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Patrick A Ott, Zhuting Hu, Derin B Keskin, Sachet A Shukla, Jing Sun, David J Bozym, Wandi Zhang, Adrienne Luoma, Anita Giobbie-Hurder, Lauren Peter, Christina Chen, Oriol Olive, Todd A Carter, Shuqiang Li, David J Lieb, Thomas Eisenhaure, Evisa Gjini, Jonathan Stevens, William J Lane, Indu Javeri, Kaliappanadar Nellaiappan, Andres M Salazar, Heather Daley, Michael Seaman, Elizabeth I Buchbinder, Charles H Yoon, Maegan Harden, Niall Lennon, Stacey Gabriel, Scott J Rodig, Dan H Barouch, Jon C Aster, Gad Getz, Kai Wucherpfennig, Donna Neuberg, Jerome Ritz, Eric S Lander, Edward F Fritsch, Nir Hacohen, Catherine J Wu
This corrects the article DOI: 10.1038/nature22991.
March 14, 2018: Nature
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
Ornella Franzese, Fiorenzo Battaini, Grazia Graziani, Lucio Tentori, Maria Luisa Barbaccia, Angelo Aquino, Mario Roselli, Maria Pia Fuggetta, Enzo Bonmassar, Francesco Torino
In recent years, immune checkpoint inhibitors (ICpI) have provided the ground to bring tumor immunity back to life thanks to their capacity to afford a real clinical benefit in terms of patient's survival. Essential to ICpI success is the presence of tumor-associated neoantigens generated by non-synonymous mutations, since a direct relationship between mutation load of malignant cells and susceptibility to ICpI has been confidently established. However, it has been also suggested that high intratumor heterogeneity (ITH) associated with subclonal neoantigens could not elicit adequate immune responses...
March 9, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Alexandra Frelau, Marc Pracht, Samuel Le Sourd, Alexandra Lespagnol, Romain Corre, Cédric Ménard, Karin Tarte, Jean Mosser, Julien Edeline
PD-1 checkpoint inhibitors are becoming the reference treatment for several types of cancers. Many patients show remarkable efficacy and low toxicity. However, some patients have a better outcome than others with PD-1 checkpoint inhibitors. So, it is crucial to identify biomarkers of response. We review here the available data of several potential biomarkers of efficacy. The expression of PD-L1, detected by immunohistochemistry on tumor cells and immune cells is a good predictive biomarker of response for some cancers; however, this method is not standardized, and there are different antibodies, different cut-off values, and different targets (tumor or microenvironment)...
March 7, 2018: Bulletin du Cancer
Xianda Zhao, Audre May, Emil Lou, Subbaya Subramanian
Immune checkpoint blockade therapy (ICBT) has resulted in extended overall survival for some patients with certain types of cancer, most prominently including colorectal cancer (CRC) associated with microsatellite instability (MSI). However, most patients with CRC whose phenotypes have microsatellite stability (MSS) are unresponsive to ICBT. In efforts to understand the responsiveness of CRC tumors to ICBT, genotypic and phenotypic signatures of CRC tumors are now being investigated. The MSI and MSS classification has been clinically validated as helpful in predicting response vs nonresponse to ICBT in patients with CRC...
February 12, 2018: Translational Research: the Journal of Laboratory and Clinical Medicine
Antonia L Pritchard
This review discusses the rapidly evolving field of immunotherapy research, focusing on the types of cancer antigens that can be recognised by the immune system and potential methods by which neoantigens can be exploited clinically to successfully target and clear tumour cells. Recent studies suggest that the likelihood of successful immunotherapeutic targeting of cancer will be reliant on immune response to neoantigens. This type of cancer-specific antigen arises from somatic variants that result in alteration of the expressed protein sequence...
March 8, 2018: BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
Robert O Dillman, Andrew N Cornforth, Gabriel I Nistor, Edward F McClay, Thomas T Amatruda, Carol Depriest
BACKGROUND: Despite improved survival following checkpoint inhibitors, there is still a potential role for anti-cancer therapeutic vaccines. Because of biological heterogeneity and neoantigens resulting from each patient's mutanome, autologous tumor may be the best source of tumor-associated antigens (TAA) for vaccines. Ex vivo loading of autologous dendritic cells with TAA may be associated with superior clinical outcome compared to injecting irradiated autologous tumor cells. We conducted a randomized phase II trial to compare autologous tumor cell vaccines (TCV) and autologous dendritic cell vaccines (DCV) loaded with autologous TAA...
March 6, 2018: Journal for Immunotherapy of Cancer
Aileen Weiwei Li, Miguel C Sobral, Soumya Badrinath, Youngjin Choi, Amanda Graveline, Alexander G Stafford, James C Weaver, Maxence O Dellacherie, Ting-Yu Shih, Omar A Ali, Jaeyun Kim, Kai W Wucherpfennig, David J Mooney
Existing strategies to enhance peptide immunogenicity for cancer vaccination generally require direct peptide alteration, which, beyond practical issues, may impact peptide presentation and result in vaccine variability. Here, we report a simple adsorption approach using polyethyleneimine (PEI) in a mesoporous silica microrod (MSR) vaccine to enhance antigen immunogenicity. The MSR-PEI vaccine significantly enhanced host dendritic cell activation and T-cell response over the existing MSR vaccine and bolus vaccine formulations...
March 5, 2018: Nature Materials
Yafeng Zhu, Lukas M Orre, Henrik J Johansson, Mikael Huss, Jorrit Boekel, Mattias Vesterlund, Alejandro Fernandez-Woodbridge, Rui M M Branca, Janne Lehtiö
Proteogenomics enable the discovery of novel peptides (from unannotated genomic protein-coding loci) and single amino acid variant peptides (derived from single-nucleotide polymorphisms and mutations). Increasing the reliability of these identifications is crucial to ensure their usefulness for genome annotation and potential application as neoantigens in cancer immunotherapy. We here present integrated proteogenomics analysis workflow (IPAW), which combines peptide discovery, curation, and validation. IPAW includes the SpectrumAI tool for automated inspection of MS/MS spectra, eliminating false identifications of single-residue substitution peptides...
March 2, 2018: Nature Communications
Khalil Saleh, Roland Eid, Fady Gh Haddad, Nadine Khalife-Saleh, Hampig Raphaël Kourie
Head and neck squamous cell carcinoma (HNSCC), a heterogeneous group of upper aerodigestive tract malignancies, is the seventh most common cancer worldwide. Tobacco use and alcohol consumption were the most identified risk factors of HNSCC. However, human papilloma virus, a sexually transmitted infection, has been determined as another primary cause of HNSCC. Early-stage disease is treated with surgery or radiotherapy. Recurrent or metastatic HNSCC is associated with poor prognosis with a median overall survival of 10 months...
2018: Therapeutics and Clinical Risk Management
C René Leemans, Peter J F Snijders, Ruud H Brakenhoff
Head and neck squamous cell carcinomas (HNSCCs) arise in the mucosal linings of the upper aerodigestive tract and are unexpectedly heterogeneous in nature. Classical risk factors are smoking and excessive alcohol consumption, and in recent years, the role of human papillomavirus (HPV) has emerged, particularly in oropharyngeal tumours. HPV-induced oropharyngeal tumours are considered a separate disease entity, which recently has manifested in an adapted prognostic staging system while the results of de-intensified treatment trials are awaited...
March 2, 2018: Nature Reviews. Cancer
Anna Maria Valentini, Federica Di Pinto, Filomena Cariola, Vito Guerra, Gianluigi Giannelli, Maria Lucia Caruso, Michele Pirrelli
Objectives: We investigated the PD-L1 expression in colorectal cancer (CRC) and in its microenvironment. Results: PD-L1 was expressed in neoplastic cells (NCs) and tumor-infiltrating immune cells (IICs). All samples PD-L1+ on NCs were also on IICs. Three types of cancers could be grouped: group A(NCs-/ IICs-); group B (NCs-/ IICs+); group C (NCs+/IICs+). To group A belong tumors characterized by poorly immunogenic competence, poor immune response but massive granulocyte infiltrate, justifying the absence of PD-L1 as an immunoinhibitor receptor...
February 2, 2018: Oncotarget
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...
February 27, 2018: Bioconjugate Chemistry
A C Eklund, Z Szallasi
Personalized cancer immunotherapy may benefit from improved computational algorithms for identifying neoantigens. Recent results demonstrate that machine learning can improve accuracy. Additional improvements may require more genomic data paired with in vitro T cell reactivity measurements, and more sophisticated algorithms that take into account T cell receptor specificity.
February 21, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Michal Bassani-Sternberg
Recent data indicate that endogenous mutated cancer proteins can be processed and presented as HLA binding peptides, leading to their recognition in vivo as "non-self." Targeting such neoantigens would enable immune cells to distinguish between normal and cancerous cells, avoiding the risk of autoimmunity. So far, discovery of such neoantigens relies mainly on prediction-based interrogation of the "mutanome" using genomic information as input, followed by highly laborious and time-consuming T cell screening assays...
2018: Methods in Molecular Biology
Guo-Chen Liu, Ran-Yi Liu, Jun-Ping Yan, Xin An, Wu Jiang, Yi-Hong Ling, Jie-Wei Chen, Jin-Xin Bei, Xiao-Yu Zuo, Mu-Yan Cai, Ze-Xian Liu, Zhi-Xiang Zuo, Ji-Hong Liu, Zhi-Zhong Pan, Pei-Rong Ding
Background: Previous studies demonstrated that prognosis of germline deficiency in mismatch repair protein (dMMR) was different from that of sporadic dMMR. The underlying mechanism has not been studied. Methods: From a prospectively maintained database, we collected dMMR colorectal cancer (CRC) patients identified by postoperative immunohistochemistry screening. According to genetic test, patients were grouped as Lynch-associated or sporadic dMMR. We compared the clinical-pathological features, prognosis, and immunoreactive differences between the two groups...
February 20, 2018: Journal of the National Cancer Institute
Yih-Lin Chung, Mei-Ling Wu
Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated lymphoepithelioma. The aim of the present study was to characterize the homogeneity and distinctness of the T-cell repertoires within and between primary and metastatic NPCs. We used ultra-deep sequencing of the hypervariably rearranged antigen-binding CDR3 regions of T-cell receptor beta (TCRbeta ) to comprehensively profile the T-cell repertoires in NPC patients receiving definitive chemoradiotherapy with long-term follow-up. We observed not only various spatially heterogeneous patient-specific TCRbeta clone compositions that changed with time but also several commonly enriched TCRbeta subclones that were constantly shared between primary NPCs in the head and neck regions, locally recurrent tumors after treatment, and later-developed distant metastatic tumors in the liver, lung and bone...
February 22, 2018: International Journal of Cancer. Journal International du Cancer
Catarina Nogueira, Johanna K Kaufmann, Hubert Lam, Jessica B Flechtner
Targeting neoantigens has become an attractive strategy for cancer immunotherapy. Epitope prediction algorithms facilitate rapid selection of potential neoantigens, but are plagued with high false-positive and false-negative rates. Here we review ex vivo technologies for biological identification of neoantigens to improve empirical prioritization for immunotherapy.
February 2018: Trends in Cancer
Nicole A P Lieberman, Kole DeGolier, Kristen Haberthur, Harrison Chinn, Kara W Moyes, Myriam N Bouchlaka, Kirsti L Walker, Christian M Capitini, Courtney A Crane
Recent advances in cellular therapies for patients with cancer, including checkpoint blockade and ex vivo -expanded, tumor-specific T cells, have demonstrated that targeting the immune system is a powerful approach to the elimination of tumor cells. Clinical efforts have also demonstrated limitations, however, including the potential for tumor cell antigenic drift and neoantigen formation, which promote tumor escape and recurrence, as well as rapid onset of T cell exhaustion in vivo . These findings suggest that antigen unrestricted cells, such as natural killer (NK) cells, may be beneficial for use as an alternative to or in combination with T cell based approaches...
2018: Frontiers in Immunology
Christopher A Miller, Sonika Dahiya, Tiandao Li, Robert Fulton, Matthew D Smyth, Gavin P Dunn, Joshua B Rubin, Elaine R Mardis
BACKGROUND: As in other brain tumors, multiple recurrences after complete resection and irradiation of supratentorial ependymoma are common and frequently result in patient death. This standard-of-care treatment was established in the pre-genomic era without the ability to evaluate the effect that mutagenic therapies may exert on tumor evolution and in promoting resistance, recurrence, and death. We seized a rare opportunity to characterize treatment effects and the evolution of a single patient's ependymoma across four recurrences after different therapies...
February 13, 2018: Cold Spring Harbor Molecular Case Studies
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