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Neoantigens

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https://www.readbyqxmd.com/read/29147619/the-jak2v617f-and-calr-exon-9-mutations-are-shared-immunogenic-neoantigens-in-hematological-malignancy
#1
Morten Orebo Holmström, Hans Carl Hasselbalch, Mads Hald Andersen
Approximately 90% of patients with the hematological malignancies termed the chronic myeloproliferative neoplasms harbor either the JAK2V617F-mutation or CALR exon 9 mutation. Both of these are recognized by T-cells, which make the mutations ideal targets for cancer immune therapy as they are shared antigens.
2017: Oncoimmunology
https://www.readbyqxmd.com/read/29133898/intertwining-dna-rna-nanocapsules-loaded-with-tumor-neoantigens-as-synergistic-nanovaccines-for-cancer-immunotherapy
#2
Guizhi Zhu, Lei Mei, Harshad D Vishwasrao, Orit Jacobson, Zhantong Wang, Yijing Liu, Bryant C Yung, Xiao Fu, Albert Jin, Gang Niu, Qin Wang, Fuwu Zhang, Hari Shroff, Xiaoyuan Chen
Nanomedicines that co-deliver DNA, RNA, and peptide therapeutics are highly desirable yet remain underdeveloped for cancer theranostics. Herein, we report self-assembled intertwining DNA-RNA nanocapsules (iDR-NCs) that efficiently delivered synergistic DNA CpG and short hairpin RNA (shRNA) adjuvants, as well as tumor-specific peptide neoantigens into antigen presenting cells (APCs) in lymph nodes for cancer immunotherapy. These nanovaccines were prepared by (1) producing tandem CpG and shRNA via concurrent rolling circle replication and rolling circle transcription, (2) self-assembling CpG and shRNA into DNA-RNA microflowers, (3) shrinking microflowers into iDR-NCs using PEG-grafted cationic polypeptides, and (4) physically loading neoantigen into iDR-NCs...
November 14, 2017: Nature Communications
https://www.readbyqxmd.com/read/29132146/identification-of-unique-neoantigen-qualities-in-long-term-survivors-of-pancreatic-cancer
#3
Vinod P Balachandran, Marta Łuksza, Julia N Zhao, Vladimir Makarov, John Alec Moral, Romain Remark, Brian Herbst, Gokce Askan, Umesh Bhanot, Yasin Senbabaoglu, Daniel K Wells, Charles Ian Ormsby Cary, Olivera Grbovic-Huezo, Marc Attiyeh, Benjamin Medina, Jennifer Zhang, Jennifer Loo, Joseph Saglimbeni, Mohsen Abu-Akeel, Roberta Zappasodi, Nadeem Riaz, Martin Smoragiewicz, Z Larkin Kelley, Olca Basturk, Mithat Gönen, Arnold J Levine, Peter J Allen, Douglas T Fearon, Miriam Merad, Sacha Gnjatic, Christine A Iacobuzio-Donahue, Jedd D Wolchok, Ronald P DeMatteo, Timothy A Chan, Benjamin D Greenbaum, Taha Merghoub, Steven D Leach
Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8(+) T-cell infiltrates, but neither alone, stratified patients with the longest survival...
November 8, 2017: Nature
https://www.readbyqxmd.com/read/29132144/a-neoantigen-fitness-model-predicts-tumour-response-to-checkpoint-blockade-immunotherapy
#4
Marta Łuksza, Nadeem Riaz, Vladimir Makarov, Vinod P Balachandran, Matthew D Hellmann, Alexander Solovyov, Naiyer A Rizvi, Taha Merghoub, Arnold J Levine, Timothy A Chan, Jedd D Wolchok, Benjamin D Greenbaum
Checkpoint blockade immunotherapies enable the host immune system to recognize and destroy tumour cells. Their clinical activity has been correlated with activated T-cell recognition of neoantigens, which are tumour-specific, mutated peptides presented on the surface of cancer cells. Here we present a fitness model for tumours based on immune interactions of neoantigens that predicts response to immunotherapy. Two main factors determine neoantigen fitness: the likelihood of neoantigen presentation by the major histocompatibility complex (MHC) and subsequent recognition by T cells...
November 8, 2017: Nature
https://www.readbyqxmd.com/read/29123950/immune-evasion-mechanisms-and-immune-checkpoint-inhibition-in-advanced-merkel-cell-carcinoma
#5
REVIEW
Dirk Schadendorf, Paul Nghiem, Shailender Bhatia, Axel Hauschild, Philippe Saiag, Lisa Mahnke, Subramanian Hariharan, Howard L Kaufman
Merkel cell carcinoma (MCC) is a rare skin cancer caused by Merkel cell polyomavirus (MCPyV) infection and/or ultraviolet radiation-induced somatic mutations. The presence of tumor-infiltrating lymphocytes is evidence that an active immune response to MCPyV and tumor-associated neoantigens occurs in some patients. However, inhibitory immune molecules, including programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1), within the MCC tumor microenvironment aid in tumor evasion of T-cell-mediated clearance...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/29123260/combining-dna-damaging-therapeutics-with-immunotherapy-more-haste-less-speed
#6
REVIEW
Jessica S Brown, Raghav Sundar, Juanita Lopez
The idea that chemotherapy can be used in combination with immunotherapy may seem somewhat counterproductive, as it can theoretically eliminate the immune cells needed for antitumour immunity. However, much preclinical work has now demonstrated that in addition to direct cytotoxic effects on cancer cells, a proportion of DNA damaging agents may actually promote immunogenic cell death, alter the inflammatory milieu of the tumour microenvironment and/or stimulate neoantigen production, thereby activating an antitumour immune response...
November 9, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/29121062/loss-of-function-jak1-mutations-occur-at-high-frequency-in-cancers-with-microsatellite-instability-and-are-suggestive-of-immune-evasion
#7
Lee A Albacker, Jeremy Wu, Peter Smith, Markus Warmuth, Philip J Stephens, Ping Zhu, Lihua Yu, Juliann Chmielecki
Immune evasion is a well-recognized hallmark of cancer and recent studies with immunotherapy agents have suggested that tumors with increased numbers of neoantigens elicit greater immune responses. We hypothesized that the immune system presents a common selective pressure on high mutation burden tumors and therefore immune evasion mutations would be enriched in high mutation burden tumors. The JAK family of kinases is required for the signaling of a host of immune modulators in tumor, stromal, and immune cells...
2017: PloS One
https://www.readbyqxmd.com/read/29114542/new-trends-in-antitumor-vaccines-in-melanoma
#8
REVIEW
Marcos Vasquez, Shirley Tenesaca, Pedro Berraondo
Antitumor therapeutic vaccines aim at priming an effector immune response able to recognize and kill tumor cells. Antitumor vaccines are composed of at least two main components: the tumor antigens and the adjuvant. Metastatic advanced melanoma has been a model disease to test novel advances in vaccine design due to the intrinsic immunogenicity of this tumor and the accessibility to melanoma lesions to monitor the immune response. In spite of a large number of clinical trials, clinical benefit remains elusive...
October 2017: Annals of Translational Medicine
https://www.readbyqxmd.com/read/29111369/personalized-neoantigen-vaccines-a-new-approach-to-cancer-immunotherapy
#9
Amanda R Aldous, Jesse Z Dong
Neoantigens arise from somatic mutations that differ from wild-type antigens and are specific to each individual patient, which provide tumor specific targets for developing personalized cancer vaccines. Decades of work has increasingly shown the potential of targeting neoantigens to generate effective clinical responses. Current clinical trials using neoantigen targeting cancer vaccines, including in combination with checkpoint blockade monoclonal antibodies, have demonstrated potent T-cell responses against those neoantigens accompanied by antitumor effects in patients...
October 19, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29109393/scalable-whole-exome-sequencing-of-cell-free-dna-reveals-high-concordance-with-metastatic-tumors
#10
Viktor A Adalsteinsson, Gavin Ha, Samuel S Freeman, Atish D Choudhury, Daniel G Stover, Heather A Parsons, Gregory Gydush, Sarah C Reed, Denisse Rotem, Justin Rhoades, Denis Loginov, Dimitri Livitz, Daniel Rosebrock, Ignaty Leshchiner, Jaegil Kim, Chip Stewart, Mara Rosenberg, Joshua M Francis, Cheng-Zhong Zhang, Ofir Cohen, Coyin Oh, Huiming Ding, Paz Polak, Max Lloyd, Sairah Mahmud, Karla Helvie, Margaret S Merrill, Rebecca A Santiago, Edward P O'Connor, Seong H Jeong, Rachel Leeson, Rachel M Barry, Joseph F Kramkowski, Zhenwei Zhang, Laura Polacek, Jens G Lohr, Molly Schleicher, Emily Lipscomb, Andrea Saltzman, Nelly M Oliver, Lori Marini, Adrienne G Waks, Lauren C Harshman, Sara M Tolaney, Eliezer M Van Allen, Eric P Winer, Nancy U Lin, Mari Nakabayashi, Mary-Ellen Taplin, Cory M Johannessen, Levi A Garraway, Todd R Golub, Jesse S Boehm, Nikhil Wagle, Gad Getz, J Christopher Love, Matthew Meyerson
Whole-exome sequencing of cell-free DNA (cfDNA) could enable comprehensive profiling of tumors from blood but the genome-wide concordance between cfDNA and tumor biopsies is uncertain. Here we report ichorCNA, software that quantifies tumor content in cfDNA from 0.1× coverage whole-genome sequencing data without prior knowledge of tumor mutations. We apply ichorCNA to 1439 blood samples from 520 patients with metastatic prostate or breast cancers. In the earliest tested sample for each patient, 34% of patients have ≥10% tumor-derived cfDNA, sufficient for standard coverage whole-exome sequencing...
November 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/29107330/allele-specific-hla-loss-and-immune-escape-in-lung-cancer-evolution
#11
Nicholas McGranahan, Rachel Rosenthal, Crispin T Hiley, Andrew J Rowan, Thomas B K Watkins, Gareth A Wilson, Nicolai J Birkbak, Selvaraju Veeriah, Peter Van Loo, Javier Herrero, Charles Swanton
Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity...
October 21, 2017: Cell
https://www.readbyqxmd.com/read/29104575/-hotspots-of-antigen-presentation-revealed-by-human-leukocyte-antigen-ligandomics-for-neoantigen-prioritization
#12
Markus Müller, David Gfeller, George Coukos, Michal Bassani-Sternberg
The remarkable clinical efficacy of the immune checkpoint blockade therapies has motivated researchers to discover immunogenic epitopes and exploit them for personalized vaccines. Human leukocyte antigen (HLA)-binding peptides derived from processing and presentation of mutated proteins are one of the leading targets for T-cell recognition of cancer cells. Currently, most studies attempt to identify neoantigens based on predicted affinity to HLA molecules, but the performance of such prediction algorithms is rather poor for rare HLA class I alleles and for HLA class II...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29093010/targeting-retired-antigens-for-cancer-immunoprevention
#13
EDITORIAL
Robert H Shoemaker, Thomas G Forsthuber
Identification of immune targets for cancer immunoprevention, or immunotherapy, has historically focused on tumor-associated (self) antigens or neoantigens expressed on malignant cells. For self-antigens, overcoming tolerance can be a difficult challenge. Neoantigens do not suffer from this limitation, but the lack of recurrent mutations yielding common neoantigens that can be exploited in vaccines is a problem for many tumor types. Targeting "retired antigens," a specialized type of self-antigen, may have considerable advantages...
November 2017: Cancer Prevention Research
https://www.readbyqxmd.com/read/29067473/the-dawn-of-immune-revolution-in-children-early-experiences-with-checkpoint-inhibitors-in-childhood-malignancies
#14
REVIEW
Maurizio Lucchesi, Iacopo Sardi, Gianfranco Puppo, Antonio Chella, Claudio Favre
Modern immunotherapy with checkpoint inhibitors has changed clinical practice of adult patients with advanced cancer. Blockade of CTLA-4 and PD-1 pathways have shown survival benefits in different diseases. In children, combination of surgery, radiotherapy and chemotherapy have improved survival rates of solid tumors. However, the outcomes for subsets of patients such as those with high-grade, refractory, or metastatic disease remain extremely poor. Currently, the treatment of these patients is almost exclusively based on standard chemotherapy...
October 24, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/29067023/selection-of-shared-and-neoantigen-reactive-t-cells-for-adoptive-cell-therapy-based-on-cd137-separation
#15
Sivan Seliktar-Ofir, Efrat Merhavi-Shoham, Orit Itzhaki, Sharon Yunger, Gal Markel, Jacob Schachter, Michal J Besser
Adoptive cell therapy (ACT) of autologous tumor infiltrating lymphocytes (TIL) is an effective immunotherapy for patients with solid tumors, yielding objective response rates of around 40% in refractory patients with metastatic melanoma. Most clinical centers utilize bulk, randomly isolated TIL from the tumor tissue for ex vivo expansion and infusion. Only a minor fraction of the administered T cells recognizes tumor antigens, such as shared and mutation-derived neoantigens, and consequently eliminates the tumor...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29061774/immune-checkpoint-inhibitors-in-gynecological-cancers-update-of-literature-and-perspectives-of-clinical-research
#16
REVIEW
Angiolo Gadducci, Maria Elena Guerrieri
The presence of tumor infiltrating lymphocytes (TILs) influences the clinical outcome of cancer patients and immune checkpoint inhibitors (ICPI) have been approved for treating different types of malignancies. In this review, we assess the scanty data from literature and the perspectives of clinical research about the use of ICPI in gynecological cancers. These agents have obtained objective response rates ranging from 5.9% to 15% in early phase Ib-II trials, including patients with platinum-resistant ovarian cancer, whereas only anecdotal data are available for patients with recurrent, heavily pretreated endometrial cancer...
November 2017: Anticancer Research
https://www.readbyqxmd.com/read/29061646/kras-mutation-and-consensus-molecular-subtypes-2-and-3-are-independently-associated-with-reduced-immune-infiltration-and-reactivity-in-colorectal-cancer
#17
Neeraj Lal, Brian S White, Ghaleb Goussous, Oliver J Pickles, Michael Mason, Andrew D Beggs, Philippe Taniere, Benjamin E Willcox, Justin Guinney, Gary Middleton
PURPOSE: KRAS mutation is a common canonical mutation in CRC, found at differing frequencies in all Consensus Molecular Subtypes (CMS). The independent immunobiological impacts of RAS mutation and CMS are unknown. Thus, we explored the immunobiological effects of KRAS mutation across the CMS spectrum. EXPERIMENTAL DESIGN: Transcriptional analysis of immune genes/signatures was performed with RNA-seq using The Cancer Genome Atlas (TCGA) and the KFSYSCC data set. Multivariate analysis included KRAS status, CMS, tumour location, MSI status, and neoantigen load...
October 23, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29054996/nivolumab-induces-tumor-evolution-in-patients-with-melanoma
#18
(no author information available yet)
Nivolumab treatment results in immunoediting and loss of tumor cells expressing neoantigens.
October 20, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29042252/the-roles-and-applications-of-autoantibodies-in-progression-diagnosis-treatment-and-prognosis-of-human-malignant-tumours
#19
REVIEW
Jing Wu, Xiaobo Li, Wuqi Song, Yong Fang, Li Yu, Siyuan Liu, Leonid P Churilov, Fengmin Zhang
The existence of autoantibodies towards an individual's own proteins or nucleic acids has been established for more than 100years, and for a long period, these autoantibodies have been believed to be closely associated with autoimmune diseases. However, in recent years, researchers have become more interested in the role and application of autoantibodies in progression, diagnosis, treatment and prognosis of human malignant tumours. Over the past few decades, numerous epidemiological studies have shown that the risk of certain cancers is significantly altered (increased or decreased) in patients with autoimmune diseases, which suggests that autoantibodies may play either promoting or suppressing roles in cancer progression...
October 16, 2017: Autoimmunity Reviews
https://www.readbyqxmd.com/read/29040258/prognostic-and-therapeutic-implications-of-dna-repair-gene-mutations-in-advanced-prostate-cancer
#20
Michael T Schweizer, Emmanuel S Antonarakis
Recent work directed toward understanding the molecular features of advanced prostate cancers has revealed a relatively high incidence of both germline and somatic alterations in genes involved in DNA damage repair (DDR). Many of these alterations likely play a critical role in the pathogenesis of more aggressive prostate cancers-leading to genomic instability and an increased probability of the development of lethal disease. However, because the ability to repair DNA damage with a high degree of fidelity is critical to an individual cell's survival, tumor cells harboring alterations in DDR pathway genes are also more susceptible to drugs that induce DNA damage or impair alternative DNA repair pathways...
October 2017: Clinical Advances in Hematology & Oncology: H&O
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