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https://www.readbyqxmd.com/read/28236768/survival-of-patients-with-melanoma-brain-metastasis-treated-with-stereotactic-radiosurgery-and-active-systemic-drug-therapies
#1
Ee Siang Choong, Serigne Lo, Martin Drummond, Gerald B Fogarty, Alexander M Menzies, Alexander Guminski, Brindha Shivalingam, Kathryn Clarke, Georgina V Long, Angela M Hong
INTRODUCTION: With new systemic therapies demonstrating activity in melanoma brain metastasis, most of the previously reported stereotactic radiosurgery (SRS) data are superseded. In this study, we report the outcomes (overall survival [OS] and brain control [BC]) and identify factors that associate with such outcomes in the era of modern systemic therapy. METHOD: A total of 108 patients treated with SRS from 2010 to 2015 were included. Systemic treatment use within 6 weeks of SRS was noted...
February 22, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28230715/a-multireferral-centre-retrospective-cohort-analysis-on-the-experience-in-treatment-of-metastatic-uveal-melanoma-and-utilization-of-sequential-liver-directed-treatment-and-immunotherapy
#2
Malinda Itchins, Paolo A Ascierto, Alexander M Menzies, Meredith Oatley, Serigne Lo, Dariush Douraghi-Zadeh, Timmothy Harrington, Richard Maher, Antonio M Grimaldi, Alexander Guminski
Metastatic uveal melanoma is a rare malignancy with a poor prognosis. To date, systemic therapy has been ineffective; however, there are few data on the benefits of anti-CTLA4 or anti-PD-1 antibodies in sequence with liver-directed therapy. A retrospective cohort analysis was carried out on 37 consecutive patients managed in a tertiary referral centre examining the safety and efficacy of treatment; patterns of care; and impact on survival. The sequential treatment with transarterial chemotherapy (TAC), systemic immunotherapy (IT) and systemic chemotherapy was reviewed...
February 22, 2017: Melanoma Research
https://www.readbyqxmd.com/read/28220815/cbx3-hp1%C3%AE-deficiency-confers-enhanced-tumor-killing-capacity-on-cd8-t-cells
#3
Michael Sun, Ngoc Ha, Duc-Hung Pham, Megan Frederick, Bandana Sharma, Chie Naruse, Masahide Asano, Matthew E Pipkin, Rani E George, To-Ha Thai
Cbx3/HP1γ is a histone reader whose function in the immune system is not completely understood. Here, we demonstrate that in CD8(+) T cells, Cbx3/HP1γ insufficiency leads to chromatin remodeling accompanied by enhanced Prf1, Gzmb and Ifng expression. In tumors obtained from Cbx3/HP1γ-insufficient mice or wild type mice treated with Cbx3/HP1γ-insufficient CD8(+) T cells, there is an increase of CD8(+) effector T cells expressing the stimulatory receptor Klrk1/NKG2D, a decrease in CD4(+) CD25(+) FOXP3(+) regulatory T cells (Treg cells) as well as CD25(+) CD4(+) T cells expressing the inhibitory receptor CTLA4...
February 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28216262/efis-lecture-understanding-the-ctla-4-checkpoint-in-the-maintenance-of-immune-homeostasis
#4
REVIEW
Lucy S K Walker
The past 20 years have heralded fascinating developments in the field of CTLA-4 biology. The CTLA-4 protein is a critical negative regulator of T cell immunity and its absence provokes severe lymphoproliferative disease. In a surprising twist, the generation of mixed bone marrow chimeric mice revealed that CTLA-4 predominantly functions in a cell-extrinsic manner, suggesting that CTLA-4 expressed on one cell can modify the behaviour of another cell. This was followed by the demonstration that CTLA-4 is highly expressed in regulatory T cells and can contribute to their suppressive activity...
February 16, 2017: Immunology Letters
https://www.readbyqxmd.com/read/28214651/a-review-on-the-evolution-of-pd-1-pd-l1-immunotherapy-for-bladder-cancer-the-future-is-now
#5
REVIEW
Joaquin Bellmunt, Thomas Powles, Nicholas J Vogelzang
The treatment of bladder cancer has evolved over time to encompass not only the traditional modalities of chemotherapy and surgery, but has been particularly impacted by the use of immunotherapy. The first immunotherapy was the live, attenuated bacterial Bacillus Calmette-Guérin vaccine, which has been the standard of care non-muscle-invasive bladder cancer since 1990. Modern immunotherapy has focused on inhibitors of checkpoint proteins, which are molecules that impede immune function, thereby allowing tumor cells to grow and proliferate unregulated...
February 2, 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28199983/a-versatile-system-for-rapid-multiplex-genome-edited-car-t-cell-generation
#6
Jiangtao Ren, Xuhua Zhang, Xiaojun Liu, Chongyun Fang, Shuguang Jiang, Carl H June, Yangbing Zhao
The therapeutic potential of CRISPR system has already been demonstrated in many instances and begun to overlap with the rapidly expanding field of cancer immunotherapy, especially on the production of genetically modified T cell receptor or chimeric antigen receptor (CAR) T cells. Efficient genomic disruption of multiple gene loci to generate universal donor cells, as well as potent effector T cells resistant to multiple inhibitory pathways such as PD-1 and CTLA4 is an attractive strategy for cell therapy...
February 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28199343/long-term-treatment-with-abatacept-or-tocilizumab-does-not-increase-epstein-barr-virus-load-in-patients-with-rheumatoid-arthritis-a-three-years-retrospective-study
#7
Nathalie Balandraud, Gaetan Texier, Emmanuel Massy, Olivier Muis-Pistor, Marielle Martin, Isabelle Auger, Marie-Caroline Guzian, Sandrine Guis, Thao Pham, Jean Roudier
BACKGROUND: Epstein-Barr Virus (EBV) is a widely disseminated lymphotropic herpes virus implicated in benign and malignant disorders. In transplant patients, immunosuppressive drugs (cyclosporine) diminish control of EBV replication, potentially leading to lymphoproliferative disorders (LPD). Rheumatoid arthritis (RA) patients have impaired control of EBV infection and have EBV load ten times higher than controls. As post transplant patients, patients with RA have increased risk of developing lymphomas...
2017: PloS One
https://www.readbyqxmd.com/read/28197383/analysis-of-the-prognostic-role-of-an-immune-checkpoint-score-in-resected-non-small-cell-lung-cancer-patients
#8
Marta Usó, Eloísa Jantus-Lewintre, Silvia Calabuig-Fariñas, Ana Blasco, Eva García Del Olmo, Ricardo Guijarro, Miguel Martorell, Carlos Camps, Rafael Sirera
Tumors develop mechanisms to recruit tolerogenic immune cells and to induce the expression of molecules that act as immune checkpoints. This regulation of the immune microenvironment favors immune tolerance to the neoplastic cells. In this study, we have investigated the prognostic role of immune-checkpoint expression markers in a cohort of resectable non-small cell lung cancer (NSCLC) patients. RNA was isolated from fresh-frozen lung specimens (tumor and normal lung) (n = 178). RTqPCR was performed to analyze the relative expression of 20 immune-related genes that were normalized by the use of endogenous genes selected by GeNorm algorithm...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28197372/fam13a-is-associated-with-non-small-cell-lung-cancer-nsclc-progression-and-controls-tumor-cell-proliferation-and-survival
#9
Felix Eisenhut, Lisanne Heim, Sonja Trump, Susanne Mittler, Nina Sopel, Katerina Andreev, Fulvia Ferrazzi, Arif B Ekici, Ralf Rieker, Rebekka Springel, Vera L Assmann, Matthias Lechmann, Sonja Koch, Marina Engelhardt, Christina Warnecke, Denis I Trufa, Horia Sirbu, Arndt Hartmann, Susetta Finotto
Genome-wide association studies (GWAS) associated Family with sequence similarity 13, member A (FAM13A) with non-small cell lung cancer (NSCLC) occurrence. Here, we found increased numbers of FAM13A protein expressing cells in the tumoral region of lung tissues from a cohort of patients with NSCLC. Moreover, FAM13A inversely correlated with CTLA4 but directly correlated with HIF1α levels in the control region of these patients. Consistently, FAM13A RhoGAP was found to be associated with T cell effector molecules like HIF1α and Tbet and was downregulated in immunosuppressive CD4(+)CD25(+)Foxp3(+)CTLA4(+) T cells...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28188716/-immunological-alterations-in-common-variable-immunodeficiency
#10
Laura Berrón-Ruiz
Common variable immunodeficiency (CVID) is the largest group of symptomatic primary immune deficiencies; it is characterized by hypogammaglobulinemia, poor response to vaccines and increased susceptibility to infections. Cellular phenotypes and abnormalities have been described both in adaptive and innate immune response. Several classifications of common variable immunodeficiency are based on defects found on T and B cells, which have been correlated with clinical manifestations. In recent years, significant progress has been made in elucidating the genetic mechanisms that result in a IDCV phenotype...
January 2017: Revista Alergia Mexico: Organo Oficial de la Sociedad Mexicana de Alergia e Inmunología, A.C
https://www.readbyqxmd.com/read/28188673/socs-potential-immune-checkpoint-molecules-for-cancer-immunotherapy
#11
REVIEW
Shunsuke Chikuma, Mitsuhiro Kanamori, Setsuko Mise-Omata, Akihiko Yoshimura
Inhibition of immune checkpoint molecules, PD-1 and CTLA4, has been shown to be a promising cancer treatment. PD-1 and CTLA4 inhibit TCR and co-stimulatory signals, respectively. The third T cell activation signal represents the signals from the cytokine receptors. The cytokine Interferon-γ (IFNγ) plays an important role in anti-tumor immunity by activating cytotoxic T cells (CTLs). Most cytokines use the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, and the suppressors of cytokine signaling (SOCS) family of proteins are major negative regulators of the JAK/STAT pathway...
February 11, 2017: Cancer Science
https://www.readbyqxmd.com/read/28186328/site-specific-monitoring-of-n-glycosylation-profiles-of-a-ctla4-fc-fusion-protein-from-the-secretory-pathway-to-the-extracellular-environment
#12
Karina Bora de Oliveira, David Spencer, Christopher Barton, Nitin Agarwal
Glycosylation often plays a key role in the safety and efficacy of therapeutic proteins to patients, thus underlying the need for consistent control of this important post-translational modification during biologics production. In this study, we profiled the site-specific evolution of N-glycans on a CTLA4-Fc-fusion protein, from the intracellular secretory pathway to the conditioned medium (CM) in fed-batch cell culture. For this, we developed an approach that combined sub-cellular fractionation with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses...
February 10, 2017: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/28185879/ctla4-ig-effectively-controls-immune-activation-and-inflammatory-disease-in-a-novel-murine-model-of-leaky-scid
#13
Stéphanie Humblet-Baron, Susann Schönefeldt, Josselyn Garcia-Perez, Frédéric Baron, Emanuela Pasciuto, Adrian Liston
BACKGROUND: Severe combined immunodeficiency (SCID) can be caused by loss-of-function mutations in genes involved in the DNA recombination machinery, such as RAG1, RAG2 or DCLRE1C. Defective DNA recombination causes a developmental block in T cells and B cells, resulting in high susceptibility to infections. Hypomorphic mutations in the same genes can also give a partial loss of T cells, in a spectrum including leaky SCID (LS) and Omenn syndrome (OS). These patients not only develop life-threatening infections due to immunodeficiency, but also develop inflammatory/autoimmune conditions due to the presence of autoreactive T cells...
February 6, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28179176/peri-srs-administration-of-immune-checkpoint-therapy-for-melanoma-metastatic-to-the-brain-investigating-efficacy-and-the-effects-of-relative-treatment-timing-on-lesion-response
#14
Mehran B Yusuf, Mark J Amsbaugh, Eric Burton, Jason Chesney, Shiao Woo
OBJECTIVE(S): To investigate the efficacy of immune checkpoint therapy (ICT) administered with stereotactic radiosurgery (SRS) and determine the effects of relative treatment timing on lesion response. METHODS: A prospective institutional database of all patients with intact brain metastases treated with SRS from 2007 to 2015 was reviewed for patients diagnosed with malignant melanoma. Lesion response was determined using a modified RECIST v1.1 criteria. Patients were grouped according to if they received ICT and the timing of ICT relative to SRS...
February 4, 2017: World Neurosurgery
https://www.readbyqxmd.com/read/28176947/silencing-of-foxp3-enhances-the-antitumor-efficacy-of-gm-csf-genetically-modified-tumor-cell-vaccine-against-b16-melanoma
#15
Antonio Miguel, Luis Sendra, Verónica Noé, Carles J Ciudad, Francisco Dasí, David Hervas, María José Herrero, Salvador F Aliño
The antitumor response after therapeutic vaccination has a limited effect and seems to be related to the presence of T regulatory cells (Treg), which express the immunoregulatory molecules CTLA4 and Foxp3. The blockage of CTLA4 using antibodies has shown an effective antitumor response conducing to the approval of the human anti-CTLA4 antibody ipilimumab by the US Food and Drug Administration. On the other hand, Foxp3 is crucial for Treg development. For this reason, it is an attractive target for cancer treatment...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28161001/-immune-checkpoint-and-hemopathies
#16
Barbara Burroni, Chloé Broudin, Diane Damotte, Camille Laurent
Immune-checkpoint inhibitors represent potent new therapies for most lymphomas, particularly for refractory diseases. Contrasting with solid tumors the majority of lymphoma are sensitive to conventional therapies and immunotherapies such as anti-CD20 or anti-CD30. But relapsing lymphoma or refractory disease have a very poor prognosis and new drugs are mandatory. Immune-checkpoint inhibitors targeting CTLA4, PD-1 et PD-L1 demonstrated efficiency with prolonged survivals even after bone marrow allograft for aggressive disease...
February 2017: Annales de Pathologie
https://www.readbyqxmd.com/read/28148840/therapy-with-ctla4-ig-and-an-antiviral-monoclonal-antibody-controls-chikungunya-virus-arthritis
#17
Jonathan J Miner, Lindsey E Cook, Jun P Hong, Amber M Smith, Justin M Richner, Raeann M Shimak, Alissa R Young, Kristen Monte, Subhajit Poddar, James E Crowe, Deborah J Lenschow, Michael S Diamond
In 2013, chikungunya virus (CHIKV) transmission was documented in the Western Hemisphere, and the virus has since spread throughout the Americas with more than 1.8 million people infected in more than 40 countries. CHIKV targets the joints, resulting in symmetric polyarthritis that clinically mimics rheumatoid arthritis and can endure for months to years. At present, no approved treatment is effective in preventing or controlling CHIKV infection or disease. We treated mice with eight different disease-modifying antirheumatic drugs and identified CLTA4-Ig (abatacept) and tofacitinib as candidate therapies based on their ability to decrease acute joint swelling...
February 1, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28148715/the-exportin-1-inhibitor-selinexor-exerts-superior-anti-tumor-activity-when-combined-with-t-cell-checkpoint-inhibitors
#18
Matthew R Farren, Rebecca C Hennessey, Reena Shakya, Omar Elnaggar, Gregory Young, Kari Kendra, Yosef Landesman, Sivan Elloul, Marsha Crochiere, Boris Klebanov, Trinayan Kashyap, Christin E Burd, Gregory B Lesinski
Selinexor, a Selective Inhibitor of Nuclear Export (SINE) compound targeting exportin-1, has previously been shown to inhibit melanoma cell growth in vivo. We hypothesized that combining selinexor with antibodies that block or disrupt T cell checkpoint molecule signaling would exert superior anti-melanoma activity. In vitro, selinexor increased PD-1 and CTLA4 gene expression in leukocytes and induced PD L1 gene expression in human melanoma cell lines. Mice bearing syngeneic B16F10 melanoma tumors demonstrated a significant reduction in tumor growth rate in response to the combination of selinexor and anti-PD-1 or anti-PD-L1 antibodies (p<0...
February 1, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28141921/a-tale-of-two-pathways-renewing-the-promise-of-anti-cd40l-blockade
#19
EDITORIAL
A W Thomson, M B Ezzelarab
Amongst the most promising alternative immunosuppressive strategies to overcome the limitations of calcineurin inhibition in organ transplantation has for some time, been the blockade of co-stimulatory pathways that are essential for naïve T cell activation. The most important and best characterized of these are the CD80/86-CD28/CTLA4 and CD40-CD40L(CD154) ligand-receptor pathways. More than twenty years ago, compelling reports (1) showed that selective blocking of these pathways was highly effective in promoting long-term allograft acceptance/tolerance in rodents...
January 31, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28141917/enhanced-bruton-s-tyrosine-kinase-activity-in-peripheral-blood-b-lymphocytes-of-autoimmune-disease-patients
#20
Odilia B J Corneth, Gwenny M P Verstappen, Sandra M J Paulissen, Marjolein J W de Bruijn, Jasper Rip, Melanie Lukkes, Jan Piet van Hamburg, Erik Lubberts, Hendrika Bootsma, Frans G M Kroese, And Rudi W Hendriks
OBJECTIVE: Bruton's tyrosine kinase (BTK) transmits crucial survival signals from the B cell receptor (BCR) in B cells. Pharmacological BTK inhibition effectively diminishes disease symptoms in mouse models of autoimmunity and, conversely, transgenic BTK overexpression induces systemic autoimmunity in mice. We investigated BTK expression and activity in human B cells in the context of autoimmune disease. METHODS: Using intracellular flow cytometry, we quantified BTK expression and phosphorylation in peripheral blood B cell subsets in patients with rheumatoid arthritis (RA; n=30) and primary Sjogren's Syndrome (pSS; n=26) and matched healthy controls...
January 31, 2017: Arthritis & Rheumatology
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