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https://www.readbyqxmd.com/read/28077675/post-hoc-assessment-of-the-immunogenicity-of-bioengineered-factor-viia-demonstrates-the-use-of-preclinical-tools
#1
Kasper Lamberth, Stine Louise Reedtz-Runge, Jonathan Simon, Ksenia Klementyeva, Gouri Shankar Pandey, Søren Berg Padkjær, Véronique Pascal, Ileana R León, Charlotte Nini Gudme, Søren Buus, Zuben E Sauna
Immunogenicity is an important consideration in the licensure of a therapeutic protein because the development of neutralizing anti-drug antibodies (ADAs) can affect both safety and efficacy. Neoantigens introduced by bioengineering of a protein drug are a particular cause for concern. The development of a bioengineered recombinant factor VIIa (rFVIIa) analog was discontinued after phase 3 trials because of the development of ADAs. The unmodified parent molecule (rFVIIa), on the other hand, has been successfully used as a drug for more than two decades with no reports of immunogenicity in congenital hemophilia patients with inhibitors...
January 11, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28007776/immune-cytolytic-activity-stratifies-molecular-subsets-of-human-pancreatic-cancer
#2
David Balli, Andrew J Rech, Ben Z Stanger, Robert H Vonderheide
PURPOSE: Immunotherapy has the potential to improve the dismal prognosis in pancreatic ductal adenocarcinoma (PDA), but clinical trials - including those with single-agent PD-1/PD-L1 inhibition - have been disappointing. Our aim was to examine the immune landscape of PDA as it relates to aspects of tumor biology, including neoepitope burden. EXPERIMENTAL DESIGN: We used publically available expression data from 134 primary resection PDA samples from The Cancer Genome Atlas to stratify patients according to a cytolytic T-cell activity expression index...
December 22, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27956380/somatic-mutations-and-neoepitope-homology-in-melanomas-treated-with-ctla-4-blockade
#3
Tavi Nathanson, Arun Ahuja, Alexander Rubinsteyn, Bulent Arman Aksoy, Matthew D Hellmann, Diana Miao, Eliezer Van Allen, Taha Merghoub, Jedd D Wolchok, Alexandra Snyder, Jeff Hammerbacher
Immune checkpoint inhibitors are promising treatments for patients with a variety of malignancies. Toward understanding the determinants of response to immune checkpoint inhibitors, it was previously demonstrated that the presence of somatic mutations is associated with benefit from checkpoint inhibition. A hypothesis was posited that neoantigen homology to pathogens may in part explain the link between somatic mutations and response. To further examine this hypothesis, we reanalyzed cancer exome data obtained from our previously published study of 64 melanoma patients treated with CTLA-4 blockade and a new dataset of RNA-Seq data from 24 of these patients...
December 12, 2016: Cancer Immunology Research
https://www.readbyqxmd.com/read/27931265/increased-caspase-6-activity-in-the-human-anterior-olfactory-nuclei-of-the-olfactory-bulb-is-associated-with-cognitive-impairment
#4
Benedicte Foveau, Steffen Albrecht, David A Bennett, José A Correa, Andrea C LeBlanc
Abnormally elevated hippocampal Caspase-6 (Casp6) activity is intimately associated with age-related cognitive impairment in humans and in mice. In humans, these high levels of Casp6 activity are initially localized in the entorhinal cortex, the area of the brain first affected by the formation of neurofibrillary tangles, according to Braak staging. The reason for the high vulnerability of entorhinal cortex neurons to neurofibrillary tangle pathology and Casp6 activity is unknown. Casp6 activity is involved in axonal degeneration, therefore, one possibility to explain increased vulnerability of the entorhinal cortex neurons would be that the afferent neurons of the olfactory bulb, some of which project their axons to the entorhinal cortex, are equally degenerating...
December 8, 2016: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/27869121/direct-identification-of-clinically-relevant-neoepitopes-presented-on-native-human-melanoma-tissue-by-mass-spectrometry
#5
Michal Bassani-Sternberg, Eva Bräunlein, Richard Klar, Thomas Engleitner, Pavel Sinitcyn, Stefan Audehm, Melanie Straub, Julia Weber, Julia Slotta-Huspenina, Katja Specht, Marc E Martignoni, Angelika Werner, Rüdiger Hein, Dirk H Busch, Christian Peschel, Roland Rad, Jürgen Cox, Matthias Mann, Angela M Krackhardt
Although mutations may represent attractive targets for immunotherapy, direct identification of mutated peptide ligands isolated from human leucocyte antigens (HLA) on the surface of native tumour tissue has so far not been successful. Using advanced mass spectrometry (MS) analysis, we survey the melanoma-associated immunopeptidome to a depth of 95,500 patient-presented peptides. We thereby discover a large spectrum of attractive target antigen candidates including cancer testis antigens and phosphopeptides...
November 21, 2016: Nature Communications
https://www.readbyqxmd.com/read/27864551/immunological-outcomes-of-antibody-binding-to-glycans-shared-between-microorganisms-and-mammals
#6
REVIEW
Preeyam Patel, John F Kearney
Glycans constitute basic cellular components of living organisms across biological kingdoms, and glycan-binding Abs participate in many cellular interactions during immune defense against pathogenic organisms. Glycan epitopes are expressed as carbohydrate-only entities or as oligomers or polymers on proteins and lipids. Such epitopes on glycoproteins may be formed by posttranslational modifications or neoepitopes resulting from metabolic-catabolic processes and can be altered during inflammation. Pathogenic organisms can display host-like glycans to evade the host immune response...
December 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27864476/anti-hinge-antibodies-recognize-igg-subclass-and-protease-restricted-neoepitopes
#7
Willem J J Falkenburg, Dirkjan van Schaardenburg, Pleuni Ooijevaar-de Heer, Michel W P Tsang-A-Sjoe, Irene E M Bultink, Alexandre E Voskuyl, Arthur E H Bentlage, Gestur Vidarsson, Gertjan Wolbink, Theo Rispens
Anti-hinge Abs (AHAs) target neoepitopes exposed after proteolytic cleavage of IgG. In this study, we explored the diversity of protease- and IgG subclass-restricted AHAs and their potential as immunological markers in healthy donors (HDs) and patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). AHA reactivity against IgG-degrading enzyme of Streptococcus pyogenes (IdeS)- or pepsin-generated F(ab')2 fragments of all four human IgG subclasses was determined. AHA reactivity against one or more out of eight F(ab')2 targets was found in 68% (68 of 100) of HDs, 69% (68 of 99) of SLE patients, and 81% (79 of 97) of RA patients...
January 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27854226/neo-epitope-peptides-as-biomarkers-of-disease-progression-for-muscular-dystrophies-and-other-myopathies
#8
A Arvanitidis, K Henriksen, M A Karsdal, A Nedergaard
For several decades, serological biomarkers of neuromuscular diseases as dystrophies, myopathies and myositis have been limited to routine clinical biochemistry panels. Gauging the pathological progression is a prerequisite for proper treatment and therefore identifying accessible, easy to monitor biomarkers that can predict the disease progression would be an important advancement. Most muscle diseases involve accelerated muscle fiber degradation, inflammation, fatty tissue substitution and/or fibrosis. All these pathological traits have been shown to give rise to serological peptide biomarkers in other tissues, underlining the potential application of existing biomarkers of such traits in muscle disorders...
August 30, 2016: Journal of Neuromuscular Diseases
https://www.readbyqxmd.com/read/27837020/density-of-immunogenic-antigens-does-not-explain-the-presence-or-absence-of-the-t-cell-inflamed-tumor-microenvironment-in-melanoma
#9
Stefani Spranger, Jason J Luke, Riyue Bao, Yuanyuan Zha, Kyle M Hernandez, Yan Li, Alexander P Gajewski, Jorge Andrade, Thomas F Gajewski
Melanoma metastases can be categorized by gene expression for the presence of a T-cell-inflamed tumor microenvironment, which correlates with clinical efficacy of immunotherapies. T cells frequently recognize mutational antigens corresponding to nonsynonymous somatic mutations (NSSMs), and in some cases shared differentiation or cancer-testis antigens. Therapies are being pursued to trigger immune infiltration into non-T-cell-inflamed tumors in the hope of rendering them immunotherapy responsive. However, whether those tumors express antigens capable of T-cell recognition has not been explored...
November 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27832200/a-platform-for-designing-genome-based-personalized-immunotherapy-or-vaccine-against-cancer
#10
Sudheer Gupta, Kumardeep Chaudhary, Sandeep Kumar Dhanda, Rahul Kumar, Shailesh Kumar, Manika Sehgal, Gandharva Nagpal, Gajendra P S Raghava
Due to advancement in sequencing technology, genomes of thousands of cancer tissues or cell-lines have been sequenced. Identification of cancer-specific epitopes or neoepitopes from cancer genomes is one of the major challenges in the field of immunotherapy or vaccine development. This paper describes a platform Cancertope, developed for designing genome-based immunotherapy or vaccine against a cancer cell. Broadly, the integrated resources on this platform are apportioned into three precise sections. First section explains a cancer-specific database of neoepitopes generated from genome of 905 cancer cell lines...
2016: PloS One
https://www.readbyqxmd.com/read/27799140/endogenous-neoantigen-specific-cd8-t-cells-identified-in-two-glioblastoma-models-using-a-cancer-immunogenomics-approach
#11
Tanner M Johanns, Jeffrey P Ward, Christopher A Miller, Courtney Wilson, Dale K Kobayashi, Diane Bender, Yujie Fu, Anton Alexandrov, Elaine R Mardis, Maxim N Artyomov, Robert D Schreiber, Gavin P Dunn
The "cancer immunogenomics" paradigm has facilitated the search for tumor-specific antigens over the last 4 years by applying comprehensive cancer genomics to tumor antigen discovery. We applied this methodology to identify tumor-specific "neoantigens" in the C57BL/6-derived GL261 and VM/Dk-derived SMA-560 tumor models. Following DNA whole-exome and RNA sequencing, high-affinity candidate neoepitopes were predicted and screened for immunogenicity by ELISPOT and tetramer analyses. GL261 and SMA-560 harbored 4,932 and 2,171 nonsynonymous exome mutations, respectively, of which less than half were expressed...
December 2016: Cancer Immunology Research
https://www.readbyqxmd.com/read/27776554/s100a8-a9-a-potent-serum-and-molecular-imaging-biomarker-for-synovial-inflammation-and-joint-destruction-in-seronegative-experimental-arthritis
#12
Edwin J W Geven, Martijn H J van den Bosch, Irene Di Ceglie, Giuliana Ascone, Shahla Abdollahi-Roodsaz, Annet W Sloetjes, Sven Hermann, Michael Schäfers, Fons A J van de Loo, Peter M van der Kraan, Marije I Koenders, Dirk Foell, Johannes Roth, Thomas Vogl, Peter L E M van Lent
BACKGROUND: Seronegative joint diseases are characterized by a lack of well-defined biomarkers since autoantibodies are not elevated. Calprotectin (S100A8/A9) is a damage-associated molecular pattern (DAMP) which is released by activated phagocytes, and high levels are found in seronegative arthritides. In this study, we investigated the biomarker potential of systemic and local levels of these S100 proteins to assess joint inflammation and joint destruction in an experimental model for seronegative arthritis...
October 24, 2016: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/27762323/exploiting-the-neoantigen-landscape-for-immunotherapy-of-pancreatic-ductal-adenocarcinoma
#13
Peter Bailey, David K Chang, Marie-Andrée Forget, Francis A San Lucas, Hector A Alvarez, Cara Haymaker, Chandrani Chattopadhyay, Sun-Hee Kim, Suhendan Ekmekcioglu, Elizabeth A Grimm, Andrew V Biankin, Patrick Hwu, Anirban Maitra, Jason Roszik
Immunotherapy approaches for pancreatic ductal adenocarcinoma (PDAC) have met with limited success. It has been postulated that a low mutation load may lead to a paucity of T cells within the tumor microenvironment (TME). However, it is also possible that while neoantigens are present, an effective immune response cannot be generated due to an immune suppressive TME. To discern whether targetable neoantigens exist in PDAC, we performed a comprehensive study using genomic profiles of 221 PDAC cases extracted from public databases...
October 20, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27642636/lack-of-immunoediting-in-murine-pancreatic-cancer-reversed-with-neoantigen
#14
Rebecca A Evans, Mark S Diamond, Andrew J Rech, Timothy Chao, Max W Richardson, Jeffrey H Lin, David L Bajor, Katelyn T Byrne, Ben Z Stanger, James L Riley, Nune Markosyan, Rafael Winograd, Robert H Vonderheide
In carcinogen-driven cancers, a high mutational burden results in neoepitopes that can be recognized immunologically. Such carcinogen-induced tumors may evade this immune response through "immunoediting," whereby tumors adapt to immune pressure and escape T cell-mediated killing. Many tumors lack a high neoepitope burden, and it remains unclear whether immunoediting occurs in such cases. Here, we evaluated T cell immunity in an autochthonous mouse model of pancreatic cancer and found a low mutational burden, absence of predicted neoepitopes derived from tumor mutations, and resistance to checkpoint immunotherapy...
September 8, 2016: JCI Insight
https://www.readbyqxmd.com/read/27622028/current-tools-for-predicting-cancer-specific-t-cell-immunity
#15
REVIEW
David Gfeller, Michal Bassani-Sternberg, Julien Schmidt, Immanuel F Luescher
Tumor exome and RNA sequencing data provide a systematic and unbiased view on cancer-specific expression, over-expression, and mutations of genes, which can be mined for personalized cancer vaccines and other immunotherapies. Of key interest are tumor-specific mutations, because T cells recognizing neoepitopes have the potential to be highly tumoricidal. Here, we review recent developments and technical advances in identifying MHC class I and class II-restricted tumor antigens, especially neoantigen derived MHC ligands, including in silico predictions, immune-peptidome analysis by mass spectrometry, and MHC ligand validation by biochemical methods on T cells...
July 2016: Oncoimmunology
https://www.readbyqxmd.com/read/27622017/mhc-multimer-guided-isolation-of-neoepitopes-specific-t-cells-as-a-potent-personalized-cancer-treatment-strategy
#16
Roni Bareli, Cyrille J Cohen
Analysis of genomic data from patient tumors provides valuable information as to potential T-cell targets such as neoepitopes. We developed an approach to characterize, isolate and utilize neoantigens-specific T cells using MHC/peptide tetramers from fresh tumor digests and peripheral blood. This bears important implications for the implementation of T cell-based immunotherapy.
July 2016: Oncoimmunology
https://www.readbyqxmd.com/read/27606571/evading-pre-existing-anti-hinge-antibody-binding-by-hinge-engineering
#17
Hok Seon Kim, Ingrid Kim, Linda Zheng, Jean-Michel Vernes, Y Gloria Meng, Christoph Spiess
Antigen-binding fragments (Fab) and F(ab')2 antibodies serve as alternative formats to full-length anti-bodies in therapeutic and immune assays. They provide the advantage of small size, short serum half-life, and lack of effector function. Several proteases associated with invasive diseases are known to cleave antibodies in the hinge-region, and this results in anti-hinge antibodies (AHA) toward the neoepitopes. The AHA can act as surrogate Fc and reintroduce the properties of the Fc that are otherwise lacking in antibody fragments...
August 9, 2016: MAbs
https://www.readbyqxmd.com/read/27602483/spaceflight-relevant-challenges-of-radiation-and-or-reduced-weight-bearing-cause-arthritic-responses-in-knee-articular-cartilage
#18
J S Willey, A T Kwok, J E Moore, V Payne, C A Lindburg, S A Balk, J Olson, P J Black, M C Walb, R R Yammani, M T Munley
There is little known about the effect of both reduced weight bearing and exposure to radiation during spaceflight on the mechanically-sensitive cartilage lining the knee joint. In this study, we characterized cartilage damage in rat knees after periods of reduced weight bearing with/without exposure to solar-flare-relevant radiation, then cartilage recovery after return to weight bearing. Male Sprague Dawley rats (n = 120) were either hindlimb unloaded (HLU) via tail suspension or remained weight bearing in cages (GROUND)...
September 7, 2016: Radiation Research
https://www.readbyqxmd.com/read/27590768/analysis-of-immune-epitopes-of-respiratory-syncytial-virus-for-designing-of-vectored-vaccines-based-on-influenza-virus-platform
#19
I N Isakova-Sivak, D A Korenkov, E A Fedorova, T S Tretiak, V A Matyushenko, T A Smolonogina, L G Rudenko
The immunoepitope database was used for analysis of experimentally detected epitopes of the respiratory syncytial virus (RSV) proteins and for selection of the epitope combinations for subsequent designing of recombinant vectored anti-RSV vaccines based on attenuated influenza viruses. Three cassettes containing the most promising B- and T-cell RSV epitopes were selected: peptide F (243-294) supporting the formation of humoral immunity in animals; fragment M2-1 (70-101+114-146) containing two MHC I epitopes (82-90 and 127-135); and MHC II-epitope (51-66)...
August 2016: Bulletin of Experimental Biology and Medicine
https://www.readbyqxmd.com/read/27588825/role-of-igm-and-angiotensin-ii-type-i-receptor-autoantibodies-in-local-complement-activation-in-placental-ischemia-induced-hypertension-in-the-rat
#20
Jean F Regal, Megan E Strehlke, Jenna M Peterson, Cameron R Wing, Jordan E Parker, Noel Fernando Nieto, Lynne T Bemis, Jeffrey S Gilbert, Sherry D Fleming
Preeclampsia is characterized by development of hypertension during pregnancy and reduced placental perfusion. Previous studies in a rat model of placental ischemia-induced hypertension demonstrated that inhibiting complement activation attenuated increased maternal blood pressure with C3a and C5a identified as the important products of complement activation. Given that in other forms of ischemia both natural IgM and antigen antibody complexes initiate complement activation, we hypothesized that placental ischemia exposes neoepitopes recognized by IgM to cause local complement activation and hypertension...
October 2016: Molecular Immunology
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