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Cancer neoantigens

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https://www.readbyqxmd.com/read/28533942/hla-a24-ligandome-analysis-of-colon-and-lung-cancer-cells-identifies-a-novel-cancer-testis-antigen-and-a-neoantigen-that-elicits-specific-and-strong-ctl-responses
#1
Vitaly Kochin, Takayuki Kanaseki, Serina Tokita, Sho Miyamoto, Yosuke Shionoya, Yasuhiro Kikuchi, Daichi Morooka, Yoshihiko Hirohashi, Tomohide Tsukahara, Kazue Watanabe, Shingo Toji, Yasuo Kokai, Noriyuki Sato, Toshihiko Torigoe
This study focused on HLA-A24 and comprehensively analyzed the ligandome of colon and lung cancer cells without the use of MHC-binding in silico prediction algorithms. Affinity purification using the antibody specific to HLA-A24 followed by LC-MS/MS sequencing was used to detect peptides, which harbored the known characteristics of HLA-A24 peptides in terms of length and anchor motifs. Ligandome analysis demonstrated the natural presentation of two different types of novel tumor-associated antigens. The ligandome contained a peptide derived from SUV39H2, a gene found to be expressed in a variety of cancers but not in normal tissues (except for the testis)...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28528510/immunogenomics-using-genomics-to-personalize-cancer-immunotherapy
#2
Rance C Siniard, Shuko Harada
While the use of genomic data has the potential to revolutionize patient care, there is still much work to be done with regard to the transformation of host-tumor interactions into favorable clinical outcomes for our patients. High-throughput technologies, such as next-generation sequencing (NGS), have rapidly advanced our understanding of oncology, and we are learning that most tumors do not simply possess consistently mutated genes that are responsible for tumorigenesis, facilitating the need for personalized cancer therapy...
May 20, 2017: Virchows Archiv: An International Journal of Pathology
https://www.readbyqxmd.com/read/28522277/-immunotherapy-and-radiotherapy
#3
S Bockel, D Antoni, É Deutsch, F Mornex
Radiotherapy, primarily known for its cytotoxic effect on the tumor cells, via the induction of DNA damages, has the ability to induce a systemic antitumoral response. By an immunologic cell death, tumor cells exposed to radiation release a large amount of neoantigenes and pro-inflammatory mediators, acting as an in situ vaccine, resulting in an tumor regression within the primary irradiated site, but also in the distant "out of field" secondary tumors. However, this phenomenon is extremly rare with radiotherapy alone, suggesting that the radiation-induced antitumor immunity is not sufficient for overcoming the tumor's and its microenvironnement immunosuppressing effect...
May 15, 2017: Cancer Radiothérapie: Journal de la Société Française de Radiothérapie Oncologique
https://www.readbyqxmd.com/read/28516256/-skin-diseases-associated-with-environmental-factors
#4
REVIEW
Vera Mahler
BACKGROUND: Multiple environmental exposures may derange the regulatory and repair mechanisms of the skin and lead to dermatological disease. OBJECTIVES: Provide an overview of non-allergic skin diseases associated with environmental factors. MATERIALS AND METHODS: Review of current scientific evidence for associations of non-allergic skin diseases with environmental exposures: irritation, chemicals, infection, UV-radiation, temperature. RESULTS: Predisposition (constitution e...
May 17, 2017: Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz
https://www.readbyqxmd.com/read/28507809/t-cell-therapy-targeting-a-public-neoantigen-in-microsatellite-instable-colon-cancer-reduces-in-vivo-tumor-growth
#5
Else M Inderberg, Sébastien Wälchli, Marit R Myhre, Sissel Trachsel, Hilde Almåsbak, Gunnar Kvalheim, Gustav Gaudernack
T-cell receptor (TCR) transfer is an attractive strategy to increase the number of cancer-specific T cells in adoptive cell therapy. However, recent clinical and pre-clinical findings indicate that careful consideration of the target antigen is required to limit the risk of off-target toxicity. Directing T cells against mutated proteins such as frequently occurring frameshift mutations may thus be a safer alternative to tumor-associated self-antigens. Furthermore, such frameshift mutations result in novel polypeptides allowing selection of TCRs from the non-tolerant T-cell repertoire circumventing the problem of low affinity TCRs due to central tolerance...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28507806/preclinical-efficacy-of-immune-checkpoint-monotherapy-does-not-recapitulate-corresponding-biomarkers-based-clinical-predictions-in-glioblastoma
#6
Abhishek D Garg, Lien Vandenberk, Matthias Van Woensel, Jochen Belmans, Marco Schaaf, Louis Boon, Steven De Vleeschouwer, Patrizia Agostinis
Glioblastoma (GBM) is resistant to most multimodal therapies. Clinical success of immune-checkpoint inhibitors (ICIs) has spurred interest in applying ICIs targeting CTLA4, PD1 or IDO1 against GBM. This amplifies the need to ascertain GBM's intrinsic susceptibility (or resistance) toward these ICIs, through clinical biomarkers that may also "guide and prioritize" preclinical testing. Here, we interrogated the TCGA and/or REMBRANDT human patient-cohorts to predict GBM's predisposition toward ICIs. We exploited various broad clinical biomarkers, including mutational or predicted-neoantigen burden, pre-existing or basal levels of tumor-infiltrating T lymphocytes (TILs), differential expression of immune-checkpoints within the tumor and their correlation with particular TILs/Treg-associated functional signature and prognostic impact of differential immune-checkpoint expression...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28494274/personalized-t-cell-mediated-cancer-immunotherapy-progress-and-challenges
#7
REVIEW
Michael T Bethune, Alok V Joglekar
Immunotherapies are yielding effective treatments for several previously untreatable cancers. Until recently, vaccines and adoptive cell therapies have been designed to target public tumor antigens common to multiple patients rather than private antigens specific to a single patient. Due to the difficulty of identifying public antigens that are expressed exclusively on tumor cells, these studies have yielded both clinical successes and serious immune-related adverse events. Multiple avenues of research now underscore the centrality of tumor-specific mutated private antigens to endogenous anti-tumor immunity...
May 8, 2017: Current Opinion in Biotechnology
https://www.readbyqxmd.com/read/28493171/immunotherapy-in-urothelial-cancer-recent-results-and-future-perspectives
#8
REVIEW
Matthew S Farina, Kevin T Lundgren, Joaquim Bellmunt
Cytotoxic chemotherapy has been the only systemic treatment of locally advanced and metastatic urothelial carcinoma for decades. Long-term survival remains stagnant around 12-14 months for patients with advanced disease who have progressed on or recurred after receiving first-line platinum-based chemotherapy. Improving clinical outcomes for patients with urothelial carcinoma in all disease settings requires the development of novel treatments, especially for patients who failed on first-line chemotherapy. Since the discovery of intravesical Bacillus-Calmette Guerin (BCG) in the 1970s for non-muscle invasive disease, there have not been any major breakthrough drugs that exploit the immune-sensitivity of bladder cancer until recently...
May 11, 2017: Drugs
https://www.readbyqxmd.com/read/28484631/tsnad-an-integrated-software-for-cancer-somatic-mutation-and-tumour-specific-neoantigen-detection
#9
Zhan Zhou, Xingzheng Lyu, Jingcheng Wu, Xiaoyue Yang, Shanshan Wu, Jie Zhou, Xun Gu, Zhixi Su, Shuqing Chen
Tumour antigens have attracted much attention because of their importance to cancer diagnosis, prognosis and targeted therapy. With the development of cancer genomics, the identification of tumour-specific neoantigens became possible, which is a crucial step for cancer immunotherapy. In this study, we developed software called the tumour-specific neoantigen detector for detecting cancer somatic mutations following the best practices of the genome analysis toolkit and predicting potential tumour-specific neoantigens, which could be either extracellular mutations of membrane proteins or mutated peptides presented by class I major histocompatibility complex molecules...
April 2017: Royal Society Open Science
https://www.readbyqxmd.com/read/28482672/next-generation-approaches-for-tumor-vaccination
#10
Anand Patel, Howard L Kaufman, Mary L Disis
Tumor vaccines have been an attractive concept in the immunotherapy of cancer based on the central role of tumor-associated antigens in allowing the immune system to recognize cancer cells and the large variety of platforms in which to present such antigens to the immune system. Early clinical studies of vaccines, however, were largely disappointing. Recent evidence that cancer-mediated T cell suppression may prevent T cell activation is leading to renewed interest in vaccine development. The use of T cell checkpoint inhibitors alone has revolutionized the contemporary treatment of human cancer, and has suggested that the emergence of neoantigens may be an important biomarker of therapeutic response...
April 2017: Chinese Clinical Oncology
https://www.readbyqxmd.com/read/28465452/human-tumor-antigens-yesterday-today-and-tomorrow
#11
REVIEW
Olivera J Finn
The question of whether human tumors express antigens that can be recognized by the immune system has been answered with a resounding YES. Most were identified through spontaneous antitumor humoral and cellular immune responses found in cancer patients and include peptides, glycopeptides, phosphopeptides, viral peptides, and peptides resulting from common mutations in oncogenes and tumor-suppressor genes, or common gene fusion events. Many have been extensively tested as candidates for anticancer vaccines. More recently, attention has been focused on the potentially large number of unique tumor antigens, mutated neoantigens, that are the predicted products of the numerous mutations revealed by exome sequencing of primary tumors...
May 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28465371/dna-polymerase-%C3%A9-deficiency-leading-to-an-ultramutator-phenotype-a-novel-clinically-relevant-entity
#12
Enrico Castellucci, Tianfang He, D Yitzchak Goldstein, Balazs Halmos, Jennifer Chuy
Deficiencies in DNA repair due to mutations in the exonuclease domain of DNA polymerase ɛ have recently been described in a subset of cancers characterized by an ultramutated and microsatellite stable (MSS) phenotype. This alteration in DNA repair is distinct from the better-known mismatch repair deficiencies which lead to microsatellite instability (MSI) and an increased tumor mutation burden. Instead, mutations in POLE lead to impaired proofreading intrinsic to Pol ɛ during DNA replication resulting in a dramatically increased mutation rate...
May 2017: Oncologist
https://www.readbyqxmd.com/read/28453704/genomic-characterization-of-her2-positive-breast-cancer-and-response-to-neoadjuvant-trastuzumab-and-chemotherapy-results-from-the-acosog-z1041-alliance-trial
#13
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. Patients and methods: In supplement to tissues from 37 Z1041 cases, 11 similarly treated cases were obtained from a single institution study (NCT00353483)...
May 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28431188/t-cell-receptor-%C3%AE-chain-repertoire-analysis-reveals-the-association-between-neoantigens-and-tumour-infiltrating-lymphocytes-in-multifocal-papillary-thyroid-carcinoma
#14
Zheming Lu, Chaoting Zhang, Jindong Sheng, Jing Shen, Baoguo Liu
To explore whether a few non-synonymous somatic mutations could induce activation and proliferation of neoantigen-specific tumour-infiltrating lymphocytes (TILs) in tumours with low mutation rates, we analysed a patient with multifocal papillary thyroid carcinoma (seven non-contiguous cancer foci) to investigate the relationship between neoantigens and TILs. These seven foci had a few or no non-synonymous somatic mutations; moreover, multiple loci had similar or different spectra of mutations. We used high-throughput sequencing of the rearranged genes in T cell receptor β-chain (TCRβ) to reveal the basic characteristics of T cells in seven tumour foci and matched adjacent normal tissue...
April 21, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28428277/immune-gene-expression-is-associated-with-genomic-aberrations-in-breast-cancer
#15
Anton Safonov, Tingting Jiang, Giampaolo Bianchini, Balázs Győrffy, Thomas Karn, Christos Hatzis, Lajos Pusztai
The presence of tumor-infiltrating lymphocytes (TIL) is a favorable prognostic factor in breast cancer, but what drives immune infiltration remains unknown. Here we examine if clonal heterogeneity, total mutation load, neoantigen load, copy number variations (CNV), gene- or pathway-level somatic mutations, or germline polymorphisms (SNP) are associated with immune metagene expression in breast cancer subtypes. Thirteen published immune metagenes correlated separately with genomic metrics in the 3 major breast cancer subtypes...
April 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/28423700/hla-class-i-loss-in-metachronous-metastases-prevents-continuous-t-cell-recognition-of-mutated-neoantigens-in-a-human-melanoma-model
#16
Barbara Schrörs, Silke Lübcke, Volker Lennerz, Martina Fatho, Anne Bicker, Catherine Wölfel, Patrick Derigs, Thomas Hankeln, Dirk Schadendorf, Annette Paschen, Thomas Wölfel
T lymphocytes against tumor-specific mutated neoantigens can induce tumor regression. Also, the size of the immunogenic cancer mutanome is supposed to correlate with the clinical efficacy of checkpoint inhibition. Herein, we studied the susceptibility of tumor cell lines from lymph node metastases occurring in a melanoma patient over several years towards blood-derived, neoantigen-specific CD8+ T cells. In contrast to a cell line established during early stage III disease, all cell lines generated at later time points from stage IV metastases exhibited partial or complete loss of HLA class I expression...
April 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28410302/tumor-infiltrating-lymphocyte-therapy-and-neoantigens
#17
Paul F Robbins
The adoptive cell transfer (ACT) of autologous tumor-infiltrating lymphocytes has been shown to be effective at mediating tumor regression in more than half of patients with metastatic melanoma and in mediating long-term complete regression in approximately one fourth of all patients with this cancer. The success of this approach in patients with cholangiocarcinoma and colon cancer supports efforts to expand ACT therapies to treatment of patients bearing a wide array of cancer types. Recent improvements in deep sequencing of the patient cancers, combined with extensive immunological testing of autologous tumor-infiltrating lymphocytes, indicate that T cells targeting epitopes arising from nonsynonymous somatic mutations, termed neoantigens, play important roles in mediating many of the effective cancer immunotherapies seen in response to ACT...
March 2017: Cancer Journal
https://www.readbyqxmd.com/read/28410301/dendritic-cell-strategies-for-eliciting-mutation-derived-tumor-antigen-responses-in-patients
#18
Sreekumar Balan, John Finnigan, Nina Bhardwaj
Dendritic cells (DCs) are equipped for sensing danger signals and capturing, processing, and presenting antigens to naive or effector cells and are critical in inducing humoral and adaptive immunity. Successful vaccinations are those that activate DCs to elicit both cellular and humoral responses, as well as long-lasting memory response against the target of interest. Recently, it has become apparent that tumor cells can provide new sources of antigens through nonsynonymous mutations or frame-shift mutations, leading to potentially hundreds of mutation-derived tumor antigens (MTAs) or neoantigens...
March 2017: Cancer Journal
https://www.readbyqxmd.com/read/28410300/applied-cancer-immunogenomics-leveraging-neoantigen-discovery-in-glioblastoma
#19
Tanner M Johanns, Gavin P Dunn
Glioblastoma (GBM) remains a significant cause of cancer-related mortality in pediatric and adult patients with limited treatment options. Immunotherapy represents a promising new therapeutic approach in many solid and hematologic malignancies, including GBM, although only a subset of patients responds clinically. Thus, current efforts are focused on identifying patients most likely to benefit from immune-based therapies. The cancer immunogenomics approach identifies candidate neoantigens from genomics information and represents a potentially exciting new space in precision neuro-oncology...
March 2017: Cancer Journal
https://www.readbyqxmd.com/read/28410296/neoantigen-discovery-in-human-cancers
#20
Elaine R Mardis
Cancer is caused by alterations to DNA that ultimately are translated into altered proteins with unique amino acid sequences when compared with their counterparts in normal cells. By inference, these altered proteins have the potential to elicit immune responses such as T-cell recognition, if properly presented by the immune system following protein degradation and major histocompatibility complex binding. Historically, identifying tumor-specific mutant antigens was painstaking work that involved molecular cloning and immune screening...
March 2017: Cancer Journal
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