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chimeric receptor

Na Fang, Niannian Zhong, Tingxuan Gu, Yahui Wang, Xiangqian Guo, Shaoping Ji
BACKGROUND: Adoptive cell therapy (ACT) based on chimeric antigen receptors (CARs) expressed on the surface of T cells shows a remarkable clinical outcome, particularly for B-cell malignancies. However, toxicity and side effects of CD19-redirected CAR T cells have been observed concurrently in most cases due to cytokine release and tumor cell lysis. Therefore, strictly controlling the amount of valid T cells re-transfused to patients seems to be an important step in reducing toxicity and side effects of CAR T cells...
December 5, 2018: Advances in Clinical and Experimental Medicine: Official Organ Wroclaw Medical University
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
Jiao Wang, Kyle B Lupo, Andrea M Chambers, Sandro Matosevic
BACKGROUND: The anti-tumor immunity of natural killer (NK) cells can be paralyzed by the CD73-induced generation of immunosuppressive adenosine from precursor ATP within the hypoxic microenvironment of solid tumors. In an effort to redirect purinergic immunosuppression of NK cell anti-tumor function, we showed, for the first time, that immunometabolic combination treatment with NKG2D-engineered CAR-NK cells alongside blockade of CD73 ectonucleotidase activity can result in significant anti-tumor responses in vivo...
December 4, 2018: Journal for Immunotherapy of Cancer
Michael M Boyiadzis, Madhav V Dhodapkar, Renier J Brentjens, James N Kochenderfer, Sattva S Neelapu, Marcela V Maus, David L Porter, David G Maloney, Stephan A Grupp, Crystal L Mackall, Carl H June, Michael R Bishop
Chimeric Antigen Receptor (CAR) T cell therapies - adoptive T cell therapies that have been genetically engineered for a new antigen-specificity - have displayed significant success in treating patients with hematologic malignancies, leading to three recent US Food and Drug Administration approvals. Based on the promise generated from these successes, the field is rapidly evolving to include new disease indications and CAR designs, while simultaneously reviewing and optimizing toxicity and management protocols...
December 4, 2018: Journal for Immunotherapy of Cancer
Elisabeth G Bjørnsen, Lavanya Thiruchelvam-Kyle, Sigurd E Hoelsbrekken, Camilla Henden, Per C Saether, Preben Boysen, Michael R Daws, Erik Dissen
NK cells kill cancer cells and infected cells upon activation by cell surface receptors. Human NKp30 is an activating receptor expressed by all mature NK cells. The B7 family member B7H6 has been identified as one ligand for NKp30. Several alternative ligands have also been reported, and the field remains unsettled. To this end, we have identified full-length functional B7H6 orthologs in rat and cattle, demonstrated by phylogenetic analysis and transfection experiments. In cell-cell contact-dependent assays, chimeric NKp30 reporter cells responded strongly to B7H6 in rat and cattle...
December 4, 2018: European Journal of Immunology
John P Murad, Anna K Kozlowska, Hee Jun Lee, Maya Ramamurthy, Wen-Chung Chang, Paul Yazaki, David Colcher, John Shively, Mihaela Cristea, Stephen J Forman, Saul J Priceman
Impressive clinical efficacy of chimeric antigen receptor (CAR)-engineered T cell therapy for hematological malignancies have prompted significant efforts in achieving similar responses in solid tumors. The lack of truly restricted and uniform expression of tumor-associated antigens, as well as limited T cell persistence and/or tumor trafficking pose major challenges for successful translation of CAR T cell therapy in solid tumors. Recent studies have demonstrated that aberrantly glycosylated cell surface proteins on tumor cells are amenable CAR targets...
2018: Frontiers in Immunology
Andrea Hembre Ulsund, Marie Dahl, Thomas M Frimurer, Ornella Manfra, Thue W Schwartz, Finn Olav Levy, Kjetil Wessel Andressen
According to early models of GPCR signaling, G proteins only interact with activated receptors. However, some GPCRs were shown to assemble with G proteins before receptor activation, in accordance with more recent models. Previously, we found that the 5-HT7 receptor, as opposed to the 5-HT4 receptor, was preassociated with Gs , but the molecular determinants for this interaction are still elusive. In a series of chimeric 5-HT7 receptors with intracellular segments from 5-HT4 , we determined the receptor-G protein interaction by performing antibody-immobilized fluorescence recovery after photobleaching and fluorescence resonance energy transfer...
December 3, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Clifford M Csizmar, Jacob Petersburg, Thomas J Perry, Lakmal Rozumalski, Benjamin J Hackel, Carston R Wagner
Nature uses multivalency to govern many biological processes. The development of macromolecular and cellular therapies has largely been dependent on engineering similar polyvalent interactions to enable effective targeting. Such therapeutics typically utilize high-affinity binding domains that have the propensity to recognize both antigen-overexpressing tumors and normal-expressing tissues, leading to "on-target, off-tumor" toxicities. One strategy to improve these agents' selectivity is to reduce the binding affinity, such that biologically relevant interactions between the therapeutic and target cell will only exist under conditions of high avidity...
December 3, 2018: Journal of the American Chemical Society
Leonard G Luyt
A chimeric drug design approach, merging the structure of an antagonist and an inverse agonist, results in a new molecular scaffold for targeting the ghrelin receptor (GHSR).
December 3, 2018: Journal of Medicinal Chemistry
Angela M Minnella, Jerry X Zhao, Xiangning Jiang, Emil Jakobsen, Fuxin Lu, Long Wu, Jamel El-Benna, John A Gray, Raymond A Swanson
NMDA-type glutamate receptors (NMDAR) trigger superoxide production by neuronal NADPH oxidase-2 (NOX2), which if sustained leads to cell death. This process involves Ca2+ influx through NMDAR channels. By contrast, comparable Ca2+ influx by other routes does not induce NOX2 activation or cell death. This contrast has been attributed to site-specific effects of Ca2+ flux through NMDAR. Here we show instead that it stems from non-ionotropic signaling by NMDAR GluN2B subunits. To evaluate non-ionotropic effects, mouse cortical neurons were treated with NMDA together with 7-chlorokynurenate, L-689,560, or MK-801, which block Ca2+ influx through NMDAR channels but not NMDA binding...
November 30, 2018: Scientific Reports
Anne F Pihl, Anna F Offersgaard, Christian K Mathiesen, Jannick Prentoe, Ulrik Fahnøe, Henrik Krarup, Jens Bukh, Judith M Gottwein
Chronic hepatitis C virus (HCV) infection poses a serious global public health burden. Despite the recent development of effective treatments there is a large unmet need for a prophylactic vaccine. Further, antiviral resistance might compromise treatment efficiency in the future. HCV cell culture systems are typically based on Huh7 and derived hepatoma cell lines cultured in monolayers. However, efficient high cell density culture systems for high-yield HCV production and studies of antivirals are lacking. We established a system based on Huh7...
November 30, 2018: Scientific Reports
Christopher R Flowers, John P Leonard, Loretta J Nastoupil
Follicular lymphoma (FL) remains a lymphoma subtype that is remarkably sensitive to immunotherapy-based treatment strategies. Anti-CD20 antibody therapy administered as a single agent and in combination as a first-line treatment and at relapse continues to be the most broadly used therapy for this disease. Autologous and allogeneic stem cell transplantation provide meaningful durable remissions for patients with FL. However, identifying the most suitable patients and the optimal timing for these approaches has become increasingly challenging with the advent of novel therapies...
November 30, 2018: Hematology—the Education Program of the American Society of Hematology
Jonathon B Cohen
Most patients with aggressive non-Hodgkin lymphoma will be cured with initial chemoimmunotherapy; however, most patients with relapsed disease will not be cured and will die as a result of their disease. In these cases, continued treatment with conventional chemotherapy is typically not of benefit and can contribute to significant toxicities and decreased quality of life for patients. Fortunately, a number of therapies are currently available or under investigation for this group of patients, ranging from oral tyrosine kinase inhibitors targeting multiple pathways within the malignant cells to adoptive cellular therapies that harness the patient's immune system to fight disease...
November 30, 2018: Hematology—the Education Program of the American Society of Hematology
Tania Jain, Mark R Litzow
Therapeutic options for acute lymphoblastic leukemia, especially in the relapsed/refractory setting, have expanded significantly in recent times. However, this comes at the cost of toxicities: medical as well as financial. We highlight some of the unique toxicities associated with the novel agents to apprise our readers about what to expect, how to recognize them, and how to manage these toxicities. One of the toxicities seen with inotuzumab, a CD22 antibody drug conjugate, is sinusoidal obstruction syndrome, which can be fatal in >80% of patients if associated with multiorgan failure...
November 30, 2018: Hematology—the Education Program of the American Society of Hematology
Michael A Pulsipher
Multicenter trials in children and young adults using second-generation CD19-targeted chimeric antigen receptor (CAR) T cells have shown dramatic levels of remission in patients with multiply relapsed/refractory disease (80% to ≥90%). Early results in adult trials have also shown significant responses, and strategies aimed at mitigating toxicities associated with the therapy have improved tolerability. Therefore, if available, CAR T-cell therapy deserves consideration for salvage of children and adults with B-lineage acute lymphoblastic leukemia (B-ALL) who are multiply relapsed, refractory, or relapsed after a previous allogeneic transplantation...
November 30, 2018: Hematology—the Education Program of the American Society of Hematology
Shira Dinner, Michaela Liedtke
The use of multiagent combination chemotherapy regimens results in cure rates of >90% for children and ∼40% for adults with acute lymphoblastic leukemia (ALL) but is associated with extensive toxicity and disappointingly low efficacy in relapsed patients. ALL blast cells express several surface antigens, including CD20, CD22, and CD19, which represent valuable targets for immunotherapy. Monoclonal antibodies, antibody-drug conjugates, and bispecific T-cell-engaging antibodies targeting these antigens offer novel mechanisms of action...
November 30, 2018: Hematology—the Education Program of the American Society of Hematology
Fang Bao, Ka Hu, Wei Wan, Lei Tian, Hong-Mei Jing
OBJECTIVE: To investigate the efficacy of CD19-targeted chimeric antigen receptor T-cell (CD19-CAR T) in the treatment of patients with refractory relapsed B cell acute lymphocyte leukemia(B-ALL). METHODS: The efficacy and safety of CD19-CAR T cells in treatment of patients with refractory relapsed B-ALL from January 2015 to July 2017 in the Department of Hematology of Peking University Third Hospital were analyzed retrospectively. RESULTS: A total of 10 patients were included in this analysis, all of which were consistent with the diagnosis of refractory relapsed B-ALL, and the immunophenotype of leukemia cells was CD19 positive...
December 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
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
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