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Lymphoma, immunity

Lisa M Ebert, Wenbo Yu, Tessa Gargett, Michael P Brown
Chimeric antigen receptor (CAR)-T cell therapy has been clinically validated as a curative treatment for the difficult to treat malignancies of relapsed/refractory B-cell acute lymphoblastic leukaemia and lymphoma. Here, the CAR-T cells are re-directed towards a single antigen, CD19, which is recognised as a virtually ideal CAR target antigen because it has strong, uniform expression on cancer cells, and is otherwise expressed only on healthy B cells, which are 'dispensable'. Notwithstanding the clinical success of CD19-CAR-T cell therapy, its single specificity has driven therapeutic resistance in 30% or more of cases with CD19-negative leukaemic relapses...
March 14, 2018: Biochemical Society Transactions
Siegfried H Reich, Paul A Sprengeler, Gary G Chiang, Jim R Appleman, Joan Chen, Jeff Clarine, Boreth Eam, Justin T Ernst, Qing Han, Vikas K Goel, Edward Zr Han, Vera Huang, Ivy Nj Hung, Adrianna Jemison, Katti A Jessen, Jolene Molter, Douglas Murphy, Melissa Neal, Gregory S Parker, Michael Shaghafi, Samuel Sperry, Jocelyn Staunton, Craig R Stumpf, Peggy A Thompson, Chinh Tran, Stephen E Webber, Christopher J Wegerski, Hong Zheng, Kevin R Webster
Dysregulated translation of mRNA plays a major role in tumorigenesis. MNK1/2 kinases are key regulators of mRNA translation integrating signals from oncogenic and immune signaling pathways through phosphorylation of eIF4E and other mRNA binding proteins. Modulation of these key effector proteins regulates mRNA which control tumor/stromal cell signaling. 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation...
March 10, 2018: Journal of Medicinal Chemistry
Samantha K Dunmire, Priya S Verghese, Henry H Balfour
Epstein-Barr virus (EBV) infects about 90% of adults worldwide. It is the main cause of infectious mononucleosis, which is observed most frequently in adolescents. The disease can last several weeks and is characterized by lymphocytosis, sore throat, lymphadenopathy, and fatigue. Exposure to oral secretions during deep kissing has been identified as the major source for primary EBV infection in adolescents. Oral secretions are also thought to be the source for younger children through intimate intact or sharing food and eating utensils, although this has not been confirmed...
March 5, 2018: Journal of Clinical Virology: the Official Publication of the Pan American Society for Clinical Virology
Mitsunori Shiroishi, Yuji Ito, Kenta Shimokawa, Jae Man Lee, Takahiro Kusakabe, Tadashi Ueda
Rheumatoid factors (RFs) are autoantibodies against the fragment-crystallizable (Fc) region of immunoglobulin G (IgG). In individuals with hematological diseases such as cryoglobulinemia and certain B-cell lymphoma forms, the RFs derived from specific heavy- and light-chain germline pairs, so-called "stereotypic RFs," are frequently produced in copious amounts and form immune complexes with IgG in serum. Of note, many structural details of the antigen-recognition mechanisms in RFs are unclear. Here, we report the crystal structure of the RF YES8c derived from the IGHV1-69/IGKV3-20 germline pair, the commonest of the stereotypic RFs, in complex with human IgG1-Fc at 2...
March 9, 2018: Journal of Biological Chemistry
Takanori Marui, Hidehiko Fukahori, Tomoko Kawashima, Misato Ito, Masahiko Akamatsu, Yoko Kaneko, Fumie Takahashi, Sunao Imada, Tatsuaki Morokata
B cell-mediated antibodies play a critical role in protecting the body from infections; however, excessive antibody production is involved in the pathogenesis of autoimmune diseases and transplanted organ rejection. Regulation of antibody production is therefore crucial for overcoming these complications. Phosphatidylinositol-3-kinase p110δ (PI3Kδ), a member of the family of PI3K lipid kinases, is a key mediator of B cell activation and proliferation, with a small molecule PI3Kδ inhibitor having been approved for the treatment of B cell lymphoma...
March 5, 2018: European Journal of Pharmacology
Junyuan Lang, Kai Ma, Jinxiu Guo, Jinhui Zhang, Qifeng Wang, Hui Sun
Objective: To investigate the potential diagnostic and prognostic values of antinuclear autoantibodies (ANAs) in diffuse large B-cell lymphoma (DLBCL). Materials and Methods: Eighty-two DLBCL patients and 120 healthy controls were selected from the Department of Hematology, Jincheng Dayi Hospital between 2005 and 2014. We examined the expression of ANA in the sera of the 82 DLBCL patients at different Ann-Arbor stages (15 at Stage I, 22 at Stage II, 27 at Stage III, and 18 at Stage IV)...
January 2018: Journal of Cancer Research and Therapeutics
Hiroki Nagai, Manabu Muto
Over the last two decades, molecular-targeted agents have become mainstream treatment for many types of malignancies and have improved the overall survival of patients. However, most patients eventually develop resistance to these targeted therapies. Recently, immunotherapies such as immune checkpoint inhibitors have revolutionized the treatment paradigm for many types of malignancies. Immune checkpoint inhibitors have been approved for treatment of melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck squamous cell carcinoma, Hodgkin's lymphoma, bladder cancer and gastric cancer...
March 7, 2018: International Journal of Clinical Oncology
Taku Fujimura, Kayo Tanita, Yota Sato, Yumi Kambayashi, Sadanori Furudate, Akira Tsukada, Akira Hashimoto, Setsuya Aiba
Mogamulizumab induces cytotoxicity against CCR4+ lymphoma cells by antibody-dependent cell-mediated cytotoxicity in advanced cutaneous T-cell lymphoma patients. Since the efficacy of mogamulizumab in mycosis fungoides (28.6%) is lower than that in Sézary syndrome (47.1%), reagents that enhance the antitumor immune response induced by mogamulizumab are needed to further optimize its use for the treatment of erythrodermic mycosis fungoides. In this report, we present a case of erythrodermic mycosis fungoides successfully treated with mogamulizumab followed by etoposide monotherapy...
January 2018: Case Reports in Oncology
Albert T Gacerez, Charles L Sentman
Chimeric antigen receptor (CAR) therapy has shown promise against B cell malignancies in the clinic. However, limited success in patients with solid tumors has prompted the development of new CAR strategies. In this study, a B7H6-specific CAR was combined with different variants of T-bet, a transcription factor that acts as the master regulator to induce a Th1 phenotype in CD4+ T cells, to create more effective CAR T cells. Skewing CD4+ CAR T cells into a Th1 improved CAR T cell functional activity while promoting a robust proinflammatory response against B7H6-expressing tumors...
March 7, 2018: Cancer Gene Therapy
Sarah L Buchan, Mohannah Fallatah, Stephen M Thirdborough, Vadim Y Taraban, Anne Rogel, Lawrence J Thomas, Christine A Penfold, Li-Zhen He, Michael A Curran, Tibor Keler, Aymen Al-Shamkhani
PURPOSE: PD-1 checkpoint blockade has revolutionized the field of cancer immunotherapy, yet the frequency of responding patients is limited by inadequate T-cell priming secondary to a paucity of activatory dendritic cells (DCs). DC signals can be bypassed by CD27 agonists and we therefore investigated if the effectiveness of anti-PD-1/L1 could be improved by combining with agonist anti-CD27 monoclonal antibodies (mAb). EXPERIMENTAL DESIGN: The efficacy of PD-1/L1 blockade or agonist anti-CD27 mAb was compared with a dual-therapy approach in multiple tumor models...
March 7, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Dai Yu-Mei, Hai-Ying Liu, Yun-Feng Liu, Yuan Zhang, Wei He
The engagement of Epstein-Barr virus (EBV)-induced protein ligands in γδ T cell-mediated anti-EBV immunity especially in EBV associated B cell malignancies has not been fully elucidated. Previously we reported the overexpression of human MutS homologue 2(hMSH2), a stress inducible protein ligand for human γδ T cells, on EBV-transformed B lymphoblastic cell lines (B-LCLs). In this study, we first generated EBV-transformed B-LCLs from peripheral blood mononuclear cells (PBMCs) of healthy volunteers with B95-8 cellular supernatant and cyclosporine A...
March 7, 2018: Immunology
Mark A Samaan, Polychronis Pavlidis, Sophie Papa, Nick Powell, Peter M Irving
Immune checkpoint inhibitor therapies are a novel group of monoclonal antibodies with proven effectiveness in a wide range of malignancies, including melanoma, renal cell carcinoma, non-small-cell lung cancer, urothelial carcinoma and Hodgkin lymphoma. Their use in a range of other indications, such as gastrointestinal and head and neck cancer, is currently under investigation. The number of agents included in this drug group is increasing, as is their use. Although they have the potential to improve the treatment of advanced malignancies, they are also associated with a substantial risk of immune-related adverse events...
March 7, 2018: Nature Reviews. Gastroenterology & Hepatology
Keith E Steele, Tze Heng Tan, René Korn, Karma Dacosta, Charles Brown, Michael Kuziora, Johannes Zimmermann, Brian Laffin, Moritz Widmaier, Lorenz Rognoni, Ruben Cardenes, Katrin Schneider, Anmarie Boutrin, Philip Martin, Jiping Zha, Tobias Wiestler
BACKGROUND: Immuno-oncology and cancer immunotherapies are areas of intense research. The numbers and locations of CD8+ tumor-infiltrating lymphocytes (TILs) are important measures of the immune response to cancer with prognostic, pharmacodynamic, and predictive potential. We describe the development, validation, and application of advanced image analysis methods to characterize multiple immunohistochemistry-derived CD8 parameters in clinical and nonclinical tumor tissues. METHODS: Commercial resection tumors from nine cancer types, and paired screening/on-drug biopsies of non-small-cell lung carcinoma (NSCLC) patients enrolled in a phase 1/2 clinical trial investigating the PD-L1 antibody therapy durvalumab (NCT01693562), were immunostained for CD8...
March 6, 2018: Journal for Immunotherapy of Cancer
B Melosky, N Blais, P Cheema, C Couture, R Juergens, S Kamel-Reid, M-S Tsao, P Wheatley-Price, Z Xu, D N Ionescu
Background: The development and approval of both targeted and immune therapies for patients with advanced non-small cell lung cancer (nsclc) has significantly improved patient survival rates and quality of life. Biomarker testing for patients newly diagnosed with nsclc, as well as for patients progressing after treatment with epidermal growth factor receptor ( EGFR ) inhibitors, is the standard of care in Canada and many parts of the world. Methods: A group of thoracic oncology experts in the field of thoracic oncology met to describe the standard for biomarker testing for lung cancer in the Canadian context, focusing on evidence-based recommendations for standard-of-care testing for EGFR , anaplastic lymphoma kinase ( ALK ), ROS1 , BRAF V600 and programmed death-ligand (PD-L1) at the time of diagnosis of advanced disease and EGFR T790M upon progression...
February 2018: Current Oncology
Thomas Patzelt, Selina J Keppler, Oliver Gorka, Silvia Thoene, Tim Wartewig, Michael Reth, Irmgard Förster, Roland Lang, Maike Buchner, Jürgen Ruland
The transcription factor Foxp1 is critical for early B cell development. Despite frequent deregulation of Foxp1 in B cell lymphoma, the physiological functions of Foxp1 in mature B cells remain unknown. Here, we used conditional gene targeting in the B cell lineage and report that Foxp1 disruption in developing and mature B cells results in reduced numbers and frequencies of follicular and B-1 B cells and in impaired antibody production upon T cell-independent immunization in vivo. Moreover, Foxp1 -deficient B cells are impaired in survival even though they exhibit an increased capacity to proliferate...
March 5, 2018: Proceedings of the National Academy of Sciences of the United States of America
Lara A Aqrawi, Janicke Liaaen Jensen, Gunnvor Øijordsbakken, Ann-Kristin Ruus, Ståle Nygård, Marit Holden, Roland Jonsson, Hilde Kanli Galtung, Kathrine Skarstein
A characteristic feature of primary Sjögren's syndrome (pSS) is the destruction of salivary and lacrimal glands mediated by mononuclear cell infiltration. Adipocytes can also occupy a large portion of the salivary gland (SG) tissue area, although little is known about their significance in pSS. We have previously investigated adipose tissue infiltration in SG biopsies from pSS patients and non-SS sicca controls. Our findings indicated the distinct incidence of adipose tissue replacement in pSS patients, where adipocytes were detected in interleukin (IL) 6 rich regions...
March 5, 2018: Autoimmunity
Muhammad Arshad Alvi, Sharifa Alghamdi, Iqtadar Seerat, Omar Al Matarfi
Schistosomiasis may cause diverse symptoms and it is usually not considered as a cause of disease especially in patients with normal immune system. We are reporting an eleven-year-old child who was initially diagnosed as a case of lymphoma but later on proved to be a case of acute schistosomiasis.
January 2018: Journal of Ayub Medical College, Abbottabad: JAMC
Anja Mottok, Christian Steidl
Hodgkin lymphoma is considered a prime example of treatment success with cure rates exceeding 80% using modern combined modality therapies. However, especially in adolescents and young adults, treatment-related toxicity and long-term morbidity still represent persistent challenges. Moreover, outcomes in patients with relapsed or refractory disease remain unfavorable in the era of high-dose chemotherapy and stem cell transplantation. Hence, there is a high demand for novel and innovative alternative treatment approaches...
March 2, 2018: Blood
Sean H Lim, Peter W M Johnson
The treatment of Hodgkin Lymphoma has evolved continuously since the introduction of extended-field radiotherapy in the 1960s to involved-field then involved-node radiotherapy, multi-agent chemotherapy, combined chemo-radiotherapy, risk-adapted and response-adapted modulation, and most recently, introduction of antibody-drug conjugates and immune checkpoint-blocking antibodies. These changes have translated into progressively increasing cure rates, so that 10-year survival figures now exceed 80%, compared to less than 50% 40 years ago...
March 2, 2018: Blood
Neha Mehta-Shah, Nancy L Bartlett
Addition of brentuximab vedotin, a CD30 targeted antibody-drug conjugate, and the PD-1 inhibitors, nivolumab and pembrolizumab, to the armamentarium for transplant-ineligible relapsed/refractory classical Hodgkin lymphoma has resulted in improved outcomes, including the potential for cure in a small minority of patients. For patients who have failed prior transplant or are unsuitable for dose-intense approaches based on age or comorbidities, an individualized approach with sequential use of single agents such as brentuximab vedotin, PD-1 inhibitors, everolimus, lenalidomide, or conventional agents such as gemcitabine or vinorelbine, may result in prolonged survivals with minimal or modest effect on quality of life...
March 2, 2018: Blood
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