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https://www.readbyqxmd.com/read/29137714/checkpoint-blockade-plus-oncolytic-virus-a-hot-therapeutic-cancer-strategy
#1
Caroline Robert
How can we transform an immune desert into a 'hot tumor' that is prone to respond to anti-programmed death (PD)-1 immunotherapy? This might be possible by injecting an oncolytic virus, engineered to induce local immune stimulation, prior to anti-PD-1 therapy. A recent study demonstrated that this combination - evaluated in a Phase Ib metastatic melanoma clinical study - yields promising results.
November 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/29137331/hdac-inhibitors-enhance-the-immunotherapy-response-of-melanoma-cells
#2
Laurence Booth, Jane L Roberts, Andrew Poklepovic, John Kirkwood, Paul Dent
We focused on the ability of the pan-histone deacetylase (HDAC) inhibitors AR42 and sodium valproate to alter the immunogenicity of melanoma cells. Treatment of melanoma cells with HDAC inhibitors rapidly reduced the expression of multiple HDAC proteins as well as the levels of PD-L1, PD-L2 and ODC, and increased expression of MHCA. In a cell-specific fashion, melanoma isolates released the immunogenic protein HMGB1 into the extracellular environment. Very similar data were obtained in ovarian and H&NSCC PDX isolates, and in established tumor cell lines from the lung and kidney...
October 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29136692/-expression-and-prognostic-values-of-pd-1-pd-l1-and-ido-1-in-sinonasal-malignant-mucosal-melanoma
#3
H Q Liu, B Q Zou, S Y Wang
Objective: To investigate the correlation between the expression of programmed death-1(PD-1), PD ligand-1(PD-L1), indoleamine 2, 3-dioxygenase 1(IDO-1) and clinical parameters in sinonasal malignant mucosal melanoma (SNM). Methods: Samples from 86 SNM patients who did not receive immune-targeted therapy and radio-chemotherapy were analyzed for PD-1, PD-L1, and IDO-1 expression by immunohistochemistry. Results: High clinical/pathologic staging, brain metastases and advanced age were independent risk factors of poor prognosis...
November 8, 2017: Zhonghua Bing Li Xue za Zhi Chinese Journal of Pathology
https://www.readbyqxmd.com/read/29135534/the-multiple-faces-of-programmed-cell-death-ligand-1-expression-in-malignant-and-nonmalignant-cells
#4
Edwin R Parra, Pamela Villalobos, Jaime Rodriguez-Canales
Preliminary data suggest that tumor expression of programmed cell death ligand 1 (PD-L1) protein in human cancers, as determined by immunohistochemistry in formalin-fixed, paraffin-embedded tissue samples, may predict clinical response to anti-PD-1/PD-L1 therapy. PD-L1 is not a specific tumor marker and its expression is also observed in various nonmalignant cells, such as macrophages and lymphocytes, causing confusion in immunohistochemistry analysis when these inflammatory cells are overlapping with tumors cells...
November 13, 2017: Applied Immunohistochemistry & Molecular Morphology: AIMM
https://www.readbyqxmd.com/read/29132144/a-neoantigen-fitness-model-predicts-tumour-response-to-checkpoint-blockade-immunotherapy
#5
Marta Łuksza, Nadeem Riaz, Vladimir Makarov, Vinod P Balachandran, Matthew D Hellmann, Alexander Solovyov, Naiyer A Rizvi, Taha Merghoub, Arnold J Levine, Timothy A Chan, Jedd D Wolchok, Benjamin D Greenbaum
Checkpoint blockade immunotherapies enable the host immune system to recognize and destroy tumour cells. Their clinical activity has been correlated with activated T-cell recognition of neoantigens, which are tumour-specific, mutated peptides presented on the surface of cancer cells. Here we present a fitness model for tumours based on immune interactions of neoantigens that predicts response to immunotherapy. Two main factors determine neoantigen fitness: the likelihood of neoantigen presentation by the major histocompatibility complex (MHC) and subsequent recognition by T cells...
November 8, 2017: Nature
https://www.readbyqxmd.com/read/29129918/intratumoral-cd40-activation-and-checkpoint-blockade-induces-t-cell-mediated-eradication-of-melanoma-in-the-brain
#6
Manisha Singh, Christina Vianden, Mark J Cantwell, Zhimin Dai, Zhilan Xiao, Meenu Sharma, Hiep Khong, Ashvin R Jaiswal, Faisal Faak, Yared Hailemichael, L M E Janssen, Uddalak Bharadwaj, Michael A Curran, Adi Diab, Roland L Bassett, David J Tweardy, Patrick Hwu, Willem W Overwijk
CD40 agonists bind the CD40 molecule on antigen-presenting cells and activate them to prime tumor-specific CD8(+) T cell responses. Here, we study the antitumor activity and mechanism of action of a nonreplicating adenovirus encoding a chimeric, membrane-bound CD40 ligand (ISF35). Intratumoral administration of ISF35 in subcutaneous B16 melanomas generates tumor-specific, CD8(+) T cells that express PD-1 and suppress tumor growth. Combination therapy of ISF35 with systemic anti-PD-1 generates greater antitumor activity than each respective monotherapy...
November 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/29127039/biodegradable-sting-agonist-nanoparticles-for-enhanced-cancer-immunotherapy
#7
David R Wilson, Rupashree Sen, Joel C Sunshine, Drew M Pardoll, Jordan J Green, Young J Kim
Therapeutic cancer vaccines require adjuvants leading to robust type I interferon and proinflammatory cytokine responses in the tumor microenvironment to induce an anti-tumor response. Cyclic dinucleotides (CDNs), a potent Stimulator of Interferon Receptor (STING) agonist, are currently in phase I trials. However, their efficacy may be limited to micromolar concentrations due to the cytosolic residence of STING in the ER membrane. Here we utilized biodegradable, poly(beta-amino ester) (PBAE) nanoparticles to deliver CDNs to the cytosol leading to robust immune response at >100-fold lower extracellular CDN concentrations in vitro...
November 7, 2017: Nanomedicine: Nanotechnology, Biology, and Medicine
https://www.readbyqxmd.com/read/29123966/pd-1-blockade-at-the-time-of-tumor-escape-potentiates-the-immune-mediated-antitumor-effects-of-a-melanoma-targeting-monoclonal-antibody
#8
Laetitia They, Henri-Alexandre Michaud, Ondine Becquart, Virginie Lafont, Bernard Guillot, Florence Boissière-Michot, Marta Jarlier, Caroline Mollevi, Jean-François Eliaou, Nathalie Bonnefoy, Laurent Gros
Tumor antigen-targeting monoclonal antibodies (TA-targeting mAbs) are used as therapeutics in many malignancies and their capacity to mobilize the host immunity puts them at the forefront of anti-cancer immunotherapies. Both innate and adaptive immune cells have been associated with the therapeutic activity of such antibodies, but tumor escape from mAb-induced tumor immune surveillance remains one of the main clinical issues. In this preclinical study, we grafted immunocompetent and immunocompromised mice with the B16F10 mouse melanoma cell line and treated them with the TA99 TA-targeting mAb to analyze the immune mechanisms associated with the tumor response and resistance to TA99 monotherapy...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/29120224/is-there-a-role-for-programmed-death-ligand-1-testing-and-immunotherapy-in-colorectal-cancer-with-microsatellite-instability-part-ii-the-challenge-of-programmed-death-ligand-1-testing-and-its-role-in-microsatellite-instability-high-colorectal-cancer
#9
Esmeralda Celia Marginean, Barbara Melosky
CONTEXT: - The world of oncology has changed dramatically in the past few years with the introduction of checkpoint inhibitors and immunotherapy. The promising findings of a small, phase 2 clinical trial that led to the US Food and Drug Administration breakthrough designation and approval of the anti-programmed death receptor-1 (PD-1) drug pembrolizumab (Keytruda, Merck, Kenilworth, New Jersey) to treat metastatic/refractory microsatellite instability-high colorectal cancer (CRC) has significantly boosted interest in immunomodulatory therapies in microsatellite instability-high CRC...
November 9, 2017: Archives of Pathology & Laboratory Medicine
https://www.readbyqxmd.com/read/29118259/matrix-binding-checkpoint-immunotherapies-enhance-antitumor-efficacy-and-reduce-adverse-events
#10
Jun Ishihara, Kazuto Fukunaga, Ako Ishihara, Hans M Larsson, Lambert Potin, Peyman Hosseinchi, Gabriele Galliverti, Melody A Swartz, Jeffrey A Hubbell
Immune checkpoint blockade exhibits considerable antitumor activity, but previous studies have reported instances of severe treatment-related adverse events. We sought to explore local immune checkpoint blockade, with an antibody (Ab) form that would be retained intra- or peritumorally, limiting systemic exposure. To accomplish this, we conjugated the checkpoint blockade Abs to an extracellular matrix (ECM)-super-affinity peptide derived from placenta growth factor-2 (PlGF-2123-144). We show enhanced tissue retention and lower Ab concentrations in blood plasma after PlGF-2123-144 conjugation, reducing systemic side effects such as the risk of autoimmune diabetes...
November 8, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29114959/focal-regression-of-a-primary-melanoma-fading-lentigines-and-poliosis-in-metastatic-melanoma-treated-with-anti-pd-1
#11
S Thomas, A Laino, R Sturm, K Nufer, D Lambie, B Shepherd, V Atkinson, L Adams, H P Soyer, H Schaider
Pembrolizumab(®) , a first line immune checkpoint inhibitor, has shown good clinical activity with an acceptable safety profile, in the management of metastatic melanoma.(1, 2) We report a patient with metastatic melanoma, treated with anti-PD-1, who demonstrated metastatic disease regression, focal complete regression of a primary melanoma, partial regression of several solar lentigines, and a patch of poliosis superficial to a thigh metastatic deposit. This article is protected by copyright. All rights reserved...
November 8, 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/29100071/cancer-evolution-during-immunotherapy
#12
M C Andrews, J A Wargo
Immune checkpoint blockade has revolutionized cancer treatment. In this issue of Cell, insights from a longitudinal multi-omics analysis of the largest yet-reported cohort of melanoma patients reveal how tumor and immunity co-evolve during anti-PD-1 therapy.
November 2, 2017: Cell
https://www.readbyqxmd.com/read/29097600/pd-l1
#13
REVIEW
Anthousa Kythreotou, Abdul Siddique, Francesco A Mauri, Mark Bower, David J Pinato
Programmed death ligand 1 (PD-L1) is the principal ligand of programmed death 1 (PD-1), a coinhibitory receptor that can be constitutively expressed or induced in myeloid, lymphoid, normal epithelial cells and in cancer. Under physiological conditions, the PD-1/PD-L1 interaction is essential in the development of immune tolerance preventing excessive immune cell activity that can lead to tissue destruction and autoimmunity. PD-L1 expression is an immune evasion mechanism exploited by various malignancies and is generally associated with poorer prognosis...
November 2, 2017: Journal of Clinical Pathology
https://www.readbyqxmd.com/read/29097493/gut-microbiome-modulates-response-to-anti-pd-1-immunotherapy-in-melanoma-patients
#14
V Gopalakrishnan, C N Spencer, L Nezi, A Reuben, M C Andrews, T V Karpinets, P A Prieto, D Vicente, K Hoffman, S C Wei, A P Cogdill, L Zhao, C W Hudgens, D S Hutchinson, T Manzo, M Petaccia de Macedo, T Cotechini, T Kumar, W S Chen, S M Reddy, R Szczepaniak Sloane, J Galloway-Pena, H Jiang, P L Chen, E J Shpall, K Rezvani, A M Alousi, R F Chemaly, S Shelburne, L M Vence, P C Okhuysen, V B Jensen, A G Swennes, F McAllister, E Marcelo Riquelme Sanchez, Y Zhang, E Le Chatelier, L Zitvogel, N Pons, J L Austin-Breneman, L E Haydu, E M Burton, J M Gardner, E Sirmans, J Hu, A J Lazar, T Tsujikawa, A Diab, H Tawbi, I C Glitza, W J Hwu, S P Patel, S E Woodman, R N Amaria, M A Davies, J E Gershenwald, P Hwu, J E Lee, J Zhang, L M Coussens, Z A Cooper, P A Futreal, C R Daniel, N J Ajami, J F Petrosino, M T Tetzlaff, P Sharma, J P Allison, R R Jenq, J A Wargo
Pre-clinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti-PD-1 immunotherapy (n=112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders (R) versus non-responders (NR). Analysis of patient fecal microbiome samples (n=43, 30R, 13NR) showed significantly higher alpha diversity (p<0...
November 2, 2017: Science
https://www.readbyqxmd.com/read/29093678/immune-related-adverse-events-associated-with-anti-pd-1-pd-l1-treatment-for-malignancies-a-meta-analysis
#15
Peng-Fei Wang, Yang Chen, Si-Ying Song, Ting-Jian Wang, Wen-Jun Ji, Shou-Wei Li, Ning Liu, Chang-Xiang Yan
Background: Treatment of cancers with programmed cell death protein 1 (PD-1) pathway inhibitors can lead to immune-related adverse events (irAEs), which could be serious and even fetal. Therefore, clinicians should be aware of the characteristics of irAEs associated with the use of such drugs. Methods: The MEDLINE, EMBASE, and Cochrane databases were searched to find potential studies using the following strategies: anti-PD-1/PD-L1 treatment; irAEs; and cancer. R© package Meta was used to pool incidence. Results: Forty-six studies representing 12,808 oncologic patients treated with anti-PD-1/PD-L1 agents were included in the meta-analysis...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29068157/running-interferonce-on-immunotherapy
#16
Sheera Rosenbaum, Andrew Aplin
A new wave of immunotherapies has considerably expanded treatment options for cutaneous melanoma patients. One strategy for boosting the anti-tumor immune response is to block inhibitory immune checkpoint proteins that restrain immune cells. Utilizing this strategy, FDA-approved immune checkpoint inhibitors targeting CTLA-4 (ipilimumab) and PD-1/PD-L1 (nivolumab, pembrolizumab) alone or in combination enhance existing immune responses and have increased patient survival and response durability. This article is protected by copyright...
October 25, 2017: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/29066909/case-report-of-a-kit-mutated-melanoma-patient-with-an-excellent-response-to-apatinib-and-temozolomide-combination-therapy
#17
Cong Luo, Jiayu Shen, Jieer Ying, Xianhua Fang, Xiaohong Wang, Zhixuan Fu, Peng Liu
Malignant melanoma is one kind of malignant disease which has high rates of mortality, metastasis, and poor prognosis. The therapeutic landscape is rapidly changing with the development of novel agents in recent decades, such as anti-PD-1 agents, anti-CTLA-4 agents, and BRAF inhibitors. However, since most of these novel agents are very expensive, not all patients can afford them. Apatinib is a novel oral small-molecule tyrosine kinase inhibitor targeting the intracellular domain of vascular endothelial growth factor receptor 2 (VEGFR-2) and may also be effective on Ret, c-KIT, and c-src...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29055015/small-molecule%C3%A2-inhibition-of-pd-1-transcription-is-an-effective-alternative-to-antibody-blockade-in-cancer-therapy
#18
Alison Taylor, David Rothstein, Christopher E Rudd
The impact of PD-1 immune checkpoint therapy prompts exploration of other strategies to downregulate PD-1 for cancer therapy. We previously showed that the serine/threonine kinase, glycogen synthase kinase GSK-3α/β, is a central regulator of PD-1 transcription in CD8+ T cells. Here, we show that the use of small molecule inhibitors of GSK-3α/β (GSK-3i) to reduce pcdc1 (PD-1) transcription and expression was as effective as anti-PD-1 and PDL-1 blocking antibodies in the control of B16 melanoma, or EL4 lymphoma, in primary tumor and metastatic settings...
October 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/29050517/the-safety-and-efficacy-of-dabrafenib-and-trametinib-for-the-treatment-of-melanoma
#19
Sarah Knispel, Lisa Zimmer, Theodora Kanaki, Selma Ugurel, Dirk Schadendorf, Elisabeth Livingstone
The introduction of BRAF and MEK inhibitors into clinical practice improved the prognosis of metastatic melanoma patients. The combination of BRAF inhibitor dabrafenib with MEK inhibitor trametinib has shown its superiority to single agent therapy and is characterized by a tolerable spectrum of adverse events which shows a decrease in incidence over time on treatment. Areas covered: The current scientific literature on safety and adverse events (AEs) related to BRAF and MEK-inhibition has been investigated with special focus on the large phase 3 studies (COMBI-v, COMBI-d and CoBRIM) as well as recent updates presented at oncology and melanoma meetings...
October 20, 2017: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/29050354/phase-i-study-of-nivolumab-combined-with-ifn-%C3%AE-for-patients-with-advanced-melanoma
#20
Taku Fujimura, Takanori Hidaka, Yumi Kambayashi, Sadanori Furudate, Aya Kakizaki, Hisayuki Tono, Akira Tsukada, Takahiro Haga, Akira Hashimoto, Ryo Morimoto, Takuhiro Yamaguchi, Tadao Takano, Setsuya Aiba
The efficacy of nivolumab is greater than that of other anti-melanoma drugs, so nivolumab-based combined therapies that enhance anti-tumor immune responses in patients with metastatic melanoma are of great interest to dermato-oncologists. As we have previously reported, IFN-β enhances the anti-tumor immune response of anti-PD-1 antibodies against B16F10 melanoma in vivo. To explore the potential of this property of IFN-β as part of a combination therapy for the treatment of metastatic melanoma patients, we performed a phase 1 trial, using a traditional rule-based 3 + 3 design, on patients with advanced melanoma...
September 19, 2017: Oncotarget
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