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https://www.readbyqxmd.com/read/27879972/responses-of-metastatic-basal-cell-and-cutaneous-squamous-cell-carcinomas-to-anti-pd1-monoclonal-antibody-regn2810
#1
Gerald S Falchook, Rom Leidner, Elizabeth Stankevich, Brian Piening, Carlo Bifulco, Israel Lowy, Matthew G Fury
BACKGROUND: Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (CSCC) share exposure to UV light as the dominant risk factor, and these tumors therefore harbor high mutation burdens. In other malignancies, high mutation burden has been associated with clinical benefit from therapy with antibodies directed against the Programmed Death 1 (PD-1) immune checkpoint receptor. Highly mutated tumors are more likely to express immunogenic tumor neoantigens that attract effector T cells, which can be unleashed by blockade of the PD-1 immune checkpoint...
2016: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/27869121/direct-identification-of-clinically-relevant-neoepitopes-presented-on-native-human-melanoma-tissue-by-mass-spectrometry
#2
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/27853827/increased-pd-l1-and-t-cell-infiltration-in-the-presence-of-hla-class-i-expression-in-metastatic-high-grade-osteosarcoma-a-rationale-for-t-cell-based-immunotherapy
#3
Yayan T Sundara, Marie Kostine, Arjen H G Cleven, Judith V M G Bovée, Marco W Schilham, Anne-Marie Cleton-Jansen
INTRODUCTION: Immunotherapy may be an excellent choice for treating osteosarcoma given its exceptionally high genomic instability, potentially generating neoantigens. In this study, we aim to investigate the HLA class I expression, PD-L1 and tumour-infiltrating lymphocytes in primary osteosarcomas and relapses/metastases, as well as their changes during disease progression. MATERIALS AND METHODS: Tumour samples from multiple stages of the disease (pretreatment biopsies, surgical resections of primary osteosarcomas, relapses and metastases) were collected and stained for HLA-A (HCA2), HLA-B/C (HC10), β2-microglobulin and PD-L1 using immunohistochemistry on whole sections...
November 16, 2016: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/27852700/genomic-evolution-after-chemoradiotherapy-in-anal-squamous-cell-carcinoma
#4
Kent W Mouw, James M Cleary, Brendan Reardon, Jonathan Pike, Lior Z Braunstein, Jaegil Kim, Ali Amin-Mansour, Diana Miao, Alexis Damish, Joanna Chin, Patrick A Ott, Charles S Fuchs, Neil E Martin, Gad Getz, Scott Carter, Harvey Mamon, Jason L Hornick, Eliezer Van Allen, Alan D D'Andrea
PURPOSE: Squamous cell carcinoma of the anal canal (ASCC) accounts for 2-4% of gastrointestinal (GI) malignancies in the US and is increasing in incidence; however, genomic features of ASCC are incompletely characterized. Primary treatment of ASCC involves concurrent chemotherapy and radiation (CRT), but the mutational landscape of resistance to CRT is unknown. Here, we aim to compare mutational features of ASCC in the pre- and post-CRT setting. EXPERIMENTAL DESIGN: We perform whole exome sequencing of primary (n=31) and recurrent (n=31) ASCCs and correlate findings with clinical data...
November 16, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27834354/gene-expression-profiling-to-predict-responsiveness-to-immunotherapy
#5
REVIEW
N B Jamieson, A V Maker
Recent clinical successes with immunotherapy have resulted in expanding indications for cancer therapy. To enhance antitumor immune responses, and to better choose specific strategies matched to patient and tumor characteristics, genomic-driven precision immunotherapy will be necessary. Herein, we explore the role that tumor gene-expression profiling (GEP) may have in the prediction of an immunotherapeutic response. Genetic markers associated with response to immunotherapy are addressed as they pertain to the tumor genomic landscape, the extent of DNA damage, tumor mutational load and tumor-specific neoantigens...
November 11, 2016: Cancer Gene Therapy
https://www.readbyqxmd.com/read/27827318/isolation-of-t-cell-receptors-specifically-reactive-with-mutated-tumor-associated-antigens-from-tumor-infiltrating-lymphocytes-based-on-cd137-expression
#6
Maria R Parkhurst, Alena Gros, Anna Pasetto, Todd D Prickett, Jessica S Crystal, Paul F Robbins, Steven A Rosenberg
PURPOSE: The adoptive transfer of lymphocytes genetically modified to express tumor reactive T cell receptors (TCRs) can mediate tumor regression. Some tumor infiltrating lymphocytes (TIL) recognize somatic mutations expressed only in the patient's tumors, and evidence suggests that clinically effective TIL target tumor specific neoantigens. Here we attempted to isolate neoantigen reactive TCRs as a prelude to the treatment of patients with autologous T cells genetically modified to express such TCRs...
November 8, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27807100/successful-treatment-of-a-patient-with-glioblastoma-and-a-germline-pole-mutation-where-next
#7
Alexandra Snyder, Jedd D Wolchok
Hypermutation and elevated neoantigen count in glioblastoma occurred in a patient harboring a germline POLE mutation and are associated with a clinical and antitumor immune response to PD-1 blockade. Cancer Discov; 6(11); 1210-11. ©2016 AACR.See related article by Johanns et al., p. 1230.
November 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27801682/blockade-of-igm-mediated-inflammation-alters-wound-progression-in-a-swine-model-of-partial-thickness-burn
#8
Hamed Sadeghipour, Radbeh Torabi, James Gottschall, Jorge Lujan-Hernandez, David H Sachs, Francis D Moore, Curtis L Cetrulo
In a mouse model, a second-degree burn elicits a severe inflammatory response that is mediated by circulating autoantibody specific for a neoantigen (nonmuscle myosin). Nonmuscle myosin is expressed by injured tissue, leading to amplified ulceration and scarring. We hypothesize that a synthetic peptide (N2) can mimic the neoantigen and competitively inhibit the autoantibody, decreasing inflammation, and reducing the extent of burn injury in a preclinical swine model of burn. Second-degree burns were created on young swine using brass cylinders, warmed to varying temperatures before skin contact...
October 27, 2016: Journal of Burn Care & Research: Official Publication of the American Burn Association
https://www.readbyqxmd.com/read/27799140/endogenous-neoantigen-specific-cd8-t-cells-identified-in-two-glioblastoma-models-using-a-cancer-immunogenomics-approach
#9
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/27797777/integrate-neo-a-pipeline-for-personalized-gene-fusion-neoantigen-discovery
#10
Jin Zhang, Elaine R Mardis, Christopher A Maher
MOTIVATION: While high-throughput sequencing (HTS) has been used successfully to discover tumor-specific mutant peptides (neoantigens) from somatic missense mutations, the field currently lacks a method for identifying which gene fusions may generate neoantigens. RESULTS: We demonstrate the application of our gene fusion neoantigen discovery pipeline, called INTEGRATE-Neo, by identifying gene fusions in prostate cancers that may produce neoantigens. AVAILABILITY: INTEGRATE-Neo is implemented in C++ and Python...
October 24, 2016: Bioinformatics
https://www.readbyqxmd.com/read/27797438/putting-t-cells-to-work-outsourcing-neoantigen-detection-in-head-and-neck-cancer
#11
Roy Xiao, Carter Van Waes, Nicole C Schmitt
The recent genomic characterization of head and neck squamous cell carcinomas by The Cancer Genome Atlas demonstrated the high frequency of mutations affecting these cancers (Cancer Genome Atlas Network, 2015). This high rate of genomic alterations allows head and neck cancers to be highly immunogenic, thus promoting responses to immune therapies (Allen et al, 2015; Ferris, 2015). For instance, inhibitors of immune checkpoints like the anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab have demonstrated promising results in head and neck cancer (Ferris et al, 2016; Chow et al, 2016), both recently receiving FDA approval in the setting of recurrent or metastatic disease...
October 31, 2016: Oral Diseases
https://www.readbyqxmd.com/read/27776977/emerging-role-of-checkpoint-inhibition-in-localized-bladder-cancer
#12
REVIEW
Parminder Singh, Peter Black
OBJECTIVE: Checkpoint inhibitors have rapidly become a standard treatment option for metastatic urothelial carcinoma. A wave of enthusiasm for these drugs has pushed them also into the setting of localized bladder cancer, including both non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive disease bladder cancer (MIBC). Here, we aimed to review the emerging role of checkpoint inhibition in localized bladder cancer. METHODS: We reviewed the current treatment landscape for both NMIBC and MIBC and established a significant unmet clinical need for novel therapies...
December 2016: Urologic Oncology
https://www.readbyqxmd.com/read/27775332/how-reactive-metabolites-induce-an-immune-response-that-sometimes-leads-to-an-idiosyncratic-drug-reaction
#13
Tiffany Elizabeth Cho, Jack Uetrecht
Little is known with certainty about the mechanisms of idiosyncratic drug reactions (IDRs); however, there is substantive evidence that reactive metabolites are involved in most, but not all, IDRs. In addition, evidence also suggests that most IDRs are immune mediated. That raises the question of how reactive metabolites induce an immune response that can lead to an IDR. The dominant hypotheses are the hapten and danger hypotheses. These are complementary hypotheses: a reactive metabolite can act as a hapten to produce neoantigens, and it can also cause cell damage leading to the release of danger-associated molecular pattern molecules that activate antigen presenting cells...
October 24, 2016: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/27769045/inducible-expression-of-cancer-testis-antigens-in-human-prostate-cancer
#14
Erika Heninger, Timothy E G Krueger, Stephanie M Thiede, Jamie M Sperger, Brianna L Byers, Madison R Kircher, David Kosoff, Bing Yang, David F Jarrard, Douglas G McNeel, Joshua M Lang
Immune tolerance to self-antigens can limit robust anti-tumor immune responses in the use of tumor vaccines. Expression of novel tumor associated antigens can improve immune recognition and lysis of tumor cells. The cancer-testis antigen (CTA) family of proteins has been hypothesized to be an ideal class of antigens due to tumor-restricted expression, a subset of which have been found to induce antibody responses in patients with prostate disease. We demonstrate that CTA expression is highly inducible in five different Prostate Cancer (PC) cell lines using a hypomethylating agent 5-Aza-2'-deoxycytidine (5AZA) and/or a histone deacetylase inhibitor LBH589...
October 17, 2016: Oncotarget
https://www.readbyqxmd.com/read/27768182/association-of-distinct-mutational-signatures-with-correlates-of-increased-immune-activity-in-pancreatic-ductal-adenocarcinoma
#15
Ashton A Connor, Robert E Denroche, Gun Ho Jang, Lee Timms, Sangeetha N Kalimuthu, Iris Selander, Treasa McPherson, Gavin W Wilson, Michelle A Chan-Seng-Yue, Ivan Borozan, Vincent Ferretti, Robert C Grant, Ilinca M Lungu, Eithne Costello, William Greenhalf, Daniel Palmer, Paula Ghaneh, John P Neoptolemos, Markus Buchler, Gloria Petersen, Sarah Thayer, Michael A Hollingsworth, Alana Sherker, Daniel Durocher, Neesha Dhani, David Hedley, Stefano Serra, Aaron Pollett, Michael H A Roehrl, Prashant Bavi, John M S Bartlett, Sean Cleary, Julie M Wilson, Ludmil B Alexandrov, Malcolm Moore, Bradly G Wouters, John D McPherson, Faiyaz Notta, Lincoln D Stein, Steven Gallinger
Importance: Outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) remain poor. Advances in next-generation sequencing provide a route to therapeutic approaches, and integrating DNA and RNA analysis with clinicopathologic data may be a crucial step toward personalized treatment strategies for this disease. Objective: To classify PDAC according to distinct mutational processes, and explore their clinical significance. Design, Setting, and Participants: We performed a retrospective cohort study of resected PDAC, using cases collected between 2008 and 2015 as part of the International Cancer Genome Consortium...
October 20, 2016: JAMA Oncology
https://www.readbyqxmd.com/read/27764823/immunological-microenvironment-of-hepatocellular-carcinoma-and-its-clinical-implication
#16
Naoshi Nishida, Masatoshi Kudo
Despite recent advances in the treatment of hepatocellular carcinoma (HCC), the prognosis of patients with advanced stage of disease remains unfavorable. Several immune therapies have been applied to HCC, and their responses have not been satisfactory. The immune response to cancer is determined by the balance between the antigenicity of the tumor and the microenvironment of cancer tissues. Generally, accumulated genetic mutations are observed in HCC, which may lead to increased neoantigens on cancer cells with high antigenicity...
October 21, 2016: Oncology
https://www.readbyqxmd.com/read/27762323/exploiting-the-neoantigen-landscape-for-immunotherapy-of-pancreatic-ductal-adenocarcinoma
#17
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/27751760/neoantigens-in-immunotherapy-and-personalized-vaccines-implications-for-head-and-neck-squamous-cell-carcinoma
#18
Paul Zolkind, Gavin P Dunn, Tianxiang Lin, Malachi Griffith, Obi L Griffith, Ravindra Uppaluri
The recent success of immunotherapies has demonstrated the potency of tumor-specific immune cells in mediating tumor rejection and generating durable tumor immunity. Our understanding of the scientific basis of these responses results from the confluence of a better comprehension of the cancer immunoediting process and the revolution in next generation sequencing of cancer genomes. Recent evidence suggests that T cell specificity for cancer cell expressed mutant proteins - termed neoantigens - is an important component of immune mediated tumor rejection...
October 14, 2016: Oral Oncology
https://www.readbyqxmd.com/read/27750214/genomic-characterization-of-high-risk-non-muscle-invasive-bladder-cancer
#19
Joshua J Meeks, Benedito A Carneiro, Sachin G Pai, Daniel T Oberlin, Alfred Rademaker, Kyle Fedorchak, Sohail Balasubramanian, Julia Elvin, Nike Beaubier, Francis J Giles
The genetic mechanisms associated with progression of high-risk non-muscle-invasive bladder cancer (HR-NMIBC) have not been described. We conducted selective next-generation sequencing (NGS) of HR-NMIBC and compared the genomic profiles of cancers that responded to intravesical therapy and those that progressed to muscle-invasive or advanced disease. DNA was extracted from paraffin-embedded sections from 25 HR-NMIBCs (22 with T1HG; 3 with TaHG with or without carcinoma in situ). Ten patients with HR-NMIBC developed progression (pT2+ or N+) ("progressors")...
October 14, 2016: Oncotarget
https://www.readbyqxmd.com/read/27729860/understanding-the-impact-of-erbb-activating-events-and-signal-transduction-on-antigen-processing-and-presentation-mhc-expression-as-a-model
#20
Anna E Kersh, Maiko Sasaki, Lee A Cooper, Haydn T Kissick, Brian P Pollack
Advances in molecular pathology have changed the landscape of oncology. The ability to interrogate tissue samples for oncogene amplification, driver mutations, and other molecular alterations provides clinicians with an enormous level of detail about their patient's cancer. In some cases, this information informs treatment decisions, especially those related to targeted anti-cancer therapies. However, in terms of immune-based therapies, it is less clear how to use such information. Likewise, despite studies demonstrating the pivotal role of neoantigens in predicting responsiveness to immune checkpoint blockade, it is not known if the expression of neoantigens impacts the response to targeted therapies despite a growing recognition of their diverse effects on immunity...
2016: Frontiers in Pharmacology
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