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https://www.readbyqxmd.com/read/29772069/nature-of-tumor-rejection-antigens-in-ovarian-cancer
#1
REVIEW
Muzamil Y Want, Amit A Lugade, Sebastiano Battaglia, Kunle Odunsi
Major progress in the analysis of human immune responses to cancer has been made through the molecular characterization of human tumor antigens. The development of therapeutic strategies for eliciting immune-mediated rejection of tumors has accelerated due to the elucidation of the molecular basis for tumor cell recognition and destruction by immune cells. Of the various human tumor antigens defined to date in ovarian cancer, the cancer-testis (CT) family of antigens have studied extensively pre-clinically and clinically due their testis-restricted expression in normal tissues and ability to elicit robust immune responses...
May 17, 2018: Immunology
https://www.readbyqxmd.com/read/29769722/bystander-cd8-t-cells-are-abundant-and-phenotypically-distinct-in-human-tumour-infiltrates
#2
Yannick Simoni, Etienne Becht, Michael Fehlings, Chiew Yee Loh, Si-Lin Koo, Karen Wei Weng Teng, Joe Poh Sheng Yeong, Rahul Nahar, Tong Zhang, Hassen Kared, Kaibo Duan, Nicholas Ang, Michael Poidinger, Yin Yeng Lee, Anis Larbi, Alexis J Khng, Emile Tan, Cherylin Fu, Ronnie Mathew, Melissa Teo, Wan Teck Lim, Chee Keong Toh, Boon-Hean Ong, Tina Koh, Axel M Hillmer, Angela Takano, Tony Kiat Hon Lim, Eng Huat Tan, Weiwei Zhai, Daniel S W Tan, Iain Beehuat Tan, Evan W Newell
Various forms of immunotherapy, such as checkpoint blockade immunotherapy, are proving to be effective at restoring T cell-mediated immune responses that can lead to marked and sustained clinical responses, but only in some patients and cancer types1-4 . Patients and tumours may respond unpredictably to immunotherapy partly owing to heterogeneity of the immune composition and phenotypic profiles of tumour-infiltrating lymphocytes (TILs) within individual tumours and between patients5,6 . Although there is evidence that tumour-mutation-derived neoantigen-specific T cells play a role in tumour control2,4,7-10 , in most cases the antigen specificities of phenotypically diverse tumour-infiltrating T cells are largely unknown...
May 16, 2018: Nature
https://www.readbyqxmd.com/read/29754820/interfaces-of-malignant-and-immunologic-clonal-dynamics-in-ovarian-cancer
#3
Allen W Zhang, Andrew McPherson, Katy Milne, David R Kroeger, Phineas T Hamilton, Alex Miranda, Tyler Funnell, Nicole Little, Camila P E de Souza, Sonya Laan, Stacey LeDoux, Dawn R Cochrane, Jamie L P Lim, Winnie Yang, Andrew Roth, Maia A Smith, Julie Ho, Kane Tse, Thomas Zeng, Inna Shlafman, Michael R Mayo, Richard Moore, Henrik Failmezger, Andreas Heindl, Yi Kan Wang, Ali Bashashati, Diljot S Grewal, Scott D Brown, Daniel Lai, Adrian N C Wan, Cydney B Nielsen, Curtis Huebner, Basile Tessier-Cloutier, Michael S Anglesio, Alexandre Bouchard-Côté, Yinyin Yuan, Wyeth W Wasserman, C Blake Gilks, Anthony N Karnezis, Samuel Aparicio, Jessica N McAlpine, David G Huntsman, Robert A Holt, Brad H Nelson, Sohrab P Shah
High-grade serous ovarian cancer (HGSC) exhibits extensive malignant clonal diversity with widespread but non-random patterns of disease dissemination. We investigated whether local immune microenvironment factors shape tumor progression properties at the interface of tumor-infiltrating lymphocytes (TILs) and cancer cells. Through multi-region study of 212 samples from 38 patients with whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T and B cell receptor sequencing, we identified three immunologic subtypes across samples and extensive within-patient diversity...
May 7, 2018: Cell
https://www.readbyqxmd.com/read/29751996/update-on-tumor-neoantigens-and-their-utility-why-it-is-good-to-be-different
#4
REVIEW
Chung-Han Lee, Roman Yelensky, Karin Jooss, Timothy A Chan
Antitumor rejection by the immune system is a complex process that is regulated by several factors. Among these factors are the quality and quantity of mutational events that occur in cancer cells. Perhaps one of the most important types of mutations that influence antitumor immunity is the neoantigen, that is, a non-self-antigen that arises as a result of somatic mutation. Recent work has demonstrated that neoantigens hold significant promise for developing new diagnostic and therapeutic modalities. Therapeutic targeting of neoantigens is important for achieving benefit following therapy with immune checkpoint blockade agents or for cancer vaccines targeting mutations...
May 8, 2018: Trends in Immunology
https://www.readbyqxmd.com/read/29747685/car-t-cell-therapy-for-breast-cancer-harnessing-the-tumor-milieu-to-drive-t-cell-activation
#5
Pradip Bajgain, Supannikar Tawinwung, Lindsey D'Elia, Sujita Sukumaran, Norihiro Watanabe, Valentina Hoyos, Premal Lulla, Malcolm K Brenner, Ann M Leen, Juan F Vera
BACKGROUND: The adoptive transfer of T cells redirected to tumor via chimeric antigen receptors (CARs) has produced clinical benefits for the treatment of hematologic diseases. To extend this approach to breast cancer, we generated CAR T cells directed against mucin1 (MUC1), an aberrantly glycosylated neoantigen that is overexpressed by malignant cells and whose expression has been correlated with poor prognosis. Furthermore, to protect our tumor-targeted cells from the elevated levels of immune-inhibitory cytokines present in the tumor milieu, we co-expressed an inverted cytokine receptor linking the IL4 receptor exodomain with the IL7 receptor endodomain (4/7ICR) in order to transform the suppressive IL4 signal into one that would enhance the anti-tumor effects of our CAR T cells at the tumor site...
May 10, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29743717/integrating-oncolytic-viruses-in-combination-cancer-immunotherapy
#6
REVIEW
Praveen K Bommareddy, Megha Shettigar, Howard L Kaufman
Oncolytic viruses can be usefully integrated into tumour immunotherapies, as they target multiple steps within the cancer-immunity cycle. Oncolytic viruses directly lyse tumour cells, leading to the release of soluble antigens, danger signals and type I interferons, which drive antitumour immunity. In addition, some oncolytic viruses can be engineered to express therapeutic genes or can functionally alter tumour-associated endothelial cells, further enhancing T cell recruitment into immune-excluded or immune-deserted tumour microenvironments...
May 9, 2018: Nature Reviews. Immunology
https://www.readbyqxmd.com/read/29732013/successful-rechallenge-with-ceritinib-after-leukocytoclastic-vasculitis-during-ceritinib-treatment-for-non-small-cell-lung-cancer-harboring-the-eml4-alk-fusion-protein
#7
Tamio Okimoto, Yukari Tsubata, Takamasa Hotta, Megumi Hamaguchi, Takae Okuno, Yohei Shiratsuki, Akari Kodama, Mika Nakao, Yoshihiro Amano, Shunichi Hamaguchi, Noriaki Kurimoto, Reiko Tobita, Takeshi Isobe
Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors (TKIs) dramatically improve progression-free survival compared to cytotoxic agents. It is therefore important to manage patients with ALK-TKIs until drug resistance occurs. Leukocytoclastic vasculitis (LCV) is a rare complication during cancer treatment and is associated with a variety of factors. Currently, it is unclear whether we should withdraw a treatment when drug-induced LCV develops. We report a 40-year-old man with advanced pulmonary adenocarcinoma harboring the EML4-ALK fusion protein who developed LCV during ceritinib treatment...
April 13, 2018: Oncotarget
https://www.readbyqxmd.com/read/29724044/mechanisms-of-intrinsic-tumor-resistance-to-immunotherapy
#8
REVIEW
John Rieth, Subbaya Subramanian
An increased understanding of the interactions between the immune system and tumors has opened the door to immunotherapy for cancer patients. Despite some success with checkpoint inhibitors including ipilimumab, pembrolizumab, and nivolumab, most cancer patients remain unresponsive to such immunotherapy, likely due to intrinsic tumor resistance. The mechanisms most likely involve reducing the quantity and/or quality of antitumor lymphocytes, which ultimately are driven by any number of developments: tumor mutations and adaptations, reduced neoantigen generation or expression, indoleamine 2,3-dioxygenase (IDO) overexpression, loss of phosphatase and tensin homologue (PTEN) expression, and overexpression of the Wnt⁻β-catenin pathway...
May 2, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29721371/complimentary-mechanisms-of-dual-checkpoint-blockade-expand-unique-t-cell-repertoires-and-activate-adaptive-anti-tumor-immunity-in-triple-negative-breast-tumors
#9
Erika J Crosby, Junping Wei, Xiao Yi Yang, Gangjun Lei, Tao Wang, Cong-Xiao Liu, Pankaj Agarwal, Alan J Korman, Michael A Morse, Kenneth Gouin, Simon R V Knott, H Kim Lyerly, Zachary C Hartman
Triple-negative breast cancer (TNBC) is an aggressive and molecularly diverse breast cancer subtype typified by the presence of p53 mutations (∼80%), elevated immune gene signatures and neoantigen expression, as well as the presence of tumor infiltrating lymphocytes (TILs). As these factors are hypothesized to be strong immunologic prerequisites for the use of immune checkpoint blockade (ICB) antibodies, multiple clinical trials testing single ICBs have advanced to Phase III, with early indications of heterogeneous response rates of <20% to anti-PD1 and anti-PDL1 ICB...
2018: Oncoimmunology
https://www.readbyqxmd.com/read/29721177/a-pilot-study-of-durvalumab-and-tremelimumab-and-immunogenomic-dynamics-in-metastatic-breast-cancer
#10
Cesar August Santa-Maria, Taigo Kato, Jae-Hyun Park, Kazuma Kiyotani, Alfred Rademaker, Ami N Shah, Leeaht Gross, Luis Z Blanco, Sarika Jain, Lisa Flaum, Claudia Tellez, Regina Stein, Regina Uthe, William J Gradishar, Massimo Cristofanilli, Yusuke Nakamura, Francis J Giles
Immune checkpoint inhibitors produce modest responses in metastatic breast cancer, however, combination approaches may improve responses. A single arm pilot study was designed to determine the overall response rate (ORR) of durvalumab and tremelimumab, and evaluate immunogenomic dynamics in metastatic endocrine receptor (ER) positive or triple negative breast cancer (TNBC). Simon two-stage design indicated at least four responses from the first 18 patients were needed to proceed with the second stage. T-cell receptor (TCR) sequencing and immune-gene expression profiling were conducted at baseline and two months, whole exome sequencing was conducted at baseline...
April 10, 2018: Oncotarget
https://www.readbyqxmd.com/read/29720713/treatment-resistance-in-urothelial-carcinoma-an-evolutionary-perspective
#11
REVIEW
Panagiotis J Vlachostergios, Bishoy M Faltas
The emergence of treatment-resistant clones is a critical barrier to cure in patients with urothelial carcinoma. Setting the stage for the evolution of resistance, urothelial carcinoma is characterized by extensive mutational heterogeneity, which is detectable even in patients with early stage disease. Chemotherapy and immunotherapy both act as selective pressures that shape the evolutionary trajectory of urothelial carcinoma throughout the course of the disease. A detailed understanding of the dynamics of evolutionary drivers is required for the rational development of curative therapies...
May 2, 2018: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/29720506/induction-of-neoantigen-specific-cytotoxic-t-cells-and-construction-of-t-cell-receptor-engineered-t-cells-for-ovarian-cancer
#12
Tatsuo Matsuda, Matthias Leisegang, Jae-Hyun Park, Lili Ren, Taigo Kato, Yuji Ikeda, Makiko Harada, Kazuma Kiyotani, Ernst Lengyel, Gini F Fleming, Yusuke Nakamura
PURPOSE: Current evolution of cancer immunotherapies, such as immune checkpoint blockade, has implicated neoantigens as major targets of anti-cancer cytotoxic T cells. Adoptive T cell therapy with neoantigen-specific T cell receptor (TCR)-engineered T cells would be an attractive therapeutic option for advanced cancers where the host anti-tumor immune function is strongly inhibited. We previously developed a rapid and efficient pipeline for production of neoantigen-specific TCR-engineered T cells using peripheral blood from an HLA-matched healthy donor...
May 2, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29710228/immune-profiling-of-premalignant-lesions-in-patients-with-lynch-syndrome
#13
Kyle Chang, Melissa W Taggart, Laura Reyes-Uribe, Ester Borras, Erick Riquelme, Reagan M Barnett, Guido Leoni, F Anthony San Lucas, Maria T Catanese, Federica Mori, Maria G Diodoro, Y Nancy You, Ernest T Hawk, Jason Roszik, Paul Scheet, Scott Kopetz, Alfredo Nicosia, Elisa Scarselli, Patrick M Lynch, Florencia McAllister, Eduardo Vilar
Importance: Colorectal carcinomas in patients with Lynch syndrome (LS) arise in a background of mismatch repair (MMR) deficiency, display a unique immune profile with upregulation of immune checkpoints, and response to immunotherapy. However, there is still a gap in understanding the pathogenesis of MMR-deficient colorectal premalignant lesions, which is essential for the development of novel preventive strategies for LS. Objective: To characterize the immune profile of premalignant lesions from a cohort of patients with LS...
April 16, 2018: JAMA Oncology
https://www.readbyqxmd.com/read/29678194/the-perfect-personalized-cancer-therapy-cancer-vaccines-against-neoantigens
#14
REVIEW
Luigi Aurisicchio, Matteo Pallocca, Gennaro Ciliberto, Fabio Palombo
In the advent of Immune Checkpoint inhibitors (ICI) and of CAR-T adoptive T-cells, the new frontier in Oncology is Cancer Immunotherapy because of its ability to provide long term clinical benefit in metastatic disease in several solid and liquid tumor types. It is now clear that ICI acts by unmasking preexisting immune responses as well as by inducing de novo responses against tumor neoantigens. Thanks to theprogress made in genomics technologies and the evolution of bioinformatics, neoantigens represent ideal targets, due to their specific expression in cancer tissue and the potential lack of side effects...
April 20, 2018: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/29676647/immunologic-effects-of-beryllium-exposure
#15
Andrew P Fontenot
Metal-induced hypersensitivity is driven by T-cell sensitization to metal ions. Although numerous metals are associated with the development of diffuse parenchymal lung disease, beryllium-induced hypersensitivity is the best-studied to date. This review focuses on the interaction between innate and adaptive immunity that leads to the development of chronic beryllium disease. After beryllium exposure, activation of the innate immune system occurs through the engagement of pattern-recognition receptors. This activation leads to cell death, release of alarmins, and activation and migration of dendritic cells to lung-draining lymph nodes...
April 2018: Annals of the American Thoracic Society
https://www.readbyqxmd.com/read/29675465/elimination-of-established-tumors-with-nanodisc-based-combination-chemoimmunotherapy
#16
Rui Kuai, Wenmin Yuan, Sejin Son, Jutaek Nam, Yao Xu, Yuchen Fan, Anna Schwendeman, James J Moon
Although immune checkpoint blockade has shown initial success for various cancers, only a small subset of patients benefits from this therapy. Some chemotherapeutic drugs have been reported to induce antitumor T cell responses, prompting a number of clinical trials on combination chemoimmunotherapy. However, how to achieve potent immune activation with traditional chemotherapeutics in a manner that is safe, effective, and compatible with immunotherapy remains unclear. We show that high-density lipoprotein-mimicking nanodiscs loaded with doxorubicin (DOX), a widely used chemotherapeutic agent, can potentiate immune checkpoint blockade in murine tumor models...
April 2018: Science Advances
https://www.readbyqxmd.com/read/29669262/dna-mismatch-repair-in-cancer
#17
REVIEW
Marina Baretti, Dung T Le
Microsatellite instability (MSI) refers to the hypermutator phenotype secondary to frequent polymorphism in short repetitive DNA sequences and single nucleotide substitution, as consequence of DNA mismatch repair (MMR) deficiency. MSI secondary to germline mutation in DNA MMR proteins is the molecular fingerprint of Lynch syndrome (LS), while epigenetic inactivation of these genes is more commonly found in sporadic MSI tumors. MSI occurs at different frequencies across malignancies, although original methods to assess MSI or MMR deficiency have been developed mostly in LS related cancers...
April 15, 2018: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29664561/the-function-and-dysfunction-of-memory-cd8-t-cells-in-tumor-immunity
#18
REVIEW
James L Reading, Felipe Gálvez-Cancino, Charles Swanton, Alvaro Lladser, Karl S Peggs, Sergio A Quezada
The generation and maintenance of CD8+ T cell memory is crucial to long-term host survival, yet the basic tenets of CD8+ T cell immunity are still being established. Recent work has led to the discovery of tissue-resident memory cells and refined our understanding of the transcriptional and epigenetic basis of CD8+ T cell differentiation and dysregulation. In parallel, the unprecedented clinical success of immunotherapy has galvanized an intense, global research effort to decipher and de-repress the anti-tumor response...
May 2018: Immunological Reviews
https://www.readbyqxmd.com/read/29662547/pd-l1-expression-testing-in-non-small-cell-lung-cancer
#19
REVIEW
Cristina Teixidó, Noelia Vilariño, Roxana Reyes, Noemí Reguart
In recent years, immunotherapy has revolutionized and changed the standard of care in patients with advanced non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors, fundamentally those that act by blocking the programmed cell death receptor-1 (PD-1) and its ligand the programmed cell death ligand-1 (PD-L1) have emerged as novel treatment strategies in NSCLC, demonstrating undoubted superiority over chemotherapy in terms of efficacy. Several of these immune checkpoint modulators have recently gained regulatory approval for the treatment of advanced NSCLC, such as nivolumab, atezolizumab and pembrolizumab in first-line (only the latter) and second-line settings, and more recently, durvalumab as maintenance after chemoradiotherapy in locally advanced disease...
2018: Therapeutic Advances in Medical Oncology
https://www.readbyqxmd.com/read/29658848/neoadjuvant-pd-1-blockade-in-resectable-lung-cancer
#20
Patrick M Forde, Jamie E Chaft, Kellie N Smith, Valsamo Anagnostou, Tricia R Cottrell, Matthew D Hellmann, Marianna Zahurak, Stephen C Yang, David R Jones, Stephen Broderick, Richard J Battafarano, Moises J Velez, Natasha Rekhtman, Zachary Olah, Jarushka Naidoo, Kristen A Marrone, Franco Verde, Haidan Guo, Jiajia Zhang, Justina X Caushi, Hok Yee Chan, John-William Sidhom, Robert B Scharpf, James White, Edward Gabrielson, Hao Wang, Gary L Rosner, Valerie Rusch, Jedd D Wolchok, Taha Merghoub, Janis M Taube, Victor E Velculescu, Suzanne L Topalian, Julie R Brahmer, Drew M Pardoll
Background Antibodies that block programmed death 1 (PD-1) protein improve survival in patients with advanced non-small-cell lung cancer (NSCLC) but have not been tested in resectable NSCLC, a condition in which little progress has been made during the past decade. Methods In this pilot study, we administered two preoperative doses of PD-1 inhibitor nivolumab in adults with untreated, surgically resectable early (stage I, II, or IIIA) NSCLC. Nivolumab (at a dose of 3 mg per kilogram of body weight) was administered intravenously every 2 weeks, with surgery planned approximately 4 weeks after the first dose...
April 16, 2018: New England Journal of Medicine
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