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Cancer and immune checkpoint

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https://www.readbyqxmd.com/read/28528510/immunogenomics-using-genomics-to-personalize-cancer-immunotherapy
#1
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/28525888/combination-of-desi2-and-ip10-gene-therapy-significantly-improves-therapeutic-efficacy-against-murine-carcinoma
#2
Chao Lin, HuaYing Yan, Jun Yang, Lei Li, Mei Tang, Xinyu Zhao, Chunlai Nie, Na Luo, Yuquan Wei, Zhu Yuan
DESI2 (also known as PNAS-4) is a novel pro-apoptotic gene activated during the early response to DNA damage. We previously reported that overexpression of DESI2 induces S phase arrest and apoptosis by activating checkpoint kinases. The present study was designed to test whether combination of DESI2 and IP10 could improve the therapy efficacy in vitro and in vivo. The recombinant plasmid co-expressing DESI2 and IP10 was encapsulated with DOTAP/Cholesterol nanoparticle. Immunocompetent mice bearing CT26 colon carcinoma and LL2 lung cancer were treated with the complex...
May 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28525386/prognostic-value-of-kras-mutation-in-advanced-non-small-cell-lung-cancer-treated-with-immune-checkpoint-inhibitors-a-metaanalysis-and-review
#3
Jung Han Kim, Hyeong Su Kim, Bum Jun Kim
Immune checkpoint inhibitors (ICIs) have emerged as a promising treatment option in the fight against advanced non-small-cell lung cancer (NSCLC). KRAS is the most frequently mutated oncogene in NSCLC. We performed this meta-analysis to investigate if KRAS mutation status affects survival benefits of ICIs in patients with advanced NSCLC. Electronic databases were searched for eligible studies. We included randomized trials with the data of overall survival stratified by KRAS mutation status. From 3 eligible studies, 138 patients with KRAS mutant NSCLC and 371 with KRAS wild-type tumor were included in the meta-analysis...
May 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28524159/hallmarks-of-response-to-immune-checkpoint-blockade
#4
Alexandria P Cogdill, Miles C Andrews, Jennifer A Wargo
Unprecedented advances have been made in the treatment of cancer through the use of immune checkpoint blockade, with approval of several checkpoint blockade regimens spanning multiple cancer types. However, responses to this form of therapy are not universal, and insights are clearly needed to identify optimal biomarkers of response and to combat mechanisms of therapeutic resistance. A working knowledge of the hallmarks of cancer yields insight into responses to immune checkpoint blockade, although the focus of this is rather tumour-centric and additional factors are pertinent, including host immunity and environmental influences...
May 18, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28522738/imaging-of-programmed-death-ligand-1-pd-l1-impact-of-protein-concentration-on-distribution-of-anti-pd-l1-spect-agent-in-an-immunocompetent-melanoma-murine-model
#5
Jessie R Nedrow, Anders Josefsson, Sunju Park, Sagar Ranka, Sanchita Roy, George Sgouros
Programmed cell Death Ligand 1 (PD-L1) is part of an immune checkpoint system that is essential for preventing autoimmunity and cancer. Recent approaches in immunotherapy targeting immune checkpoints have shown great promise in a variety of cancers, including metastatic melanoma. The use of targeted molecular imaging would help identify patients who will best respond to anti-PD-L1 treatment while potentially providing key information to limit immune-related adverse effects (irAEs). Recently, we developed an antibody based PD-L1-targeted imaging agent to identify PD-L1 positive tumors in vivo...
May 18, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/28522460/soluble-pd-l1-as-a-biomarker-in-malignant-melanoma-and-checkpoint-blockade
#6
Jun Zhou, Kathleen M Mahoney, Anita Giobbie-Hurder, Fengmin Zhao, Sandra Lee, Xiaoyun Liao, Scott Rodig, Jingjing Li, Xinqi Wu, Lisa H Butterfield, Matthias Piesche, Michael P Manos, Lauren M Eastman, Glenn Dranoff, Gordon J Freeman, F Stephen Hodi
Blockade of the pathway including Programmed death-ligand 1 (PD-L1) and its receptor Programmed cell death protein 1 (PD-1) has produced clinical benefits in patients with a variety of cancers.  Elevated levels of soluble PD-L1 (sPD-L1) have been associated with worse prognosis in renal cell carcinoma and multiple myeloma.  However, the regulatory roles and function of sPD-L1 particularly in connection with immune checkpoint blockade treatment are not fully understood.  We identified four splice variants of PD-L1 in melanoma cells, and all of them are secreted...
May 18, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28521532/new-antivirals-for-the-treatment-of-chronic-hepatitis-b
#7
Vincent Soriano, Pablo Barreiro, Laura Benitez, Jose M Peña, Carmen de Mendoza
Current treatment with oral nucleos(t)ides entecavir or tenofovir provide sustained suppression of HBV replication and clinical benefit in most chronic hepatitis B virus (HBV) infected persons. However, HBV rebound generally occurs upon drug discontinuation due to persistence of genomic HBV reservoirs as episomic cccDNA and chromosomic integrated HBV-DNA. There is renewed enthusiasm on HBV drug discovery following recent successes with antivirals for hepatitis C and immunotherapies for some cancers. Areas covered: New drugs that target distinct steps of the HBV life cycle are been developed, including inhibitors of viral entry, new polymerase inhibitors, capsid and assembly inhibitors, virus release blockers, and disruptors of cccDNA formation and transcription...
May 18, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28516435/management-considerations-in-cancer-patients-with-rheumatoid-arthritis
#8
Richard J Zogala, Kristina Goutsouliak, Maria E Suarez-Almazor
Rheumatoid arthritis is a common inflammatory disease that requires treatment with immunosuppressants to control symptoms and avoid joint destruction. Managing cancer in patients with concomitant rheumatoid arthritis poses special challenges that require close coordination of care between oncologists and rheumatologists. Potential clinical issues needing special consideration include: 1) perioperative management in patients undergoing cancer surgery, which often requires discontinuation of antirrheumatic therapy; 2) use of immunosuppressant therapies for rheumatoid arthritis, especially biologic agents that inhibit cytokine and immune pathways, which conceivably could affect immune-mediated antitumor responses (the issues are different in patients with active cancer vs those with a past history of cancer and no recurrences); 3) management in the palliative care setting; and 4) use of cancer immunotherapy, such as checkpoint inhibitor agents, in patients with pre-existing rheumatoid arthritis...
May 15, 2017: Oncology (Williston Park, NY)
https://www.readbyqxmd.com/read/28516152/cdk4-6-inhibitors-in-cancer-therapy-a%C3%A2-novel-treatement-strategy-for-bladder-cancer
#9
REVIEW
Qi Pan, Anuja Sathe, Peter C Black, Peter J Goebell, Ashish M Kamat, Bernd Schmitz-Draeger, Roman Nawroth
Patients with metastatic bladder cancer (mBC) treated with cisplatin-based chemotherapy have a limited median survival of only around 14 months [1]. Despite over 30 years of basic and clinical research, until recently no therapeutic options beyond cisplatin-based therapy had entered clinical routine and, at least in the US, none of the tested agents had been approved for second-line treatment. This has changed with the advent of immune checkpoint blockade, including especially PD-1/PD-L1 inhibitors. The high response rates of 24% over a 14...
April 27, 2017: Bladder Cancer
https://www.readbyqxmd.com/read/28515962/analyses-of-publicly-available-genomics-resources-define-fgf-2-expressing-bladder-carcinomas-as-emt-prone-proliferative-tumors-with-low-mutation-rates-and-high-expression-of-ctla-4-pd-1-and-pd-l1
#10
Elizabeth A McNiel, Philip N Tsichlis
FGF-2 is overexpressed in a subset of invasive bladder carcinomas and its overexpression correlates with poor prognosis. Analyses of publicly available databases addressing the molecular mechanisms that may be responsible for the poor prognosis of these tumors, revealed that FGF-2 expression correlates positively with the expression of EMT-promoting transcription factors and with changes in gene expression that are characteristic of EMT. The same analyses also revealed that FGF-2 correlates negatively with the expression, mutation and copy number variations of FGFR-3, all of which are associated with non-invasive bladder carcinomas...
2017: Signal Transduction and Targeted Therapy
https://www.readbyqxmd.com/read/28515940/nivolumab-induced-autoimmune-diabetes-mellitus-presenting-as-diabetic-ketoacidosis-in-a-patient-with-metastatic-lung-cancer
#11
James Luke Godwin, Shuchie Jaggi, Imali Sirisena, Pankaj Sharda, Ajay D Rao, Ranee Mehra, Colleen Veloski
BACKGROUND: Advances in cancer immunotherapy have generated encouraging results in multiple malignancies refractory to standard chemotherapies. As the use of immune checkpoint inhibitors (ICI) proliferates, the incidence of autoimmune side effects associated with these agents, termed immune related adverse events (irAE), is expected to increase. The frequency of significant irAE in ICI treated patients is about 10-20% and early recognition is critical to prevent serious morbidity and even mortality...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28515726/comparative-analysis-of-immune-checkpoint-molecules-and-their-potential-role-in-the-transmissible-tasmanian-devil-facial-tumor-disease
#12
Andrew S Flies, Nicholas B Blackburn, Alan Bruce Lyons, John D Hayball, Gregory M Woods
Immune checkpoint molecules function as a system of checks and balances that enhance or inhibit immune responses to infectious agents, foreign tissues, and cancerous cells. Immunotherapies that target immune checkpoint molecules, particularly the inhibitory molecules programmed cell death 1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have revolutionized human oncology in recent years, yet little is known about these key immune signaling molecules in species other than primates and rodents. The Tasmanian devil facial tumor disease is caused by transmissible cancers that have resulted in a massive decline in the wild Tasmanian devil population...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28515147/increased-t-cell-infiltration-elicited-by-erk5-deletion-in-a-pten-deficient-mouse-model-of-prostate-carcinogenesis
#13
Carolyn Loveridge, Ernest Mui, Rachana Patel, Ee Hong Tan, Imran Ahmad, Michelle Welsh, Julie Galbraith, Ann Hedley, Colin Nixon, Karen Blyth, Owen J Sansom, Hing Y Leung
Prostate cancer (PCa) does not appear to respond to immune checkpoint therapies where T cell infiltration may be a key limiting factor. Here we report evidence that ablating the growth regulatory kinase Erk5 can increase T cell infiltration in an established Pten-deficient mouse model of human PCa. Mice that were doubly mutant in prostate tissue for Pten and Erk5 (prostate DKO) exhibited a markedly increased median survival with reduced tumor size and proliferation compared to control Pten-mutant mice, the latter of which exhibited increased Erk5 mRNA expression...
May 17, 2017: Cancer Research
https://www.readbyqxmd.com/read/28514453/chromatin-states-define-tumour-specific-t-cell-dysfunction-and-reprogramming
#14
Mary Philip, Lauren Fairchild, Liping Sun, Ellen L Horste, Steven Camara, Mojdeh Shakiba, Andrew C Scott, Agnes Viale, Peter Lauer, Taha Merghoub, Matthew D Hellmann, Jedd D Wolchok, Christina S Leslie, Andrea Schietinger
Tumour-specific CD8 T cells in solid tumours are dysfunctional, allowing tumours to progress. The epigenetic regulation of T cell dysfunction and therapeutic reprogrammability (for example, to immune checkpoint blockade) is not well understood. Here we show that T cells in mouse tumours differentiate through two discrete chromatin states: a plastic dysfunctional state from which T cells can be rescued, and a fixed dysfunctional state in which the cells are resistant to reprogramming. We identified surface markers associated with each chromatin state that distinguished reprogrammable from non-reprogrammable PD1(hi) dysfunctional T cells within heterogeneous T cell populations from tumours in mice; these surface markers were also expressed on human PD1(hi) tumour-infiltrating CD8 T cells...
May 17, 2017: Nature
https://www.readbyqxmd.com/read/28514441/pd-1-expression-by-tumour-associated-macrophages-inhibits-phagocytosis-and-tumour-immunity
#15
Sydney R Gordon, Roy L Maute, Ben W Dulken, Gregor Hutter, Benson M George, Melissa N McCracken, Rohit Gupta, Jonathan M Tsai, Rahul Sinha, Daniel Corey, Aaron M Ring, Andrew J Connolly, Irving L Weissman
Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor that is upregulated on activated T cells for the induction of immune tolerance. Tumour cells frequently overexpress the ligand for PD-1, programmed cell death ligand 1 (PD-L1), facilitating their escape from the immune system. Monoclonal antibodies that block the interaction between PD-1 and PD-L1, by binding to either the ligand or receptor, have shown notable clinical efficacy in patients with a variety of cancers, including melanoma, colorectal cancer, non-small-cell lung cancer and Hodgkin's lymphoma...
May 17, 2017: Nature
https://www.readbyqxmd.com/read/28512646/mri-in-glioma-immunotherapy-evidence-pitfalls-and-perspectives
#16
REVIEW
Domenico Aquino, Andrea Gioppo, Gaetano Finocchiaro, Maria Grazia Bruzzone, Valeria Cuccarini
Pseudophenomena, that is, imaging alterations due to therapy rather than tumor evolution, have an important impact on the management of glioma patients and the results of clinical trials. RANO (response assessment in neurooncology) criteria, including conventional MRI (cMRI), addressed the issues of pseudoprogression after radiotherapy and concomitant chemotherapy and pseudoresponse during antiangiogenic therapy of glioblastomas (GBM) and other gliomas. The development of cancer immunotherapy forced the identification of further relevant response criteria, summarized by the iRANO working group in 2015...
2017: Journal of Immunology Research
https://www.readbyqxmd.com/read/28512504/a-case-report-of-drug-induced-myopathy-involving-extraocular-muscles-after-combination-therapy-with-tremelimumab-and-durvalumab-for-non-small-cell-lung-cancer
#17
William Carrera, Brandon J Baartman, Gregory Kosmorsky
Recently developed anti-tumour therapies targeting immune checkpoints include tremelimumab and durvalumab. These agents have incompletely characterised side effect profiles. The authors report a 68-year-old man treated for non-small cell lung cancer (NSCLC) with a combination of tremelimumab and durvalumab. After treatment he developed diplopia, ptosis, fatigue, weakness, and an inflammatory myopathy affecting the extraocular muscles requiring hospitalisation. Electromyography (EMG) testing and muscle biopsy suggested inflammatory myopathy without sign of myasthenia...
June 2017: Neuro-ophthalmology
https://www.readbyqxmd.com/read/28512174/dynamic-changes-in-pd-l1-expression-and-immune-infiltrates-early-during-treatment-predict-response-to-pd-1-blockade-in-melanoma
#18
Ricardo E Vilain, Alexander M Menzies, James S Wilmott, Hojabr Kakavand, Jason Madore, Alexander Guminski, Elizabeth Liniker, Ben Kong, Adam Cooper, Julie R Howle, Robyn P M Saw, Valerie Jakrot, Serigne Lo, John F Thompson, Matteo S Carlino, Richard F Kefford, Georgina V Long, Richard A Scolyer
Disruption of PD-L1/cytotoxic T-cell PD-1 signalling by immune-checkpoint inhibitors improves survival in cancer patients. This study sought to identify changes in tumoral PD-L1 expression and tumor-associated immune cell flux with anti-PD1 therapies in melanoma patients, particularly early during treatment, and correlate them with treatment response<br /><br />Experimental Design: Forty-six tumor biopsies from 23 unresectable AJCC Stage III/IV melanoma patients receiving pembrolizumab/nivolumab were analyzed...
May 16, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28511705/pd-l1-expressing-circulating-tumour-cells-in-head-and-neck-cancers
#19
Arutha Kulasinghe, Chris Perry, Liz Kenny, Majid E Warkiani, Colleen Nelson, Chamindie Punyadeera
BACKGROUND: Blockade of the PD-1/PD-L1 immune checkpoint pathway is emerging as a promising immunotherapeutic approach for the management and treatment of head and neck cancer patients who do not respond to 1st/2nd line therapy. However, as checkpoint inhibitors are cost intensive, identifying patients who would most likely benefit from anti PD-L1 therapy is required. Developing a non-invasive technique would be of major benefit to the patient and to the health care system. CASE PRESENTATION: We report the case of a 56 year old man affected by a supraglottic squamous cell carcinoma (SCC)...
May 16, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28511092/epigenetics-and-immunotherapy-the-current-state-of-play
#20
REVIEW
Jennifer Dunn, Sudha Rao
Cancer cells employ a number of mechanisms to escape immunosurveillance and facilitate tumour progression. The recent explosion of interest in immunotherapy, especially immune checkpoint blockade, is a result of discoveries about the fundamental ligand-receptor interactions that occur between immune and cancer cells within the tumour microenvironment. Distinct ligands expressed by cancer cells engage with cell surface receptors on immune cells, triggering inhibitory pathways (such as PD-1/PD-L1) that render immune cells immunologically tolerant...
May 13, 2017: Molecular Immunology
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