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Neoantigens

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https://www.readbyqxmd.com/read/28329770/antigen-presentation-profiling-reveals-recognition-of-lymphoma-immunoglobulin-neoantigens
#1
Michael S Khodadoust, Niclas Olsson, Lisa E Wagar, Ole A W Haabeth, Binbin Chen, Kavya Swaminathan, Keith Rawson, Chih Long Liu, David Steiner, Peder Lund, Samhita Rao, Lichao Zhang, Caleb Marceau, Henning Stehr, Aaron M Newman, Debra K Czerwinski, Victoria E H Carlton, Martin Moorhead, Malek Faham, Holbrook E Kohrt, Jan Carette, Michael R Green, Mark M Davis, Ronald Levy, Joshua E Elias, Ash A Alizadeh
Cancer somatic mutations can generate neoantigens that distinguish malignant from normal cells. However, the personalized identification and validation of neoantigens remains a major challenge. Here we discover neoantigens in human mantle-cell lymphomas by using an integrated genomic and proteomic strategy that interrogates tumour antigen peptides presented by major histocompatibility complex (MHC) class I and class II molecules. We applied this approach to systematically characterize MHC ligands from 17 patients...
March 22, 2017: Nature
https://www.readbyqxmd.com/read/28327987/pssmhcpan-a-novel-pssm-based-software-for-predicting-class-i-peptide-hla-binding-affinity
#2
Geng Liu, Dongli Li, Zhang Li, Si Qiu, Wenhui Li, Cheng-Chi Chao, Naibo Yang, Handong Li, Zhen Cheng, Xin Song, Le Cheng, Xiuqing Zhang, Jian Wang, Huanming Yang, Kun Ma, Yong Hou, Bo Li
Background: Predicting peptides binding affinity with human leukocyte antigen (HLA) is a crucial step in developing powerful antitumor vaccine for cancer immunotherapy. Currently available methods work quite well in predicting peptide binding affinity with HLA alleles such as HLA-A*0201, HLA-A*0101, and HLA-B*0702 in terms of sensitivity and specificity. However, quite a few types of HLA alleles that are present in majority of human populations including HLA-A*0202, HLA-A*0203, HLA-A*6802, HLA-B*5101, HLA-B*5301, HLA-B*5401 and HLA-B*5701 still cannot be predicted with satisfactory accuracy using currently available methods...
March 15, 2017: GigaScience
https://www.readbyqxmd.com/read/28327926/genomic-characterisation-of-her2-positive-breast-cancer-and-response-to-neoadjuvant-trastuzumab-and-chemotherapy-results-from-the-acosog-z1041-alliance-trial
#3
R Lesurf, O L Griffith, M Griffith, J Hundal, L Trani, M A Watson, R Aft, M J Ellis, D Ota, V J Suman, F Meric-Bernstam, A M Leitch, J C Boughey, G Unzeitig, A U Buzdar, K K Hunt, E R Mardis
Background: HER2 ( ERBB2 ) gene amplification and its corresponding overexpression are present in 15-30% of invasive breast cancers. While HER2-targeted agents are effective treatments, resistance remains a major cause of death. The American College of Surgeons Oncology Group Z1041 trial (NCT00513292) was designed to compare the pathologic complete response (pCR) rate of distinct regimens of neoadjuvant chemotherapy and trastuzumab, but ultimately identified no difference [1]. Patients and methods: In supplement to tissues from 37 Z1041 cases, 11 similarly treated cases were obtained from a single institution study (NCT00353483)...
February 21, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28324831/primary-and-acquired-resistance-to-pd-1-pd-l1-blockade-in-cancer-treatment
#4
REVIEW
Qiaohong Wang, Xia Wu
PD-1/PD-L1 blockade appears to be a very promising immunotherapy with significant clinical benefits and durable responses in multiple tumor types. However, the effectual clinical benefits of PD-1/PD-L1 blockade are hampered by a high rate of primary resistance, where patients do not respond to PD-1/PD-L1 blockade initially. And more distressingly, most patients eventually develop acquired resistance after an initial response to PD-1/PD-L1 blockade. The mechanisms underlying primary and acquired resistance to PD-1/PD-L1 blockade have remained ambiguous...
March 18, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28314751/identification-of-glycopeptides-as-post-translationally-modified-neoantigens-in-leukemia
#5
Stacy A Malaker, Sarah A Penny, Lora G Steadman, Paisley T Myers, Justin Loke, Manoj Raghavan, Dina L Bai, Jeffery Shabanowitz, Donald Hunt, Mark Cobbold
Leukemias are highly immunogenic but have a low mutational load, providing few mutated peptide targets. Thus, the identification of alternative neoantigens is a pressing need. Here, we identify 36 MHC class I-associated peptide antigens with O-linked β-N-acetylglucosamine (O-GlcNAc) modifications as candidate neoantigens, using three experimental approaches. Thirteen of these peptides were also detected with disaccharide units on the same residues and two contain either mono- and/or di-methylated arginine residues...
March 17, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28306559/immunotherapy-a-new-treatment-paradigm-in-bladder-cancer
#6
Nicole N Davarpanah, Akira Yuno, Jane B Trepel, Andrea B Apolo
PURPOSE OF REVIEW: T-cell checkpoint blockade has become a dynamic immunotherapy for bladder cancer. In 2016, atezolizumab, an immune checkpoint inhibitor, became the first new drug approved in metastatic urothelial carcinoma (mUC) in over 30 years. In 2017, nivolumab was also approved for the same indication. This overview of checkpoint inhibitors in clinical trials focuses on novel immunotherapy combinations, predictive biomarkers including mutational load and neoantigen identification, and an evaluation of the future of bladder cancer immunotherapy...
March 16, 2017: Current Opinion in Oncology
https://www.readbyqxmd.com/read/28304339/the-five-immune-forces-impacting-dna-based-cancer-immunotherapeutic-strategy
#7
REVIEW
Suneetha Amara, Venkataswarup Tiriveedhi
DNA-based vaccine strategy is increasingly realized as a viable cancer treatment approach. Strategies to enhance immunogenicity utilizing tumor associated antigens have been investigated in several pre-clinical and clinical studies. The promising outcomes of these studies have suggested that DNA-based vaccines induce potent T-cell effector responses and at the same time cause only minimal side-effects to cancer patients. However, the immune evasive tumor microenvironment is still an important hindrance to a long-term vaccine success...
March 17, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28282342/new-developments-in-the-biology-and-the-treatment-of-metastatic-merkel-cell-carcinoma
#8
Patrick Terheyden, Jürgen C Becker
PURPOSE OF REVIEW: Patients with stage IIIB und IV metastatic Merkel cell carcinoma (mMCC), who are not suitable candidates for surgery or radiotherapy, are unlikely to achieve lasting remission or tumor control by chemo or targeted therapy. In the majority of cases, the tumor arises from viral carcinogenesis associated with the Merkel cell polyomavirus (MCPyV). In MCPyV-negative tumors with a presumable ultraviolet carcinogenesis, a high mutational burden resulting in neoantigens was discovered...
March 9, 2017: Current Opinion in Oncology
https://www.readbyqxmd.com/read/28279220/short-course-rapamycin-treatment-enables-engraftment-of-immunogenic-gene-engineered-bone-marrow-under-low-dose-irradiation-to-permit-long-term-immunological-tolerance
#9
Kunal H Bhatt, Rajeev Rudraraju, Jeremy F Brooks, Ji-Won Jung, Ryan Galea, James W Wells, Raymond J Steptoe
BACKGROUND: Application of genetically modified hematopoietic stem cells is increasingly mooted as a clinically relevant approach to protein replacement therapy, immune tolerance induction or conditions where both outcomes may be helpful. Hematopoietic stem and progenitor cell (HSPC)-mediated gene therapy often requires highly toxic pretransfer recipient conditioning to provide a 'niche' so that transferred HSPCs can engraft effectively and to prevent immune rejection of neoantigen-expressing engineered HSPCs...
March 9, 2017: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/28277646/efficient-nanovaccine-delivery-in-cancer-immunotherapy
#10
Guizhi Zhu, Fuwu Zhang, Qianqian Ni, Gang Niu, Xiaoyuan Chen
Vaccines hold tremendous potential for cancer immunotherapy by treating the immune system. Subunit vaccines, including molecular adjuvants and cancer-associated antigens or cancer-specific neoantigens, can elicit potent antitumor immunity. However, subunit vaccines have shown limited clinical benefit in cancer patients, which is in part attributed to inefficient vaccine delivery. In this Perspective, we discuss vaccine delivery by synthetic nanoparticles or naturally derived nanoparticles for cancer immunotherapy...
March 9, 2017: ACS Nano
https://www.readbyqxmd.com/read/28274144/prospect-of-rindopepimut-in-the-treatment-of-glioblastoma
#11
Aladine A Elsamadicy, Pakawat Chongsathidkiet, Rupen Desai, Karolina Woroniecka, S Harrison Farber, Peter E Fecci, John H Sampson
Rindopepimut (CDX-110) is a peptide vaccine that targets epidermal growth factor receptor variant III (EGFRvIII), a tumor-specific epitope expressed in the most common and lethal primary malignant neoplasm of the brain - glioblastoma (GBM). Areas covered: The EGFRvIII mutation introduces an 801 base pair in-frame deletion of the extracellular domain of the transmembrane tyrosine kinase, resulting in constitutive kinase activity, amplification of cell growth, and inhibition of apoptosis. Rindopepimut contains a 14mer amino acid peptide spanning the EGFRvIII mutation site that is conjugated to keyhole limpet hemocyanin (KLH)...
April 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/28273450/atr-mutations-promote-the-growth-of-melanoma-tumors-by-modulating-the-immune-microenvironment
#12
Chi-Fen Chen, Rolando Ruiz-Vega, Priya Vasudeva, Francisco Espitia, Tatiana B Krasieva, Sebastien de Feraudy, Bruce J Tromberg, Sharon Huang, Chad P Garner, Jie Wu, Dave S Hoon, Anand K Ganesan
Melanomas accumulate a high burden of mutations that could potentially generate neoantigens, yet somehow suppress the immune response to facilitate continued growth. In this study, we identify a subset of human melanomas that have loss-of-function mutations in ATR, a kinase that recognizes and repairs UV-induced DNA damage and is required for cellular proliferation. ATR mutant tumors exhibit both the accumulation of multiple mutations and the altered expression of inflammatory genes, resulting in decreased T cell recruitment and increased recruitment of macrophages known to spur tumor invasion...
March 7, 2017: Cell Reports
https://www.readbyqxmd.com/read/28257957/the-cancer-immunity-cycle-as-rational-design-for-synthetic-cancer-drugs-novel-dc-vaccines-and-car-t-cells
#13
REVIEW
Mohanraj Ramachandran, Anna Dimberg, Magnus Essand
Cell therapy is an advanced form of cancer immunotherapy that has had remarkable clinical progress in the past decade in the search for cure of cancer. Most success has been achieved for chimeric antigen receptor (CAR) T-cells where CAR T-cells targeting CD19 show very high complete response rates for patients with refractory acute B-cell acute lymphoblastic leukemia (ALL) and are close to approval for this indication. CD19 CAR T-cells are also effective against B-cell chronic lymphoblastic leukemia (CLL) and B-cell lymphomas...
February 28, 2017: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/28254786/clinical-impact-of-tumor-dna-repair-expression-and-t-cell-infiltration-in-breast-cancers
#14
Andrew R Green, Mohammed A Aleskandarany, Reem Ali, Eleanor Grace Hodgson, Suha Atabani, Karen De Souza, Emad Rakha, Ian O Ellis, Srinivasan Madhusudan
Impaired DNA repair drives mutagenicity, which increases neoantigen load and immunogenicity. We investigated the expression of proteins involved in the DNA damage response (ATM, Chk2), double-strand break repair (BRCA1, BLM, WRN, RECQL4, RECQL5, TOPO2A, DNA-PKcs, Ku70/Ku80), nucleotide excision repair (ERCC1), base excision repair (XRCC1, pol β, FEN1, PARP1), and immune responses (CD8, PD-1, PD-L1, FOXP3) in 1269 breast cancers and validated our findings in an independent estrogen receptor (ER)- cohort (n = 279)...
March 2, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28254528/candidate-immune-biomarkers-for-radioimmunotherapy
#15
REVIEW
Antonin Levy, Giulia Nigro, Philippe J Sansonetti, Eric Deutsch
Newly available immune checkpoint blockers (ICBs), capable to revert tumor immune tolerance, are revolutionizing the anticancer armamentarium. Recent evidence also established that ionizing radiation (IR) could produce antitumor immune responses, and may as well synergize with ICBs. Multiple radioimmunotherapy combinations are thenceforth currently assessed in early clinical trials. Past examples have highlighted the need for treatment personalization, and there is an unmet need to decipher immunological biomarkers that could allow selecting patients who could benefit from these promising but expensive associations...
February 28, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28228279/loss-of-pten-is-associated-with-resistance-to-anti-pd-1-checkpoint-blockade-therapy-in-metastatic-uterine-leiomyosarcoma
#16
Suzanne George, Diana Miao, George D Demetri, Dennis Adeegbe, Scott J Rodig, Sachet Shukla, Mikel Lipschitz, Ali Amin-Mansour, Chandrajit P Raut, Scott L Carter, Peter Hammerman, Gordon J Freeman, Catherine J Wu, Patrick A Ott, Kwok-Kin Wong, Eliezer M Van Allen
Response to immune checkpoint blockade in mesenchymal tumors is poorly characterized, but immunogenomic dissection of these cancers could inform immunotherapy mediators. We identified a treatment-naive patient who has metastatic uterine leiomyosarcoma and has experienced complete tumor remission for >2 years on anti-PD-1 (pembrolizumab) monotherapy. We analyzed the primary tumor, the sole treatment-resistant metastasis, and germline tissue to explore mechanisms of immunotherapy sensitivity and resistance...
February 21, 2017: Immunity
https://www.readbyqxmd.com/read/28217703/babesiosis-associated-immune-thrombocytopenia
#17
Roshni Narurkar, Aleksandra Mamorska-Dyga, Anup Agarwal, John C Nelson, Delong Liu
Thrombocytopenia is a common feature of babesiosis. The mechanism for thrombocytopenia in babesiosis remains elusive. We report a case of babesiosis with severe new onset immune thrombocytopenia (ITP). In addition to antibiotics treatment for babesiosis, ITP therapy was administered. ITP in the present case was most likely triggered by the babesia infection. The severity of ITP in this case was not proportional to the severity of parasitemia. The neoantigen triggering the autoimmune response in babesiosis requires further characterization...
2017: Stem Cell Investigation
https://www.readbyqxmd.com/read/28210865/the-impact-of-melanoma-genetics-on-treatment-response-and-resistance-in-clinical-and-experimental-studies
#18
M Kunz, M Hölzel
Recent attempts to characterize the melanoma mutational landscape using high-throughput sequencing technologies have identified new genes and pathways involved in the molecular pathogenesis of melanoma. Apart from mutated BRAF, NRAS, and KIT, a series of new recurrently mutated candidate genes with impact on signaling pathways have been identified such as NF1, PTEN, IDH1, RAC1, ARID2, and TP53. Under targeted treatment using BRAF and MEK1/2 inhibitors either alone or in combination, a majority of patients experience recurrences, which are due to different genetic mechanisms such as gene amplifications of BRAF or NRAS, MEK1/2 and PI3K mutations...
February 16, 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/28202532/cd40-signaling-drives-potent-cellular-immune-responses-in-heterologous-cancer-vaccinations
#19
Supot Nimanong, Dmitrij Ostroumov, Jessica Wingerath, Sarah Knocke, Norman Woller, Engin Guerlevik, Christine Falk, Michael P Manns, Florian Kuehnel, Thomas C Wirth
Antagonistic antibodies targeting co-inhibitory receptors have revolutionized the treatment of cancer by inducing durable immune responses and clinical remissions in patients. In contrast, success of agonistic costimulatory antibodies has thus far been limited due to insufficient induction of adaptive immune responses. Here we describe a novel vaccination method consisting of a primary dendritic cell immunization followed by a composite vaccination including an agonistic CD40 antibody, soluble antigen and a TLR3 agonist, referred to as CoAT...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28198830/-final-common-pathway-of-human-cancer-immunotherapy-targeting-random-somatic-mutations
#20
REVIEW
Eric Tran, Paul F Robbins, Steven A Rosenberg
Effective clinical cancer immunotherapies, such as administration of the cytokine IL-2, adoptive cell transfer (ACT) and the recent success of blockade of the checkpoint modulators CTLA-4 and PD-1, have been developed without clear identification of the immunogenic targets expressed by human cancers in vivo. Immunotherapy of patients with cancer through the use of ACT with autologous lymphocytes has provided an opportunity to directly investigate the antigen recognition of lymphocytes that mediate cancer regression in humans...
February 15, 2017: Nature Immunology
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