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CAR immune therapy

Malak Abedalthagafi, Duna Barakeh, Kara M Foshay
The prognosis of glioblastoma has changed little over the past two decades, with only minor improvements in length of overall survival through the addition of temozolomide (temodal) to standard of care and the recommended use of alternating electric field therapy (optune) to newly diagnosed patients. In an effort to define novel therapeutic targets across molecularly heterogeneous disease subgroups, researchers have begun to uncover the complex interplay between epigenetics, cell signaling, metabolism, and the immunosuppressive tumor microenvironment...
2018: NPJ Precision Oncology
Amber Tahir
Clinical trials with chimeric antigen receptor (CAR) T-cell therapy in oncology have been promising. The spectrum of this novel therapy is being expanded to include autoimmunity. It ensures "targeted treatment," resulting in more selective outcomes, fewer toxic effects, and a permanent restoration of immune system imbalance. The preliminary results of preclinical and clinical studies support the application of CAR therapy in autoimmunity, especially in regulating adverse autoimmune responses. This novel therapy should be considered for the treatment of autoimmune diseases and further clinical studies should be conducted to study all aspects of this treatment modality...
October 3, 2018: Curēus
Srinivas Ramishetti, Dan Peer
Lymphocytes are the gatekeepers of the body's immune system and are involved in pathogenesis if their surveillance is stalled by inhibitory molecules or when they act as mediators for viral entry. Engineering lymphocytes in order to restore their functions is an unmet need in immunological disorders, cancer and in lymphotropic viral infections. Recently, the FDA approved several therapeutic antibodies for blocking inhibitory signals on T cells. This has revolutionized the field of solid tumor care, together with chimeric antigen receptor T cell (CAR-T) therapy that did the same for hematological malignancies...
December 5, 2018: Advanced Drug Delivery Reviews
Sonia Guedan, Marco Ruella, Carl H June
Genetically engineered T cells are powerful new medicines, offering hope for curative responses in patients with cancer. Chimeric antigen receptor (CAR) T cells were recently approved by the US Food and Drug Administration and are poised to enter the practice of medicine for leukemia and lymphoma, demonstrating that engineered immune cells can serve as a powerful new class of cancer therapeutics. The emergence of synthetic biology approaches for cellular engineering provides a broadly expanded set of tools for programming immune cells for enhanced function...
December 10, 2018: Annual Review of Immunology
Wanghong Hu, Zhenguo Zi, Yanling Jin, Gaoxin Li, Kang Shao, Qiliang Cai, Xiaojing Ma, Fang Wei
The interaction between programmed cell death protein 1 (PD-1) on activated T cells and its ligands on a target tumour may limit the capacity of chimeric antigen receptor (CAR) T cells to eradicate solid tumours. PD-1 blockade could potentially enhance CAR T cell function. Here, we show that mesothelin is overexpressed in human triple-negative breast cancer cells and can be targeted by CAR T cells. To overcome the suppressive effect of PD-1 on CAR T cells, we utilized CRISPR/Cas9 ribonucleoprotein-mediated editing to disrupt the programmed cell death-1 (PD-1) gene locus in human primary T cells, resulting in a significantly reduced PD-1hi population...
December 6, 2018: Cancer Immunology, Immunotherapy: CII
(no author information available yet)
For patients with B-cell malignancies who experience poor initial responses to chimeric antigen receptor T-cell therapy, the addition of immune checkpoint blockade may prove beneficial, according to clinical reports presented at the 2018 American Society of Hematology Annual Meeting.
December 6, 2018: Cancer Discovery
Bruno L Ferreyro, Laveena Munshi
PURPOSE OF REVIEW: A wide spectrum of heterogeneous conditions can render a patient immunocompromised. Recent years have seen an increase in the number of immunocompromised patients given the earlier detection of conditions that require immunosuppressive therapies, changes in immunosuppressive regimens leading to increased survival or novel therapeutic advancements in oncologic care. Acute respiratory failure (ARF) is the leading cause of critical illness and mortality in this population...
December 3, 2018: Current Opinion in Critical Care
Walid Warda, Fabrice Larosa, Mathieu Neto Da Rocha, Rim Trad, Eric Deconinck, Ziad Fajloun, Cyril Faure, Denis Caillot, Marius Moldovan, Severine Valmary-Degano, Sabeha Biichle, Etienne Daguindau, Francine Garnache-Ottou, Sebastien Tabruyn, Olivier Adotévi, Marina Deschamps, Christophe Ferrand
Chronic myeloid leukemia (CML) is a chronic disease resulting in myeloid cell expansion through expression of the BCR-ABL1 fusion transcript. Tyrosine kinase inhibitors (TKI) have significantly increased survival of CML patients, and deep responders may consider stopping the treatment. However, more than 50% of patients relapse and restart TKI, subsequently suffering unknown toxicity. Because CML is a model immune system-sensitive disease, we hypothesize that chimeric antigen receptor (CAR) T cells targeting interleukin-1 receptor-associated protein (IL-1RAP) in quiescent CML stem cells may offer an opportunity for a permanent cure...
December 4, 2018: Cancer Research
Stephen J Schuster, Michael R Bishop, Constantine S Tam, Edmund K Waller, Peter Borchmann, Joseph P McGuirk, Ulrich Jäger, Samantha Jaglowski, Charalambos Andreadis, Jason R Westin, Isabelle Fleury, Veronika Bachanova, S Ronan Foley, P Joy Ho, Stephan Mielke, John M Magenau, Harald Holte, Serafino Pantano, Lida B Pacaud, Rakesh Awasthi, Jufen Chu, Özlem Anak, Gilles Salles, Richard T Maziarz
BACKGROUND: Patients with diffuse large B-cell lymphoma that is refractory to primary and second-line therapies or that has relapsed after stem-cell transplantation have a poor prognosis. The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel targets and eliminates CD19-expressing B cells and showed efficacy against B-cell lymphomas in a single-center, phase 2a study. METHODS: We conducted an international, phase 2, pivotal study of centrally manufactured tisagenlecleucel involving adult patients with relapsed or refractory diffuse large B-cell lymphoma who were ineligible for or had disease progression after autologous hematopoietic stem-cell transplantation...
December 1, 2018: New England Journal of Medicine
Navneet S Majhail, Rajshekhar Chakraborty, Gunjan L Shah, Betty K Hamilton, Michael Scordo, Surbhi Sidana
Patient-reported outcomes (PROs) are an important tool to assess the impact of a new therapy on symptom burden and health-related quality of life (HRQoL). Chimeric Antigen Receptor-T (CAR-T) cell therapies have been approved for use in relapsed or refractory leukemia and lymphoma based on promising efficacy in clinical trials. However, there is a lack of data on patient-reported toxicity and impact on HRQoL. This review provides an overview of the incorporation of PROs in CAR-T cell therapy and the specific challenges in this context...
November 27, 2018: Biology of Blood and Marrow Transplantation
Maartje W Rohaan, Sofie Wilgenhof, John B A G Haanen
For many cancer types, the immune system plays an essential role in their development and growth. Based on these rather novel insights, immunotherapeutic strategies have been developed. In the past decade, immune checkpoint blockade has demonstrated a major breakthrough in cancer treatment and has currently been approved for the treatment of multiple tumor types. Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) or gene-modified T cells expressing novel T cell receptors (TCR) or chimeric antigen receptors (CAR) is another strategy to modify the immune system to recognize tumor cells and thus carry out an anti-tumor effector function...
November 23, 2018: Virchows Archiv: An International Journal of Pathology
Andrea Schmidts, Marcela V Maus
Adoptive cell therapy with chimeric antigen receptor (CAR) T cells aims to redirect the patient's own immune system to selectively attack cancer cells. To do so, CAR T cells are endowed with specific antigen recognition moieties fused to signaling and costimulatory domains. While this approach has shown great success for the treatment of B cell malignancies, response rates among patients with solid cancers are less favorable. The major challenges for CAR T cell immunotherapy in solid cancers are the identification of unique tumor target antigens, as well as improving CAR T cell trafficking to and expansion at the tumor site...
2018: Frontiers in Immunology
Yan Leyfman
Background: Chimeric antigen receptors (CARs) represent a novel facet of modern day synthetic biology that exemplifies personalized medicine at work through their ability to harness and redirect a patient's immune system to fight cancer. Body: By combining the target-specificity of antibodies to the effector capabilities of T cells, CARs have yielded high remission rates for many late staged and relapsed/refractory (r/r) hematological malignancies, including acute lymphoblastic leukemias (ALL) and Non-Hodgkin's lymphomas...
2018: Cancer Cell International
Yixin Zou, Wei Xu, Jianyong Li
Chronic lymphocytic leukemia (CLL), a common type of B cell chronic lymphoproliferative disorder in adults, has witnessed enormous development in its treatment in recent years. New drugs such as ibrutinib, idelalisib, and venetoclax have achieved great success in treating relapsed and refractory (R/R) CLL. In addition, with the development of immunotherapy, chimeric antigen receptor-engineered T cells (CAR-T) therapy, a novel adoptive immune treatment, has also become more and more important in treating R/R CLL...
November 20, 2018: Journal of Hematology & Oncology
Bryan D Choi, Marcela V Maus, Carl H June, John H Sampson
Glioblastoma (GBM) is a devastating disease with an extremely poor prognosis. Immune therapy via adoptive cell transfer (ACT), especially with T cells engineered to express chimeric antigen receptors (CARs), represents a particularly promising approach. Despite the recent success of CAR T cells for blood cancers, the question remains whether this powerful anti-cancer therapy will ultimately work for brain tumors, and if the primary immunologic challenges in this disease-which include antigenic heterogeneity, immune suppression and T-cell exhaustion-can be adequately addressed...
November 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Sushmita Nair, Jing-Bo Wang, Shih-Ting Tsao, Yuchen Liu, Wei Zhu, William B Slayton, Jan S Moreb, Lujia Dong, Lung-Ji Chang
Recent studies of CD19-specific chimeric antigen receptor (CAR)-modified T cells (CARTs) have demonstrated unprecedented successes in treating refractory and relapsed B cell malignancies. The key to the latest CART therapy advances can be attributed to the improved co-stimulatory signals in the CAR design. Here we established several novel CARs by incorporating T cell signaling domains of CD28 in conjunction with intracellular signaling motif of 4-1BB, CD27, OX40, ICOS, and IL-15Rα. These novel CARs were functionally assessed based on a simple target cell killing assay...
November 15, 2018: Current Gene Therapy
Przemyslaw Wielgat, Emil Trofimiuk, Robert Czarnomysy, Jan J Braszko, Halina Car
Glucocorticosteroids, including dexamethasone (Dex), are commonly used to control tumor-induced edema in the brain tumor patients. There are increasing evidences that immunosuppressive action of Dex interferes with immune surveillance resulting in lower patients overall survival; however, the mechanisms underlying these actions remain unclear. Changes in the expression of sialic acids are critical features of many cancers that reduce their immunogenicity and increase viability. Sialoglycans can be recognized by CD33-related Siglecs that negatively regulate the immune response and thereby impair immune surveillance...
November 15, 2018: Molecular and Cellular Biochemistry
Carl DeSelm, M Lia Palomba, Joachim Yahalom, Mohamad Hamieh, Justin Eyquem, Vinagolu K Rajasekhar, Michel Sadelain
CD19 chimeric antigen receptors (CARs) have demonstrated great efficacy against a range of B cell malignancies. However, antigen escape and, more generally, heterogeneous antigen expression pose a challenge to applying CAR therapy to a wide range of cancers. We find that low-dose radiation sensitizes tumor cells to immune rejection by locally activated CAR T cells. In a model of pancreatic adenocarcinoma heterogeneously expressing sialyl Lewis-A (sLeA), we show that not only sLeA+ but also sLeA- tumor cells exposed to low-dose radiation become susceptible to CAR therapy, reducing antigen-negative tumor relapse...
November 7, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Qing Zhang, Haixu Zhang, Jiage Ding, Hongyan Liu, Huizhong Li, Hailong Li, Mengmeng Lu, Yangna Miao, Liantao Li, Junnian Zheng
Adoptive chimeric antigen receptor-modified T or NK cells (CAR-T or CAR-NK) offer new options for cancer treatment. CAR-T therapy has achieved encouraging breakthroughs in the treatment of hematological malignancies. However, their therapeutic efficacy against solid tumors is limited. New regimens, including combinations with chemical drugs, need to be studied to enhance the therapeutic efficacy of CAR-T or NK cells for solid tumors. An epithelial cell adhesion molecule- (EpCAM-) specific second-generation CAR was constructed and transduced into NK-92 cells by lentiviral vectors...
2018: Journal of Immunology Research
Mohammad Yousef Memar, Mina Yekani, Naser Alizadeh, Hossein Bannazadeh Baghi
Hyperbaric oxygen therapy (HBOT) is a treatment procedure that involves breathing 100% O2 for a certain time and under a certain pressure. HBOT is commonly administrated as a primary or alternative therapy for different diseases such as infections. In this paper, we reviewed the general aspect of HBOT procedures, the mechanisms of antimicrobial effects and the application in the treatment of infections. Parts of the antimicrobial effects of HBOT are believed to result of reactive from the formation of reactive oxygen species (ROS)...
November 3, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
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