric antigen receptors (CARs). The prototypical CAR encodes a VH and VL from one monoclonal antibody (mAb), coupled to a transmembrane domain and one or more cytoplasmic signaling domains...
2016: PloS One
Andreas A Hombach, Hinrich Abken
INTRODUCTION: Adoptive therapy with chimeric antigen receptor (CAR) T cells redirected towards CD19 produces remissions of B cell malignancies, however, it also eradicates healthy B cells sharing the target antigen. Such 'on-target off-tumor' toxicity raises serious safety concerns when the target antigen is also expressed by tissue stem cells, with the risk of lasting tissue destruction. AREAS COVERED: We discuss CAR T cell targeting of activation antigens versus lineage associated antigens on the basis of recent experimental and animal data and the literature in the field...
August 22, 2016: Expert Review of Clinical Immunology
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