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https://www.readbyqxmd.com/read/29244203/pediatric-tolerogenic-dcs-expressing-cd4-and-immunoglobulin-like-transcript-receptor-ilt-4-secrete-il-10-in-response-to-fc-and-adenosine
#1
Alessandra Franco, Jeetendra Kumar, Gene Lin, Negar Behnamfar, Li-En Hisieh, Chisato Shimizu, Adriana H Tremoulet, Jane C Burns, Joel Linden
We characterized a novel population of tolerogenic myeloid dendritic cells (tmDCs) defined as CD11c+ CD11b+ CD14+ CD4+ and immunoglobulin-like transcript receptor (ILT)-4+ that are significantly more abundant in the circulation of infants and young children than in adults. TmDCs secrete the immunosuppressive lymphokine interleukin (IL)-10 when stimulated with the heavy constant region of immunoglobulins (Fc) and express high levels of the adenosine A2A receptor (A2A R), which, when activated by adenosine, inhibits the release of pro-inflammatory cytokines from most immune cells...
December 15, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/29244145/biological-and-therapeutic-implications-of-multisector-sequencing-in-newly-diagnosed-glioblastomas
#2
Tatenda Mahlokozera, Ananth K Vellimana, Tiandao Li, Diane D Mao, Zohny S Zohny, David H Kim, David D Tran, Daniel S Marcus, Sarah J Fouke, Jian L Campian, Gavin P Dunn, Christopher A Miller, Albert H Kim
Background: Diagnostic workflows for glioblastoma (GBM) patients increasingly include DNA sequencing-based analysis of a single tumor site following biopsy or resection. We hypothesized that sequencing of multiple sectors within a given tumor would provide a more comprehensive representation of the molecular landscape and potentially inform therapeutic strategies. Methods: 10 newly diagnosed, IDH1 wildtype GBM tumor samples were obtained from two (n = 9) or four (n = 1) spatially distinct tumor regions...
December 13, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/29234329/neoantigens-generated-by-individual-mutations-and-their-role-in-cancer-immunity-and-immunotherapy
#3
REVIEW
Mirjana Efremova, Francesca Finotello, Dietmar Rieder, Zlatko Trajanoski
Recent preclinical and clinical studies have proved the long-standing hypothesis that tumors elicit adaptive immune responses and that the antigens driving effective T-cell response are neoantigens, i.e., peptides that are generated from somatically mutated genes. Hence, the characterization of neoantigens and the identification of the immunogenic ones are of utmost importance for improving cancer immunotherapy and broadening its efficacy to a larger fraction of patients. In this review, we first introduce the methods used for the quantification of neoantigens using next-generation sequencing data and then summarize results obtained using these tools to characterize the neoantigen landscape in solid cancers...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29227308/medical-bioinformatics-in-melanoma
#4
Phil F Cheng
PURPOSE OF REVIEW: Bioinformatic insights from next-generation sequencing has been integral in understanding melanoma biology, resistance to treatment and provided new avenues for melanoma treatment. Whole-genome sequencing, whole-exome sequencing and RNA sequencing has redefined the molecular classification of melanoma, revealed distinct genetic aberrations that define clinical subtypes of melanoma and uncovered the diverse heterogeneity that resides in an individual tumor. RECENT FINDINGS: In this review, we will summarize the recent whole-genome study that catalogs the genomic landscape across many melanoma subtypes, the single-cell RNA sequencing studies that interrogates tumor heterogeneity and the personalized vaccine approaches to melanoma treatment...
December 8, 2017: Current Opinion in Oncology
https://www.readbyqxmd.com/read/29226910/towards-personalized-tumour-specific-therapeutic-vaccines-for-cancer
#5
REVIEW
Zhuting Hu, Patrick A Ott, Catherine J Wu
Cancer vaccines, which are designed to amplify tumour-specific T cell responses through active immunization, have long been envisioned as a key tool of effective cancer immunotherapy. Despite a clear rationale for such vaccines, extensive past efforts were unsuccessful in mediating clinically relevant antitumour activity in humans. Recently, however, next-generation sequencing and novel bioinformatics tools have enabled the systematic discovery of tumour neoantigens, which are highly desirable immunogens because they arise from somatic mutations of the tumour and are therefore tumour specific...
December 11, 2017: Nature Reviews. Immunology
https://www.readbyqxmd.com/read/29222190/loss-of-dna-repair-drives-neoantigen-renewal-and-inhibits-tumor-growth
#6
(no author information available yet)
DNA mismatch repair in tumors promotes enhanced immune surveillance.
December 8, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29217585/patient-hla-class-i-genotype-influences-cancer-response-to-checkpoint-blockade-immunotherapy
#7
Diego Chowell, Luc G T Morris, Claud M Grigg, Jeffrey K Weber, Robert M Samstein, Vladimir Makarov, Fengshen Kuo, Sviatoslav M Kendall, David Requena, Nadeem Riaz, Benjamin Greenbaum, James Carroll, Edward Garon, David M Hyman, Ahmet Zehir, David Solit, Michael Berger, Ruhong Zhou, Naiyer A Rizvi, Timothy A Chan
CD8+ T cell-dependent killing of cancer cells requires efficient presentation of tumor antigens by human leukocyte antigen class I (HLA-I) molecules. However, the extent to which patient-specific HLA-I genotype influences response to anti-PD-1 or anti-CTLA-4 is currently unknown. We determined the HLA-I genotype of 1,535 advanced cancer patients treated with immune checkpoint blockade (ICB). Maximal heterozygosity at HLA-I loci (A, B, and C) improved overall survival after ICB compared to patients who were homozygous for at least one HLA locus...
December 7, 2017: Science
https://www.readbyqxmd.com/read/29217527/merkel-cell-carcinoma-in-the-age-of-immunotherapy-facts-and%C3%A2-hopes
#8
Aric Colunga, Thomas Pulliam, Paul Nghiem
Merkel cell carcinoma (MCC) is a rare (~2,000 US cases/year) but aggressive neuroendocrine tumor of the skin. For advanced MCC, cytotoxic chemotherapy only infrequently (<10% of cases) offers durable clinical responses (>1 year) suggesting a great need for improved therapeutic options. In 2008, the Merkel cell polyomavirus (MCPyV) was discovered and is clonally integrated in ~80% of MCC tumors. The remaining 20% of MCC tumors have large numbers of UV-associated mutations. Importantly, both the UV-induced-neoantigens in virus-negative tumors and the MCPyV T antigen oncogenes that are required for virus-positive tumor growth are immunogenic...
December 7, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29212853/emergence-of-high-avidity-melan-a-specific-clonotypes-as-a-reflection-of-anti-pd-1-clinical-efficacy
#9
Sylvain Simon, Virginie Vignard, Emilie Varey, Tiphaine Parrot, Anne-Chantal Knol, Amir Khammari, Nadine Gervois, Francois Lang, Brigitte Dreno, Nathalie Labarriere
Therapeutic strategies using anti-PD-1-blocking antibodies reported unparalleled effectiveness for melanoma immunotherapy, but deciphering immune responses modulated by anti-PD-1 treatment remains a crucial issue. Here, we analyzed the composition and functions of the large Melan-A-specific T-cell repertoire in the peripheral blood of 9 melanoma patients before and after 2 months of treatment with anti-PD-1. We observed amplification of Melan-A-specific Vß subfamilies undetectable before therapy (thereafter called emerging Vß subfamilies) in responding patients, with a predominant expansion in patients with a complete response...
December 6, 2017: Cancer Research
https://www.readbyqxmd.com/read/29209918/molecular-classification-and-precision-therapy-of-cancer-immune-checkpoint-inhibitors
#10
Yingyan Yu
On May 23, 2017, the US Food and Drug Administration (FDA) approved a treatment for cancer patients with positive microsatellite instability-high (MSI-H) markers or mismatch repair deficient (dMMR) markers. This approach is the first approved tumor treatment using a common biomarker rather than specified tumor locations in the body. FDA previously approved Keytruda for treatment of several types of malignancies, such as metastatic melanoma, metastatic non-small-cell lung cancer, recurrent or metastatic head and neck cancer, refractory Hodgkin lymphoma, and urothelial carcinoma, all of which carry positive programmed death-1/programmed death-ligand 1 biomarkers...
December 5, 2017: Frontiers of Medicine
https://www.readbyqxmd.com/read/29203539/novel-and-shared-neoantigen-derived-from-histone-3-variant-h3-3k27m-mutation-for-glioma-t-cell-therapy
#11
Zinal S Chheda, Gary Kohanbash, Kaori Okada, Naznin Jahan, John Sidney, Matteo Pecoraro, Xinbo Yang, Diego A Carrera, Kira M Downey, Shruti Shrivastav, Shuming Liu, Yi Lin, Chetana Lagisetti, Pavlina Chuntova, Payal B Watchmaker, Sabine Mueller, Ian F Pollack, Raja Rajalingam, Angel M Carcaboso, Matthias Mann, Alessandro Sette, K Christopher Garcia, Yafei Hou, Hideho Okada
The median overall survival for children with diffuse intrinsic pontine glioma (DIPG) is less than one year. The majority of diffuse midline gliomas, including more than 70% of DIPGs, harbor an amino acid substitution from lysine (K) to methionine (M) at position 27 of histone 3 variant 3 (H3.3). From a CD8+ T cell clone established by stimulation of HLA-A2+ CD8+ T cells with synthetic peptide encompassing the H3.3K27M mutation, complementary DNA for T cell receptor (TCR) α- and β-chains were cloned into a retroviral vector...
December 4, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29193094/expression-of-programmed-death-1-in-sentinel-lymph-nodes-of-breast-cancer
#12
Takashi Tatara, Toru Mukohara, Yohei Shimono, Takashi Yamasaki, Yoshinori Imamura, Yohei Funakoshi, Masanori Toyoda, Naomi Kiyota, Shintaro Takao, Seishi Kono, Yoshihiro Kakeji, Hironobu Minami
BACKGROUND AND OBJECTIVES: To explore whether lymphocytes in sentinel lymph nodes (SLNs) are highly exposed to tumor neoantigens and thus express high level of programmed death 1 (PD-1), we examined PD-1 expression in SLNs and non-sentinel regional lymph nodes (non-SLNs) in breast cancer. METHODS: We performed PD-1 immunohistochemistry in two cohorts: 40 metastasis-negative SLNs including 10 patients for each subtype (luminal A-like, luminal B-like, HER2, and triple negative breast cancer [TNBC]); and 25 pairs of metastasis-positive SLNs and non-SLNs (10 luminal A-like, 10 luminal B-like, and 5 TNBC)...
November 28, 2017: Journal of Surgical Oncology
https://www.readbyqxmd.com/read/29189709/non-canonical-thinking-for-targeting-alk-fusion-onco-proteins-in-lung-cancer
#13
REVIEW
Wei Wu, Franziska Haderk, Trever G Bivona
Anaplastic lymphoma kinase (ALK) gene rearrangements have been identified in lung cancer at 3-7% frequency, thus representing an important subset of genetic lesions that drive oncogenesis in this disease. Despite the availability of multiple FDA-approved small molecule inhibitors targeting ALK fusion proteins, drug resistance to ALK kinase inhibitors is a common problem in clinic. Thus, there is an unmet need to deepen the current understanding of genomic characteristics of ALK rearrangements and to develop novel therapeutic strategies that can overcome ALK inhibitor resistance...
November 30, 2017: Cancers
https://www.readbyqxmd.com/read/29186113/inactivation-of-dna-repair-triggers-neoantigen-generation-and-impairs-tumour-growth
#14
Giovanni Germano, Simona Lamba, Giuseppe Rospo, Ludovic Barault, Alessandro Magrì, Federica Maione, Mariangela Russo, Giovanni Crisafulli, Alice Bartolini, Giulia Lerda, Giulia Siravegna, Benedetta Mussolin, Roberta Frapolli, Monica Montone, Federica Morano, Filippo de Braud, Nabil Amirouchene-Angelozzi, Silvia Marsoni, Maurizio D'Incalci, Armando Orlandi, Enrico Giraudo, Andrea Sartore-Bianchi, Salvatore Siena, Filippo Pietrantonio, Federica Di Nicolantonio, Alberto Bardelli
Molecular alterations in genes involved in DNA mismatch repair (MMR) promote cancer initiation and foster tumour progression. Cancers deficient in MMR frequently show favourable prognosis and indolent progression. The functional basis of the clinical outcome of patients with tumours that are deficient in MMR is not clear. Here we genetically inactivate MutL homologue 1 (MLH1) in colorectal, breast and pancreatic mouse cancer cells. The growth of MMR-deficient cells was comparable to their proficient counterparts in vitro and on transplantation in immunocompromised mice...
November 29, 2017: Nature
https://www.readbyqxmd.com/read/29182456/levels-of-oxidative-damage-and-proinflammatory-cytokines-are-enhanced-in-patients-with-active-vitiligo
#15
Sneha Mitra, Sritama De Sarkar, Ayan Pradhan, Ayan K Pati, Richeek Pradhan, Debolina Mondal, Sumit Sen, Arghyaprasun Ghosh, Suparna Chatterjee, Mitali Chatterjee
Vitiligo is an autoimmune depigmenting skin disease characterised by loss of melanocytes wherein oxidative stress is proposed to be the initial triggering factor with subsequent immune dysregulation. This study aimed to evaluate the relationship, if any, between the generation of reactive oxygen species (ROS), markers of oxidative damage and circulating cytokines in patients with active vitiligo. The generation of ROS in erythrocytes and neutrophils was significantly higher in patients with active vitiligo than healthy controls...
December 2017: Free Radical Research
https://www.readbyqxmd.com/read/29180478/perioperative-spatiotemporally-coordinated-activation-of-t-and-nk-cells-prevents-recurrence-of-pancreatic-cancer
#16
Jennifer Brooks, Bettina Fleischmann-Mundt, Norman Woller, Julia Niemann, Silvia Ribback, Kristin Peters, Ihsan Ekin Demir, Nina Armbrecht, Guralp O Ceyhan, Michael P Manns, Thomas C Wirth, Stefan Kubicka, Gunter Bernhardt, Mark J Smyth, Diego F Calvisi, Engin Gürlevik, Florian Kühnel
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and disseminating cancer resistant to therapy, including checkpoint immunotherapies, and early tumor resection and (neo)adjuvant chemotherapy fails to improve a poor prognosis. In a transgenic mouse model of resectable PDAC, we investigated the coordinated activation of T and NK cells in addition to gemcitabine chemotherapy to prevent tumor recurrence. Only neoadjuvant, but not adjuvant treatment with a PD-1 antagonist effectively supported chemotherapy and suppressed local tumor recurrence and improved survival involving both NK and T cells...
November 27, 2017: Cancer Research
https://www.readbyqxmd.com/read/29174843/an-efficient-single-cell-rna-seq-approach-to-identify-neoantigen-specific-t-cell-receptors
#17
Yong-Chen Lu, Zhili Zheng, Paul F Robbins, Eric Tran, Todd D Prickett, Jared J Gartner, Yong F Li, Satyajit Ray, Zulmarie Franco, Valery Bliskovsky, Peter C Fitzgerald, Steven A Rosenberg
The adoptive transfer of neoantigen-reactive tumor-infiltrating lymphocytes (TILs) can result in tumor regression in patients with metastatic cancer. To improve the efficacy of adoptive T cell therapy targeting these tumor-specific mutations, we have proposed a new therapeutic strategy, which involves the genetic modification of autologous T cells with neoantigen-specific T cell receptors (TCRs) and the transfer of these modified T cells back to cancer patients. However, the current techniques to isolate neoantigen-specific TCRs are labor intensive, time consuming, and technically challenging, not suitable for clinical applications...
October 28, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29170503/mutational-and-putative-neoantigen-load-predict-clinical-benefit-of-adoptive-t-cell-therapy-in-melanoma
#18
Martin Lauss, Marco Donia, Katja Harbst, Rikke Andersen, Shamik Mitra, Frida Rosengren, Maryem Salim, Johan Vallon-Christersson, Therese Törngren, Anders Kvist, Markus Ringnér, Inge Marie Svane, Göran Jönsson
Adoptive T-cell therapy (ACT) is a highly intensive immunotherapy regime that has yielded remarkable response rates and many durable responses in clinical trials in melanoma; however, 50-60% of the patients have no clinical benefit. Here, we searched for predictive biomarkers to ACT in melanoma. Whole exome- and transcriptome sequencing and neoantigen prediction were applied to pre-treatment samples from 27 patients recruited to a clinical phase I/II trial of ACT in stage IV melanoma. All patients had previously progressed on other immunotherapies...
November 23, 2017: Nature Communications
https://www.readbyqxmd.com/read/29164593/immune-correlates-of-clinical-outcome-in-melanoma
#19
REVIEW
Graham Pawelec
Melanoma has long been recognized as a potentially immunogenic tumour, but only recently has it become clear that the reason for this resides in its many UV-induced mutations and expression of multiple autoantigens which can be targeted by the immune system. The first successful applications of immune-based treatments included passive immunotherapy using high-dose IL-2 and/or adoptive transfer of NK-cells, as well as active immunotherapy using whole cell-derived or peptide vaccines. In the intervening decades, it has become clear that these approaches can lead to durable responses in stage III/IV melanoma, and even to functional cures - but only in a vanishingly small fraction of patients...
November 21, 2017: Immunology
https://www.readbyqxmd.com/read/29163500/antibodies-to-senescent-antigen-and-c3-are-not-required-for-normal-red-blood-cell-lifespan-in-a-murine-model
#20
Krystalyn E Hudson, Karen de Wolski, Linda M Kapp, Amanda L Richards, Matthew J Schniederjan, James C Zimring
Red blood cells (RBCs) have a well-defined lifespan, indicating a mechanism by which senescent cells of a certain age are removed from circulation. However, the specifics by which senescent cells are recognized and removed are poorly understood. There are multiple competing hypotheses for this process, perhaps the most commonly cited is that senescent RBCs expose neoantigens [or senescent antigen(s)] that are then recognized by naturally occurring antibodies, which opsonize the senescent cells and result in clearance from circulation...
2017: Frontiers in Immunology
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