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https://www.readbyqxmd.com/read/28813655/making-it-personal-neoantigen-vaccines-in-metastatic-melanoma
#1
Matthew D Hellmann, Alexandra Snyder
Somatic mutations in cancer can be translated into peptides, termed neoantigens, which can be recognized by the immune system as "foreign" epitopes. Two recent studies in Nature (Sahin et al., 2017; Ott et al., 2017) examine the effects of neoantigen vaccines on patients with stage III or IV melanoma and demonstrate immunogenicity and intriguing clinical safety and efficacy data in phase I studies.
August 15, 2017: Immunity
https://www.readbyqxmd.com/read/28802495/the-immunology-of-melanoma
#2
REVIEW
Jennifer S Ko
The relatively high DNA mutational burden in melanoma allows for the creation of potentially "foreign," immune-stimulating neoantigens, and leads to its exceptional immunogenicity. Brisk tumor-infiltrating lymphocytes, a marker of immune editing, confer improved overall survival in melanoma, possibly due to reduced sentinel lymph node spread. Meanwhile, T-cell-stimulating drugs, so-called T-cell checkpoint inhibitors, which reverse peripheral tolerance-dependent tumor escape, have demonstrated unparalleled clinical success in metastatic melanoma...
September 2017: Clinics in Laboratory Medicine
https://www.readbyqxmd.com/read/28770222/mismatch-repair-deficiency-as-a-predictive-biomarker-for-immunotherapy-efficacy
#3
REVIEW
Giulia Viale, Dario Trapani, Giuseppe Curigliano
Immunotherapy has revolutionized cancer treatment. Immune-checkpoint inhibitors, on balance, showed a favorable efficacy/toxicity profile with durable response in different cancer types. No predictive biomarker has been validated thus far to select patients who would benefit from therapy. Among the candidate predictive biomarkers, mismatch repair status of the tumor is currently one of the most promising. Indeed, tumors displaying mismatch repair deficiency or microsatellite instability showed remarkable response to immunotherapy in clinical trials...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28761058/heterogeneity-of-tumor-infiltrating-lymphocytes-ascribed-to-local-immune-status-rather-than-neoantigens-by-multi-omics-analysis-of-glioblastoma-multiforme
#4
Lin Feng, Haipeng Qian, Xuexin Yu, Kan Liu, Ting Xiao, Chengli Zhang, Manchao Kuang, Shujun Cheng, Xueji Li, Jinghai Wan, Kaitai Zhang
Hypothetically, intratumoral genomic heterogeneity has the potential to foster tumor-infiltrating lymphocyte (TIL) diversity; however, no study has directly tested this hypothesis by simultaneously investigating somatic mutations, TIL diversity, and immune response activity. Thus, we performed whole-exome sequencing, immune repertoire sequencing and gene expression on ten spatially separated tumor samples obtained from two tumor masses excised from a glioblastoma multiforme (GBM) patient, and we included peripheral blood as control...
July 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28754680/versican-derived-matrikines-regulate-batf3-dendritic-cell-differentiation-and-promote-t-cell-infiltration-in-colorectal-cancer
#5
Chelsea Hope, Philip B Emmerich, Athanasios Papadas, Adam Pagenkopf, Kristina A Matkowskyj, Dana R Van De Hey, Susan N Payne, Linda Clipson, Natalie S Callander, Peiman Hematti, Shigeki Miyamoto, Michael G Johnson, Dustin A Deming, Fotis Asimakopoulos
Colorectal cancer originates within immunologically complex microenvironments. To date, the benefits of immunotherapy have been modest, except in neoantigen-laden mismatch repair-deficient tumors. Approaches to enhance tumor-infiltrating lymphocytes in the tumor bed may substantially augment clinical immunotherapy responses. In this article, we report that proteolysis of the tolerogenic matrix proteoglycan versican (VCAN) strongly correlated with CD8(+) T cell infiltration in colorectal cancer, regardless of mismatch repair status...
July 28, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28750120/association-between-genomic-metrics-and-immune-infiltration-in-triple-negative-breast-cancer
#6
Thomas Karn, Tingting Jiang, Christos Hatzis, Nicole Sänger, Ahmed El-Balat, Achim Rody, Uwe Holtrich, Sven Becker, Giampaolo Bianchini, Lajos Pusztai
Importance: Why some triple-negative breast cancers (TNBCs) have high and others have low immune cell infiltration is unknown. Understanding how immune surveillance shapes the cancer genome could help in the selection of patients and the development of more effective immunotherapy strategies. Objective: To examine the association between genomic metrics and the extent of immune infiltration in TNBCs. Design, Setting, and Participants: This study, performed from June 1, 2015, through January 31, 2017, used DNA and RNA sequencing data and messenger RNA expression results from The Cancer Genome Atlas (TCGA) breast cancer data set (n = 1215) to calculate previously described immune metagene expression values and histologic lymphocyte counts to quantify immune infiltration and assign prognostic categories to TNBCs...
July 27, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/28739880/neoantigen-expression-in-steady-state-langerhans-cells-induces-ctl-tolerance
#7
Helen Strandt, Douglas Florindo Pinheiro, Daniel H Kaplan, Dagmar Wirth, Iris Karina Gratz, Peter Hammerl, Josef Thalhamer, Angelika Stoecklinger
The skin hosts a variety of dendritic cells (DCs), which act as professional APC to control cutaneous immunity. Langerhans cells (LCs) are the only DC subset in the healthy epidermis. However, due to the complexity of the skin DC network, their relative contribution to either immune activation or immune tolerance is still not entirely understood. To specifically study the function of LCs in vivo, without altering the DC subset composition in the skin, we have generated transgenic mouse models for tamoxifen-inducible de novo expression of Ags in LCs but no other langerin(+) DCs...
July 24, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28734759/nivolumab-in-patients-with-metastatic-dna-mismatch-repair-deficient-or-microsatellite-instability-high-colorectal-cancer-checkmate-142-an-open-label-multicentre-phase-2-study
#8
Michael J Overman, Ray McDermott, Joseph L Leach, Sara Lonardi, Heinz-Josef Lenz, Michael A Morse, Jayesh Desai, Andrew Hill, Michael Axelson, Rebecca A Moss, Monica V Goldberg, Z Alexander Cao, Jean-Marie Ledeine, Gregory A Maglinte, Scott Kopetz, Thierry André
BACKGROUND: Metastatic DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer has a poor prognosis after treatment with conventional chemotherapy and exhibits high levels of tumour neoantigens, tumour-infiltrating lymphocytes, and checkpoint regulators. All of these features are associated with the response to PD-1 blockade in other tumour types. Therefore, we aimed to study nivolumab, a PD-1 immune checkpoint inhibitor, in patients with dMMR/MSI-H metastatic colorectal cancer...
July 19, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28733428/tcr-repertoire-intratumor-heterogeneity-in-localized-lung-adenocarcinomas-an-association-with-predicted-neoantigen-heterogeneity-and-postsurgical-recurrence
#9
Alexandre Reuben, Rachel M Gittelman, Jianjun Gao, Jiexin Zhang, Erik Yusko, Chang-Jiun Wu, Ryan Emerson, Jianhua Zhang, Christopher M Tipton, Jun Li, Kelly Quek, Vancheswaran Gopalakrishnan, Runzhe Chen, Luis Vence, Tina Cascone, Marissa Vignali, Junya Fujimoto, Jaime Rodriguez-Canales, Edwin R Parra, Latasha D Little, Curtis Gumbs, Marie-Andrée Forget, Lorenzo Federico, Cara Haymaker, Carmen Behrens, Sharon Benzeno, Chantale Bernatchez, Boris Sepesi, Don L Gibbons, Jennifer A Wargo, William N William, Stephen G Swisher, John Heymach, Harlan Robins, J Jack Lee, Padmanee Sharma, James P Allison, P Andrew Futreal, Ignacio I Wistuba, Jianjun Zhang
Genomic intratumor heterogeneity (ITH) may be associated with postsurgical relapse of localized lung adenocarcinomas. Recently, mutations, through generation of neoantigens were shown to alter tumor immunogenicity through T cell responses. Here, we performed sequencing of the T cell receptor (TCR) in 45 tumor regions from 11 localized lung adenocarcinomas and observed substantial intratumor differences in T cell density and clonality with the majority of T cell clones restricted to individual tumor regions...
July 21, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28733426/frameshift-indels-generate-highly-immunogenic-tumor-neoantigens
#10
(no author information available yet)
Renal clear cell carcinomas have the highest proportion of indels, which are linked to immune activation.
July 21, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28726535/mismatch-repair-deficient-metastatic-colon-cancer-and-urothelial-cancer-a-case-report-of-sequential-immune-checkpoint-therapy
#11
Pooja Ghatalia, Rajeswari Nagarathinam, Harry Cooper, Daniel M Geynisman, Wafik S El-Deiry
A major recent advance in cancer therapy involves the use of immune checkpoint therapy for tumors with mismatch repair deficiency, as they have a high tumor mutation load and neoantigen burden. Approximately 4% of advanced colorectal cancer harbors a mismatch repair deficiency. When mismatch repair deficiency exists in the germline, there is increased susceptibility to a variety of cancers including colorectal cancer, uterine cancer, urothelial carcinoma, and skin cancer. Herein we report the case of a 62-year-old man with mismatch repair deficient metastatic colorectal adenocarcinoma, urothelial carcinoma and a history of sebaceous carcinomas...
July 20, 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/28723478/low-t-cell-receptor-diversity-high-somatic-mutation-burden-and-high-neoantigen-load-as-predictors-of-clinical-outcome-in-muscle-invasive-bladder-cancer
#12
Noura J Choudhury, Kazuma Kiyotani, Kai Lee Yap, Alexa Campanile, Tatjana Antic, Poh Yin Yew, Gary Steinberg, Jae Hyun Park, Yusuke Nakamura, Peter H O'Donnell
BACKGROUND: The success of cancer immunotherapies has highlighted the potent ability of local adaptive immune responses to eradicate cancer cells by targeting neoantigens generated by somatic alterations. However, how these factors interact to drive the natural history of muscle-invasive bladder cancer (MIBC) is not well understood. OBJECTIVE: To investigate the role of immune regulation in MIBC disease progression, we performed massively parallel T-cell receptor (TCR) sequencing of tumor-infiltrating T cells (TILs), in silico neoantigen prediction from exome sequences, and expression analysis of immune-related genes...
October 2016: European Urology Focus
https://www.readbyqxmd.com/read/28714780/atezolizumab-for-the-treatment-of-non-small-cell-lung-cancer
#13
Fernando C Santini, Charles M Rudin
The immune system can restrain or promote cancer development and growth. Antibodies targeting immune checkpoints have revolutionized cancer treatment. Among the best responses have been in non-small cell lung cancer (NSCLC) which is largely caused by chronic exposure to carcinogens; associated with high neoantigen creation and sensitization to immune recognition. Atezolizumab was the first approved antibody that targets the PD-1 ligand (PD-L1). Areas covered: This drug profile article covers the basics of the cancer-immunity cycle and reviews some aspects of innate and adaptive immunology...
July 27, 2017: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/28714192/secreted-tumor-antigens-immune-biomarkers-for-diagnosis-and-therapy
#14
REVIEW
Els N Meeusen, Elgene Lim, Suresh Mathivanan
With the advent of immunotherapies for cancer, there is growing interest in the identification of tumor antigens. Tumor antigens are self-molecules altered through genetic mutations (neoantigens), protein truncation, protein misfolding or abnormal post translational modifications. To induce an immune response, tumor antigens need to be secreted into the tumor environment and presented to the immune system in the draining lymph nodes, resulting in the generation of tumor-specific effector cells and antibodies...
July 17, 2017: Proteomics
https://www.readbyqxmd.com/read/28713588/genomic-landscape-of-high-grade-meningiomas
#15
Wenya Linda Bi, Noah F Greenwald, Malak Abedalthagafi, Jeremiah Wala, Will J Gibson, Pankaj K Agarwalla, Peleg Horowitz, Steven E Schumacher, Ekaterina Esaulova, Yu Mei, Aaron Chevalier, Matthew Ducar, Aaron R Thorner, Paul van Hummelen, Anat Stemmer-Rachamimov, Maksym Artyomov, Ossama Al-Mefty, Gavin P Dunn, Sandro Santagata, Ian F Dunn, Rameen Beroukhim
High-grade meningiomas frequently recur and are associated with high rates of morbidity and mortality. To determine the factors that promote the development and evolution of these tumors, we analyzed the genomes of 134 high-grade meningiomas and compared this information with data from 587 previously published meningiomas. High-grade meningiomas had a higher mutation burden than low-grade meningiomas but did not harbor any statistically significant mutated genes aside from NF2. High-grade meningiomas also possessed significantly elevated rates of chromosomal gains and losses, especially among tumors with monosomy 22...
2017: NPJ Genomic Medicine
https://www.readbyqxmd.com/read/28706143/integrated-analysis-of-somatic-mutations-and-immune-microenvironment-of-multiple-regions-in-breast-cancers
#16
Taigo Kato, Jae-Hyun Park, Kazuma Kiyotani, Yuji Ikeda, Yasuo Miyoshi, Yusuke Nakamura
Next-generation sequencing technology enables us to analyze the complexity of intra- and inter-tumoral heterogeneity, which may influence to prognosis of cancer patients. In this study, we collected surgically-resected tumor tissues from five breast cancer patients and characterized three different portions of individual tumors through somatic mutation analysis by whole exome sequencing, T cell receptor beta (TCRB) repertoire analysis of tumor-infiltrating lymphocytes (TILs), and the expression analysis of immune-related genes at 15 different sites...
June 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28698955/role-of-natural-igm-autoantibodies-igm-naa-and-igm-anti-leukocyte-antibodies-igm-ala-in-regulating-inflammation
#17
Peter I Lobo
Natural IgM autoantibodies (IgM-NAA) are rapidly produced to inhibit pathogens and abrogate inflammation mediated by invading microorganisms and host neoantigens. IgM-NAA achieve this difficult task by being polyreactive with low binding affinity but with high avidity, characteristics that allow these antibodies to bind antigenic determinants shared by pathogens and neoantigens. Hence the same clones of natural IgM can bind and mask host neoantigens as well as inhibit microorganisms. In addition, IgM-NAA regulate the inflammatory response via mechanisms involving binding of IgM to apoptotic cells to enhance their removal and binding of IgM to live leukocytes to regulate their function...
July 12, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/28694034/insertion-and-deletion-derived-tumour-specific-neoantigens-and-the-immunogenic-phenotype-a-pan-cancer-analysis
#18
Samra Turajlic, Kevin Litchfield, Hang Xu, Rachel Rosenthal, Nicholas McGranahan, James L Reading, Yien Ning S Wong, Andrew Rowan, Nnennaya Kanu, Maise Al Bakir, Tim Chambers, Roberto Salgado, Peter Savas, Sherene Loi, Nicolai J Birkbak, Laurent Sansregret, Martin Gore, James Larkin, Sergio A Quezada, Charles Swanton
BACKGROUND: The focus of tumour-specific antigen analyses has been on single nucleotide variants (SNVs), with the contribution of small insertions and deletions (indels) less well characterised. We investigated whether the frameshift nature of indel mutations, which create novel open reading frames and a large quantity of mutagenic peptides highly distinct from self, might contribute to the immunogenic phenotype. METHODS: We analysed whole-exome sequencing data from 5777 solid tumours, spanning 19 cancer types from The Cancer Genome Atlas...
August 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28680756/amplification-of-n-myc-is-associated-with-a-t-cell-poor-microenvironment-in-metastatic-neuroblastoma-restraining-interferon-pathway-activity-and-chemokine-expression
#19
Julian P Layer, Marie T Kronmüller, Thomas Quast, Debby van den Boorn-Konijnenberg, Maike Effern, Daniel Hinze, Kristina Althoff, Alexander Schramm, Frank Westermann, Martin Peifer, Gunther Hartmann, Thomas Tüting, Waldemar Kolanus, Matthias Fischer, Johannes Schulte, Michael Hölzel
Immune checkpoint inhibitors have significantly improved the treatment of several cancers. T-cell infiltration and the number of neoantigens caused by tumor-specific mutations are correlated to favorable responses in cancers with a high mutation load. Accordingly, checkpoint immunotherapy is thought to be less effective in tumors with low mutation frequencies such as neuroblastoma, a neuroendocrine tumor of early childhood with poor outcome of the high-risk disease group. However, spontaneous regressions and paraneoplastic syndromes seen in neuroblastoma patients suggest substantial immunogenicity...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28678778/an-immunogenic-personal-neoantigen-vaccine-for-patients-with-melanoma
#20
Patrick A Ott, Zhuting Hu, Derin B Keskin, Sachet A Shukla, Jing Sun, David J Bozym, Wandi Zhang, Adrienne Luoma, Anita Giobbie-Hurder, Lauren Peter, Christina Chen, Oriol Olive, Todd A Carter, Shuqiang Li, David J Lieb, Thomas Eisenhaure, Evisa Gjini, Jonathan Stevens, William J Lane, Indu Javeri, Kaliappanadar Nellaiappan, Andres M Salazar, Heather Daley, Michael Seaman, Elizabeth I Buchbinder, Charles H Yoon, Maegan Harden, Niall Lennon, Stacey Gabriel, Scott J Rodig, Dan H Barouch, Jon C Aster, Gad Getz, Kai Wucherpfennig, Donna Neuberg, Jerome Ritz, Eric S Lander, Edward F Fritsch, Nir Hacohen, Catherine J Wu
Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens, a class of HLA-bound peptides that arise from tumour-specific mutations. They are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response, their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumours, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules...
July 13, 2017: Nature
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