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Neoepitope and cancer

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https://www.readbyqxmd.com/read/29731959/identification-of-neoepitopes-recognized-by-tumor-infiltrating-lymphocytes-tils-from-patients-with-glioma
#1
Davide Valentini, Martin Rao, Qingda Meng, Anna von Landenberg, Jiri Bartek, Georges Sinclair, Georgia Paraschoudi, Elke Jäger, Inti Harvey-Peredo, Ernest Dodoo, Markus Maeurer
Neoepitope-specific T-cell responses have been shown to induce durable clinical responses in patients with advanced cancers. We explored the recognition patterns of tumor-infiltrating T lymphocytes (TILs) from patients with glioblastoma multiforme (GBM), the most fatal form of tumors of the central nervous system. Whole-genome sequencing was used for generating DNA sequences representing the entire spectrum of 'private' somatic mutations in GBM tumors from five patients, followed by 15-mer peptide prediction and subsequent peptide synthesis...
April 13, 2018: Oncotarget
https://www.readbyqxmd.com/read/29643231/personalized-cancer-vaccine-effectively-mobilizes-antitumor-t-cell-immunity-in-ovarian-cancer
#2
Janos L Tanyi, Sara Bobisse, Eran Ophir, Sandra Tuyaerts, Annalisa Roberti, Raphael Genolet, Petra Baumgartner, Brian J Stevenson, Christian Iseli, Denarda Dangaj, Brian Czerniecki, Aikaterini Semilietof, Julien Racle, Alexandra Michel, Ioannis Xenarios, Cheryl Chiang, Dimitri S Monos, Drew A Torigian, Harvey L Nisenbaum, Olivier Michielin, Carl H June, Bruce L Levine, Daniel J Powell, David Gfeller, Rosemarie Mick, Urania Dafni, Vincent Zoete, Alexandre Harari, George Coukos, Lana E Kandalaft
We conducted a pilot clinical trial testing a personalized vaccine generated by autologous dendritic cells (DCs) pulsed with oxidized autologous whole-tumor cell lysate (OCDC), which was injected intranodally in platinum-treated, immunotherapy-naïve, recurrent ovarian cancer patients. OCDC was administered alone (cohort 1, n = 5), in combination with bevacizumab (cohort 2, n = 10), or bevacizumab plus low-dose intravenous cyclophosphamide (cohort 3, n = 10) until disease progression or vaccine exhaustion. A total of 392 vaccine doses were administered without serious adverse events...
April 11, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29567706/personalized-vaccines-for-cancer-immunotherapy
#3
REVIEW
Ugur Sahin, Özlem Türeci
Cancer is characterized by an accumulation of genetic alterations. Somatic mutations can generate cancer-specific neoepitopes that are recognized by autologous T cells as foreign and constitute ideal cancer vaccine targets. Every tumor has its own unique composition of mutations, with only a small fraction shared between patients. Technological advances in genomics, data science, and cancer immunotherapy now enable the rapid mapping of the mutations within a genome, rational selection of vaccine targets, and on-demand production of a therapy customized to a patient's individual tumor...
March 23, 2018: Science
https://www.readbyqxmd.com/read/29541393/effective-screening-of-t-cells-recognizing-neoantigens-and-construction-of-t-cell-receptor-engineered-t-cells
#4
Taigo Kato, Tatsuo Matsuda, Yuji Ikeda, Jae-Hyun Park, Matthias Leisegang, Sachiko Yoshimura, Tetsuro Hikichi, Makiko Harada, Makda Zewde, Sho Sato, Kosei Hasegawa, Kazuma Kiyotani, Yusuke Nakamura
Neoantigens are the main targets of tumor-specific T cells reactivated by immune checkpoint-blocking antibodies or when using tumor-infiltrating T cells for adoptive therapy. While cancers often accumulate hundreds of mutations and harbor several immunogenic neoantigens, the repertoire of mutation-specific T cells in patients might be restricted. To bypass suboptimal conditions, which impede the reactivation of existing T cells or the priming of neoantigen-specific T cells in a patient, we employ T cells of healthy donors with an overlapping HLA repertoire to target cancer neoantigens...
February 16, 2018: Oncotarget
https://www.readbyqxmd.com/read/29507106/the-immunogenicity-of-a-proline-substituted-altered-peptide-ligand-toward-the-cancer-associated-teipp-neoepitope-trh4-is-unrelated-to-complex-stability
#5
Ida Hafstrand, Elien M Doorduijn, Renhua Sun, Anna Talyzina, Marjolein Sluijter, Sara Pellegrino, Tatyana Sandalova, Adil Doganay Duru, Thorbald van Hall, Adnane Achour
Human cancers frequently display defects in Ag processing and presentation allowing for immune evasion, and they therefore constitute a significant challenge for T cell-based immunotherapy. We have previously demonstrated that the antigenicity of tumor-associated Ags can be significantly enhanced through unconventional residue modifications as a novel tool for MHC class I (MHC-I)-based immunotherapy approaches. We have also previously identified a novel category of cancer neo-epitopes, that is, T cell epitopes associated with impaired peptide processing (TEIPP), that are selectively presented by MHC-I on cells lacking the peptide transporter TAP...
April 15, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29505699/translating-immunopeptidomics-to-immunotherapy-decision-making-for-patient-and-personalized-target-selection
#6
Jens Fritsche, Barbara Rakitsch, Franziska Hoffgaard, Michael Römer, Heiko Schuster, Daniel J Kowalewski, Martin Priemer, Vlatka Stos-Zweifel, Helen Hörzer, Arun Satelli, Annika Sonntag, Valentina Goldfinger, Colette Song, Andrea Mahr, Martina Ott, Oliver Schoor, Toni Weinschenk
Immunotherapy is revolutionizing cancer treatment and has shown success in particular for tumors with a high mutational load. These effects have been linked to neoantigens derived from patient-specific mutations. To expand efficacious immunotherapy approaches to the vast majority of tumor types and patient populations carrying only a few mutations and maybe not a single presented neoepitope, it is necessary to expand the target space to non-mutated cancer-associated antigens. Mass spectrometry enables the direct and unbiased discovery and selection of tumor-specific human leukocyte antigen (HLA) peptides that can be used to define targets for immunotherapy...
March 5, 2018: Proteomics
https://www.readbyqxmd.com/read/29485848/subcutaneous-nanodisc-vaccination-with-neoantigens-for-combination-cancer-immunotherapy
#7
Rui Kuai, Xiaoqi Sun, Wenmin Yuan, Yao Xu, Anna Schwendeman, James J Moon
While cancer immunotherapy provides new exciting treatment options for patients, there is an urgent need for new strategies that can synergize with immune checkpoint blockers and boost the patient response rates. We have developed a personalized vaccine nanodisc platform based on synthetic high-density lipoproteins for co-delivery of immunostimulatory agents and tumor antigens, including tumor-specific neoantigens. Here we examined the route of delivery, safety profiles, and therapeutic efficacy of nanodisc vaccination against established tumors...
March 21, 2018: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/29409514/immune-monitoring-and-tcr-sequencing-of-cd4-t-cells-in-a-long-term-responsive-patient-with-metastasized-pancreatic-ductal-carcinoma-treated-with-individualized-neoepitope-derived-multipeptide-vaccines-a-case-report
#8
Katja Sonntag, Hisayoshi Hashimoto, Matthias Eyrich, Moritz Menzel, Max Schubach, Dennis Döcker, Florian Battke, Carolina Courage, Helmut Lambertz, Rupert Handgretinger, Saskia Biskup, Karin Schilbach
BACKGROUND: Cancer vaccines can effectively establish clinically relevant tumor immunity. Novel sequencing approaches rapidly identify the mutational fingerprint of tumors, thus allowing to generate personalized tumor vaccines within a few weeks from diagnosis. Here, we report the case of a 62-year-old patient receiving a four-peptide-vaccine targeting the two sole mutations of his pancreatic tumor, identified via exome sequencing. METHODS: Vaccination started during chemotherapy in second complete remission and continued monthly thereafter...
February 6, 2018: Journal of Translational Medicine
https://www.readbyqxmd.com/read/29399398/cancer-vaccine-based-on-a-combination-of-an-infection-enhanced-adenoviral-vector-and-pro-inflammatory-allogeneic-dcs-leads-to-sustained-antigen-specific-immune-responses-in-three-melanoma-models
#9
Grammatiki Fotaki, Chuan Jin, Iliana Kyriaki Kerzeli, Mohanraj Ramachandran, Minttu-Maria Martikainen, Alex Karlsson-Parra, Di Yu, Magnus Essand
Autologous patient-derived dendritic cells (DCs) modified ex vivo to present tumor-associated antigens (TAAs) are frequently used as cancer vaccines. However, apart from the stringent logistics in producing DCs on a patient basis, accumulating evidence indicate that ex vivo engineered DCs are poor in migration and in fact do not directly present TAA epitopes to naïve T cells in vivo . Instead, it is proposed that bystander host DCs take up material from vaccine-DCs, migrate and subsequently initiate antitumor T-cell responses...
2018: Oncoimmunology
https://www.readbyqxmd.com/read/29350327/hypermutated-tumors-and-immune-checkpoint-inhibition
#10
Kristen K Ciombor, Richard M Goldberg
Microsatellite instability-high/DNA mismatch repair deficient tumors are found across the cancer spectrum and often harbor markedly increased numbers of mutations when compared to microsatellite stable/DNA mismatch repair proficient tumors. As a result of this high mutational load, tumor-infiltrating lymphocyte density is increased and more immunogenic neoepitopes are expressed, leading to upregulation of immune checkpoints in these tumors. Checkpoint inhibitors such as pembrolizumab and nivolumab, both immunoglobulin G4 (IgG4) monoclonal antibodies that block interactions between the programmed cell death receptor-1 and its ligands, have significant activity in this tumor class...
February 2018: Drugs
https://www.readbyqxmd.com/read/29226910/towards-personalized-tumour-specific-therapeutic-vaccines-for-cancer
#11
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...
March 2018: Nature Reviews. Immunology
https://www.readbyqxmd.com/read/29187854/an-analysis-of-natural-t-cell-responses-to-predicted-tumor-neoepitopes
#12
Anne-Mette Bjerregaard, Morten Nielsen, Vanessa Jurtz, Carolina M Barra, Sine Reker Hadrup, Zoltan Szallasi, Aron Charles Eklund
Personalization of cancer immunotherapies such as therapeutic vaccines and adoptive T-cell therapy may benefit from efficient identification and targeting of patient-specific neoepitopes. However, current neoepitope prediction methods based on sequencing and predictions of epitope processing and presentation result in a low rate of validation, suggesting that the determinants of peptide immunogenicity are not well understood. We gathered published data on human neopeptides originating from single amino acid substitutions for which T cell reactivity had been experimentally tested, including both immunogenic and non-immunogenic neopeptides...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29180478/perioperative-spatiotemporally-coordinated-activation-of-t-and-nk-cells-prevents-recurrence-of-pancreatic-cancer
#13
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 natural killier (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...
January 15, 2018: Cancer Research
https://www.readbyqxmd.com/read/29092006/novel-tools-to-assist-neoepitope-targeting-in-personalized-cancer-immunotherapy
#14
S K Saini, N Rekers, S R Hadrup
Current cancer immunotherapy approaches utilize the remarkable surveillance capacity of the human immune system, which is capable of recognizing and eliminating cancer cells based on identification of tumor-associated antigens arising as a consequence of the transformation process. Among these, mutational-derived neoepitopes have proved to be powerful targets for tumor elimination and mutational load has been shown to correlate with the clinical response to treatment with checkpoint inhibitors in many different tumor types...
December 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28976134/tumor-protein-53-mutations-mapping-to-its-tertiary-structure-with-in-silico-prediction-of-neoepitopic-vaccine-candidates-in-bone-tumors
#15
Hamid Nawaz Tipu, Abdul Rehman Arshad
Mapping of tp 53 mutations in bone cancers present in COSMIC database to its secondary and tertiary structure with in silico prediction of newly formed HLA binding epitopes as candidates for synthetic peptide vaccine. Mutations in bone cancers present in COSMIC database were listed and manually induced in wt p53 FASTA sequence. Wt p53 secondary structure was predicted. Template identified and tertiary structure of wt p53 was modelled in Cn3D followed by individual mutations mapping onto this model. HLA class I binding affinity was determined for mutated sequences to determine any newly binding peptide sequences...
September 2017: Journal of Experimental Therapeutics & Oncology
https://www.readbyqxmd.com/read/28961847/intratumoural-evolutionary-landscape-of-high-risk-prostate-cancer-the-progeny-study-of-genomic-and-immune-parameters
#16
M Linch, G Goh, C Hiley, Y Shanmugabavan, N McGranahan, A Rowan, Y N S Wong, H King, A Furness, A Freeman, J Linares, A Akarca, J Herrero, R Rosenthal, N Harder, G Schmidt, G A Wilson, N J Birkbak, R Mitter, S Dentro, P Cathcart, M Arya, E Johnston, R Scott, M Hung, M Emberton, G Attard, Z Szallasi, S Punwani, S A Quezada, T Marafioti, M Gerlinger, H U Ahmed, C Swanton
Background: Intratumoural heterogeneity (ITH) is well recognised in prostate cancer (PC), but its role in high-risk disease is uncertain. A prospective, single-arm, translational study using targeted multiregion prostate biopsies was carried out to study genomic and T-cell ITH in clinically high-risk PC aiming to identify drivers and potential therapeutic strategies. Patients and methods: Forty-nine men with elevated prostate-specific antigen and multiparametric-magnetic resonance imaging detected PC underwent image-guided multiregion transperineal biopsy...
October 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28954787/mutational-analysis-of-gene-fusions-predicts-novel-mhc-class-i-restricted-t-cell-epitopes-and-immune-signatures-in-a-subset-of-prostate-cancer
#17
Jennifer L Kalina, David S Neilson, Yen-Yi Lin, Phineas T Hamilton, Alexandra P Comber, Emma M H Loy, S Cenk Sahinalp, Colin C Collins, Faraz Hach, Julian J Lum
Purpose: Gene fusions are frequently found in prostate cancer and may result in the formation of unique chimeric amino acid sequences (CASQ) that span the breakpoint of two fused gene products. This study evaluated the potential for fusion-derived CASQs to be a source of tumor neoepitopes, and determined their relationship to patterns of immune signatures in prostate cancer patients. Experimental Design: A computational strategy was used to identify CASQs and their corresponding predicted MHC class I epitopes using RNA-Seq data from The Cancer Genome Atlas of prostate tumors...
December 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28912897/genomic-analysis-of-tumor-microenvironment-immune-types-across-14-solid-cancer-types-immunotherapeutic-implications
#18
Yu-Pei Chen, Yu Zhang, Jia-Wei Lv, Ying-Qin Li, Ya-Qin Wang, Qing-Mei He, Xiao-Jing Yang, Ying Sun, Yan-Ping Mao, Jing-Ping Yun, Na Liu, Jun Ma
We performed a comprehensive immuno-genomic analysis of tumor microenvironment immune types (TMITs), which is classified into four groups based on PD-L1+CD8A or PD-L1+cytolytic activity (CYT) expression, across a broad spectrum of solid tumors in order to help identify patients who will benefit from anti- PD-1/PD-L1 therapy. The mRNA sequencing data from The Cancer Genome Atlas (TCGA) of 14 solid cancer types representing 6,685 tumor samples was analyzed. TMIT was classified only for those tumor types that both PD-L1 and CD8A/CYT could prefict mutation and/or neoantigen number...
2017: Theranostics
https://www.readbyqxmd.com/read/28854978/the-neoepitope-landscape-in-pediatric-cancers
#19
Ti-Cheng Chang, Robert A Carter, Yongjin Li, Yuxin Li, Hong Wang, Michael N Edmonson, Xiang Chen, Paula Arnold, Terrence L Geiger, Gang Wu, Junmin Peng, Michael Dyer, James R Downing, Douglas R Green, Paul G Thomas, Jinghui Zhang
BACKGROUND: Neoepitopes derived from tumor-specific somatic mutations are promising targets for immunotherapy in childhood cancers. However, the potential for such therapies in targeting these epitopes remains uncertain due to a lack of knowledge of the neoepitope landscape in childhood cancer. Studies to date have focused primarily on missense mutations without exploring gene fusions, which are a major class of oncogenic drivers in pediatric cancer. METHODS: We developed an analytical workflow for identification of putative neoepitopes based on somatic missense mutations and gene fusions using whole-genome sequencing data...
August 31, 2017: Genome Medicine
https://www.readbyqxmd.com/read/28854952/clinical-implications-of-neoepitope-landscapes-for-adult-and-pediatric-cancers
#20
REVIEW
Yang-Yang Feng, Obi L Griffith, Malachi Griffith
Many immunotherapies rely on the presence of neoepitopes derived from somatic mutations that lead to altered peptide sequences. Several studies have now analyzed the neoepitope landscape of different cancer subtypes, predominantly for adult samples, which tend to feature significantly higher mutational burden. However, a new report publishing the first comprehensive analysis of the pediatric neoepitope landscape suggests that immunotherapies could also hold promise for pediatric cancers.See related research article 10...
August 31, 2017: Genome Medicine
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