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Chimeric Antigen Receptor T cells

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https://www.readbyqxmd.com/read/28533272/chimeric-pd-1-28-receptor-upgrades-low-avidity-t-cells-and-restores-effector-function-of-tumor-infiltrating-lymphocytes-for-adoptive-cell-therapy
#1
Ramona Schlenker, Luis Felipe Olguín-Contreras, Matthias Leisegang, Julia Schnappinger, Anja Disovic, Svenja Rühland, Peter J Nelson, Heinrich Leonhardt, Hartmann Harz, Susanne Wilde, Dolores J Schendel, Wolfgang Uckert, Gerald Willimsky, Elfriede Noessner
Inherent intermediate-to-low affinity T cell receptors (TCR) that develop during the natural course of immune responses may not allow sufficient activation for tumor elimination, making the majority of T cells suboptimal for adoptive T cell therapy (ATT). TCR affinity enhancement has been implemented to provide stronger T cell activity but carries the risk of creating undesired cross-reactivity leading to potential serious adverse effects in clinical application. We demonstrate here that engineering of low-avidity T cells recognizing a naturally processed and presented tumor-associated antigen with a chimeric PD-1:28 receptor increases effector function to levels seen with high-avidity T cells of identical specificity...
May 22, 2017: Cancer Research
https://www.readbyqxmd.com/read/28529898/preclinical-rationale-for-combining-radiation-therapy-and-immunotherapy-beyond-checkpoint-inhibitors-i-e-cart
#2
REVIEW
James P Flynn, Mark H O'Hara, Saumil J Gandhi
An increasing appreciation for the role of the immune system in targeting cancer cells over the last decade has led to the development of several immunomodulatory agents aimed at enhancing the systemic antitumor immune response. One such method is the use of T cells that are genetically engineered to express chimeric antigen receptors (CARs). The remarkable success of this approach in advanced hematologic malignancies has garnered much enthusiasm for using this novel tool in treating other cancers. However, multiple challenges have hampered the application of this therapy to a broader set of solid tumors, most notably lung cancer...
April 2017: Translational Lung Cancer Research
https://www.readbyqxmd.com/read/28515942/a-tandem-cd19-cd20-car-lentiviral-vector-drives-on-target-and-off-target-antigen-modulation-in-leukemia-cell-lines
#3
Dina Schneider, Ying Xiong, Darong Wu, Volker Nӧlle, Sarah Schmitz, Waleed Haso, Andrew Kaiser, Boro Dropulic, Rimas J Orentas
BACKGROUND: Clinical success with chimeric antigen receptor (CAR)- based immunotherapy for leukemia has been accompanied by the associated finding that antigen-escape variants of the disease are responsible for relapse. To target hematologic malignancies with a chimeric antigen receptor (CAR) that targets two antigens with a single vector, and thus potentially lessen the chance of leukemic escape mutations, a tandem-CAR approach was investigated. METHODS: Antigen binding domains from the FMC63 (anti-CD19) and Leu16 (anti-CD20) antibodies were linked in differing configurations to transmembrane and T cell signaling domains to create tandem-CARs...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28514768/driving-better-and-safer-her2-specific-cars-for-cancer-therapy
#4
REVIEW
Xianqiang Liu, Nan Zhang, Huan Shi
Given the clinical efficacy of chimeric antigen receptor (CAR)-based therapy in hematological malignancies, CAR T-cell therapy for a number of solid tumors has been actively investigated. Human epidermal growth factor receptor 2 (HER2) is a well-established therapeutic target in breast, as well as other types of cancer. However, HER2 CAR T cells pose a risk of lethal toxicity including cytokine release syndrome from "on-target, off-tumor" recognition of HER2. In this review, we summarize the development of conventional HER2 CAR technology, the alternative selection of CAR hosts, the novel HER2 CAR designs, clinical studies and toxicity...
April 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28507794/a-novel-nanobody-based-target-module-for-retargeting-of-t-lymphocytes-to-egfr-expressing-cancer-cells-via-the-modular-unicar-platform
#5
Susann Albert, Claudia Arndt, Anja Feldmann, Ralf Bergmann, Dominik Bachmann, Stefanie Koristka, Florian Ludwig, Pauline Ziller-Walter, Alexandra Kegler, Sebastian Gärtner, Marc Schmitz, Armin Ehninger, Marc Cartellieri, Gerhard Ehninger, Hans-Jürgen Pietzsch, Jens Pietzsch, Jörg Steinbach, Michael Bachmann
Recent treatments of leukemias with chimeric antigen receptor (CAR) expressing T cells underline their impressive therapeutic potential. However, once adoptively transferred into patients, there is little scope left to shut them down after elimination of tumor cells or in case adverse side effects occur. This becomes of special relevance if they are directed against commonly expressed tumor associated antigens (TAAs) such as receptors of the ErbB family. To overcome this limitation, we recently established a modular CAR platform technology termed UniCAR...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28506593/a-rational-strategy-for-reducing-on-target-off-tumor-effects-of-cd38-chimeric-antigen-receptors-by-affinity-optimization
#6
Esther Drent, Maria Themeli, Renée Poels, Regina de Jong-Korlaar, Huipin Yuan, Joost de Bruijn, Anton C M Martens, Sonja Zweegman, Niels W C J van de Donk, Richard W J Groen, Henk M Lokhorst, Tuna Mutis
Chimeric antigen receptors (CARs) can effectively redirect cytotoxic T cells toward highly expressed surface antigens on tumor cells. The low expression of several tumor-associated antigens (TAAs) on normal tissues, however, hinders their safe targeting by CAR T cells due to on-target/off-tumor effects. Using the multiple myeloma (MM)-associated CD38 antigen as a model system, here, we present a rational approach for effective and tumor-selective targeting of such TAAs. Using "light-chain exchange" technology, we combined the heavy chains of two high-affinity CD38 antibodies with 176 germline light chains and generated ∼124 new antibodies with 10- to >1,000-fold lower affinities to CD38...
May 13, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28506444/monocyte-lineage-derived-il-6-does-not-affect-chimeric-antigen-receptor-t-cell-function
#7
Nathan Singh, Ted J Hofmann, Zachary Gershenson, Bruce L Levine, Stephan A Grupp, David T Teachey, David M Barrett
BACKGROUND AIMS: Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 has demonstrated remarkable success in targeting B-cell malignancies but is often complicated by serious systemic toxicity in the form of cytokine release syndrome (CRS). CRS symptoms are primarily mediated by interleukin 6 (IL-6), and clinical management has focused on inhibition of IL-6 signaling. The cellular source and function of IL-6 in CRS remain unknown. METHODS: Using co-culture assays and data from patients on our clinical CAR T-cell trials, we investigated the cellular source of IL-6, as well as other CRS-associated cytokines, during CAR T-cell activation...
May 11, 2017: Cytotherapy
https://www.readbyqxmd.com/read/28502785/car-t-cell-therapy-for-lung-cancer-and-malignant-pleural-mesothelioma
#8
REVIEW
Masha Zeltsman, Jordan Dozier, Erin McGee, Daniel Ngai, Prasad S Adusumilli
Immunotherapy is a promising field that harnesses the power of the immune system as a therapeutic agent for cancer treatment. Beneficial outcomes shown in patients with non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM) with relatively higher tumor-infiltrating T cells, combined with impressive responses obtained in a cohort of patients with NSCLC following checkpoint blockade therapy, lays a strong foundation to promote effector immune responses in these patients. One such approach being investigated is administration of tumor antigen-targeted T cells with transduction of a chimeric antigen receptor (CAR)...
April 26, 2017: Translational Research: the Journal of Laboratory and Clinical Medicine
https://www.readbyqxmd.com/read/28497159/current-status-of-chimeric-antigen-receptor-engineered-t-cell-based-and-immune-checkpoint-blockade-based-cancer-immunotherapies
#9
REVIEW
Upendra P Hegde, Bijay Mukherji
Adoptive cell therapies with chimeric antigen receptor (CAR) engineered T cells (CAR-T) and immune checkpoint inhibition (ICI)-based cancer immunotherapies have lately shown remarkable success in certain tumor types. CAR-T cell-based therapies targeting CD19 can now induce durable remissions as well as prolong disease-free survival of patients with CD19 positive treatment refractory B cell malignancies and ICI-based therapies with humanized monoclonal antibodies against the T cell inhibitory receptors CTLA-4 and PD-1 as well as against the PD-1 ligand, PD-L1, can now achieve durable remissions as well as prolongation of life of a sizeable fraction of patients with melanoma and Hodgkin's lymphoma and non-small cell cancers...
May 11, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28496440/fc%C3%AE-chimeric-receptor-engineered-t-cells-methodology-advantages-limitations-and-clinical-relevance
#10
REVIEW
Sara Caratelli, Tommaso Sconocchia, Roberto Arriga, Andrea Coppola, Giulia Lanzilli, Davide Lauro, Adriano Venditti, Maria Ilaria Del Principe, Francesco Buccisano, Luca Maurillo, Soldano Ferrone, Giuseppe Sconocchia
For many years, disappointing results have been generated by many investigations, which have utilized a variety of immunologic strategies to enhance the ability of a patient's immune system to recognize and eliminate malignant cells. However, in recent years, immunotherapy has been used successfully for the treatment of hematologic and solid malignancies. The impressive clinical responses observed in many types of cancer have convinced even the most skeptical clinical oncologists that a patient's immune system can recognize and reject his tumor if appropriate strategies are implemented...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28496177/targeting-flt3-by-chimeric-antigen-receptor-t-cells-for-the-treatment-of-acute-myeloid-leukemia
#11
L Chen, H Mao, J Zhang, J Chu, S Devine, M A Caligiuri, J Yu
Leukemia accepted article preview online, 12 May 2017. doi:10.1038/leu.2017.147.
May 12, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28494200/a-new-therapeutic-potential-for-cancers-one-car-with-2-different-engines
#12
Abdolkarim Sheikhi, Abdollah Jafarzadeh
Tumor cells escape from immune recognition by several mechanisms such as down-regulating of MHC class I molecules, losing of tumor antigens, etc. The purpose of cancer immunotherapy is to robust or reconstruct the capacity of the immune system to recognize and kill tumor cells by overwhelming the mechanisms by which tumors escape the immune response. One of the novel immunotherapeutic strategies were used to potentiate NK- and T cell functions is chimeric antigen receptor (CAR). CARs are composed of an antigen-binding domain of a molecule such as an antibody (that binds to a tumor associated antigens expressed on the surface of tumor cells) and an intracellular T cell activation domain...
May 11, 2017: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/28488245/chimeric-antigen-receptor-car-modified-natural-killer-cell-based-immunotherapy-and-immunological-synapse-formation-in-cancer-and-hiv
#13
REVIEW
Dongfang Liu, Shuo Tian, Kai Zhang, Wei Xiong, Ndongala Michel Lubaki, Zhiying Chen, Weidong Han
Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells contribute to the body's immune defenses. Current chimeric antigen receptor (CAR)-modified T cell immunotherapy shows strong promise for treating various cancers and infectious diseases. Although CAR-modified NK cell immunotherapy is rapidly gaining attention, its clinical applications are mainly focused on preclinical investigations using the NK92 cell line. Despite recent advances in CAR-modified T cell immunotherapy, cost and severe toxicity have hindered its widespread use...
May 9, 2017: Protein & Cell
https://www.readbyqxmd.com/read/28483281/preclinical-data-support-leveraging-cs1-chimeric-antigen-receptor-t-cell-therapy-for-systemic-light-chain-amyloidosis
#14
Michael Rosenzweig, Ryan Urak, Miriam Walter, Laura Lim, James F Sanchez, Amrita Krishnan, Stephen Forman, Xiuli Wang
BACKGROUND AIMS: Light chain amyloidosis (AL) is a protein deposition disorder that is a result of a plasma cell dyscrasia, similar to multiple myeloma (MM). Immunotherapy is an attractive approach because of the low burden of disease, but the optimal target for AL is unclear. CS1 and B-cell maturation antigen (BCMA) are two potential targets because they are expressed on normal plasma cells and MM cells. METHODS: We performed a prospective study evaluating bone marrow specimens of 20 patients with plasma cell diseases, 10 with AL and 10 with MM...
May 5, 2017: Cytotherapy
https://www.readbyqxmd.com/read/28482671/advances-in-evidence-based-cancer-adoptive-cell-therapy
#15
Chunlei Ge, Ruilei Li, Xin Song, Shukui Qin
Adoptive cell therapy (ACT) has been developed in cancer treatment by transferring/infusing immune cells into cancer patients, which are able to recognize, target, and destroy tumor cells. Recently, sipuleucel-T and genetically-modified T cells expressing chimeric antigen receptors (CAR) show a great potential to control metastatic castration-resistant prostate cancer and hematologic malignancies in clinic. This review summarized some of the major evidence-based ACT and the challenges to improve cell quality and reduce the side effects in the field...
April 2017: Chinese Clinical Oncology
https://www.readbyqxmd.com/read/28479045/balance-of-anti-cd123-chimeric-antigen-receptor-binding-affinity-and-density-for-the-targeting-of-acute-myeloid-leukemia
#16
Silvia Arcangeli, Maria Caterina Rotiroti, Marco Bardelli, Luca Simonelli, Chiara Francesca Magnani, Andrea Biondi, Ettore Biagi, Sarah Tettamanti, Luca Varani
Chimeric antigen receptor (CAR)-redirected T lymphocytes are a promising immunotherapeutic approach and object of pre-clinical evaluation for the treatment of acute myeloid leukemia (AML). We developed a CAR against CD123, overexpressed on AML blasts and leukemic stem cells. However, potential recognition of low CD123-positive healthy tissues, through the on-target, off-tumor effect, limits safe clinical employment of CAR-redirected T cells. Therefore, we evaluated the effect of context-dependent variables capable of modulating CAR T cell functional profiles, such as CAR binding affinity, CAR expression, and target antigen density...
May 3, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28474504/mouse-nidovirus-ldv-infection-alleviates-graft-versus-host-disease-and-induces-type-i-ifn-dependent-inhibition-of-dendritic-cells-and-allo-responsive-t-cells
#17
Mélanie Gaignage, Reece G Marillier, Catherine Uyttenhove, Nicolas Dauguet, Anubha Saxena, Bernard Ryffel, Thomas Michiels, Jean-Paul Coutelier, Jacques Van Snick
INTRODUCTION: Viruses have developed multiple mechanisms to alter immune reactions. In 1969, it was reported that lactate dehydrogenase-elevating virus (LDV), a single stranded positive sense mouse nidovirus, delays skin allograft rejection and inhibits spleen alterations in graft versus host disease (GVHD). As the underlying mechanisms have remained unresolved and given the need for new therapies of this disease, we reassessed the effects of the virus on GVHD and tried to uncover its mode of action...
June 2017: Immunity, Inflammation and Disease
https://www.readbyqxmd.com/read/28466386/current-status-and-perspectives-of-chimeric-antigen-receptor-modified-t-cells-for-cancer-treatment
#18
REVIEW
Zhenguang Wang, Yelei Guo, Weidong Han
Chimeric antigen receptor (CAR) is a recombinant immunoreceptor combining an antibody-derived targeting fragment with signaling domains capable of activating cells, which endows T cells with the ability to recognize tumor-associated surface antigens independent of the expression of major histocompatibility complex (MHC) molecules. Recent early-phase clinical trials of CAR-modified T (CAR-T) cells for relapsed or refractory B cell malignancies have demonstrated promising results (that is, anti-CD19 CAR-T in B cell acute lymphoblastic leukemia (B-ALL))...
May 2, 2017: Protein & Cell
https://www.readbyqxmd.com/read/28461969/engineering-chimeric-antigen-receptors
#19
S V Kulemzin, V V Kuznetsova, M Mamonkin, A V Taranin, A A Gorchakov
Chimeric antigen receptors (CARs) are recombinant protein molecules that redirect cytotoxic lymphocytes toward malignant and other target cells. The high feasibility of manufacturing CAR-modified lymphocytes for the therapy of cancer has spurred the development and optimization of new CAR T cells directed against a broad range of target antigens. In this review, we describe the main structural and functional elements constituting a CAR, discuss the roles of these elements in modulating the anti-tumor activity of CAR T cells, and highlight alternative approaches to CAR engineering...
January 2017: Acta Naturae
https://www.readbyqxmd.com/read/28456379/chimeric-antigen-receptors-a-cell-and-gene-therapy-perspective
#20
REVIEW
Isabelle Rivière, Michel Sadelain
Chimeric antigen receptors (CARs) are synthetic receptors that reprogram T lymphocytes to target chosen antigens. The targeting of CD19, a cell surface molecule expressed in the vast majority of leukemias and lymphomas, has been successfully translated in the clinic, earning CAR therapy a special distinction in the selection of "cancer immunotherapy" by Science as the breakthrough of the year in 2013. CD19 CAR therapy is predicated on advances in genetic engineering, T cell biology, tumor immunology, synthetic biology, target identification, cell manufacturing sciences, and regulatory compliance-the central tenets of CAR therapy...
May 3, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
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