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Melanoma pd-1

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https://www.readbyqxmd.com/read/28439919/motor-polyradiculopathy-during-pembrolizumab-treatment-of-metastatic-melanoma
#1
Maria Sepúlveda, Eugenia Martinez-Hernandez, Lydia Gaba, Ivan Victoria, Nuria Sola-Valls, Neus Falgàs, Jordi Casanova-Molla, Francesc Graus
INTRODUCTION: Pembrolizumab, a monoclonal antibody directed against the immune checkpoint PD-1 (programmed cell death-1 receptor), has improved survival in patients with advanced melanoma. Neuromuscular immune-mediated side effects have been rarely reported. METHODS: We describe a 44-year-old man with metastatic melanoma who presented with progressive muscle weakness after 23 doses of pembrolizumab. RESULTS: The patient developed asymmetric, proximal muscle weakness and atrophy in all four limbs...
April 25, 2017: Muscle & Nerve
https://www.readbyqxmd.com/read/28438383/remitting-seronegative-symmetrical-synovitis-with-pitting-edema-rs3pe-syndrome-induced-by-nivolumab
#2
Marie-Léa Gauci, Barouyr Baroudjian, Pauline Laly, Isabelle Madelaine, Laetitia Da Meda, Laetitia Vercellino, Martine Bagot, Frédéric Lioté, Cécile Pages, Céleste Lebbé
INTRODUCTION: A new articular syndrome described as immunrelated side effect of immunotherapy: PD-1 inhibitors have revolutionized the treatment of advanced melanoma but are responsible for immune-related toxicity. We report a case of remitting seronegative symetrical synovitis with pitting edema (RS3PE) syndrome induced by nivolumab. CASE REPORT: A 80 year-old man with stage IV BRAF-wild type and NRAS exon 2-mutated melanoma was treated first line by nivolumab 3mg/kg every 2 weeks...
March 8, 2017: Seminars in Arthritis and Rheumatism
https://www.readbyqxmd.com/read/28436963/a-sting-activating-nanovaccine-for-cancer-immunotherapy
#3
Min Luo, Hua Wang, Zhaohui Wang, Haocheng Cai, Zhigang Lu, Yang Li, Mingjian Du, Gang Huang, Chensu Wang, Xiang Chen, Matthew R Porembka, Jayanthi Lea, Arthur E Frankel, Yang-Xin Fu, Zhijian J Chen, Jinming Gao
The generation of tumour-specific T cells is critically important for cancer immunotherapy. A major challenge in achieving a robust T-cell response is the spatiotemporal orchestration of antigen cross-presentation in antigen-presenting cells with innate stimulation. Here, we report a minimalist nanovaccine, comprising a simple physical mixture of an antigen and a synthetic polymeric nanoparticle, PC7A NP, which generates a strong cytotoxic T-cell response with low systemic cytokine expression. Mechanistically, the PC7A NP achieves efficient cytosolic delivery of tumour antigens to antigen-presenting cells in draining lymph nodes, leading to increased surface presentation while simultaneously activating type I interferon-stimulated genes...
April 24, 2017: Nature Nanotechnology
https://www.readbyqxmd.com/read/28435677/control-of-immune-cell-entry-through-the-tumour-vasculature-a-missing-link-in-optimising-melanoma-immunotherapy
#4
REVIEW
Lih Yin Tan, Carmela Martini, Zvi G Fridlender, Claudine S Bonder, Michael P Brown, Lisa M Ebert
Metastatic melanoma remains a fatal disease to many worldwide, even after the breakthrough introduction of targeted therapies such as BRAF inhibitors and immune checkpoint blockade therapies such as CTLA-4 and PD-1 inhibitors. With advances in our understanding of this disease, as well as the increasing data gathered from patient studies, the significance of the host immune response to cancer progression and response to treatment is becoming clear. More specifically, the presence of intratumoral CD8(+) cytotoxic T-cells correlates with better prognosis whereas the accumulation of monocytes/macrophages and neutrophils in the tumour is often associated with worse prognosis...
March 2017: Clinical & Translational Immunology
https://www.readbyqxmd.com/read/28435391/programmed-cell-death-1-checkpoint-inhibitors-in-the-treatment-of-patients-with-advanced-melanoma
#5
REVIEW
Jacek Mackiewicz, Andrzej Mackiewicz
The treatment landscape of advanced melanoma has changed significantly following the discovery and marketing authorisation of immune checkpoints inhibitors. Ipilimumab (anti-CTLA-4) was the first one to be approved, and it. demonstrated long-term survival in about 20% of patients. Subsequently, anti-programmed cell death-1 (a-PD-1) antibodies (pembrolizuamb, nivolumab), inhibitors of PD-1/programmed cell death-1 ligand (PD1-L) synapse, showed higher clinical efficacy with lower toxicity comparing to ipilimumab...
2017: Contemporary Oncology Współczesna Onkologia
https://www.readbyqxmd.com/read/28434400/role-of-modern-immunotherapy-in-gastrointestinal-malignancies-a-review-of-current-clinical-progress
#6
REVIEW
Zin W Myint, Gaurav Goel
Gastrointestinal (GI) cancers are a group of highly aggressive malignancies with a huge disease burden worldwide. There is clearly a significant unmet need for new drugs and therapies to further improve the treatment outcomes of GI malignancies. Immunotherapy is a novel treatment strategy that is emerging as an effective and promising treatment option against several types of cancers. CTLA-4 and PD-1 are critical immune checkpoint molecules that negatively regulate T cell activation via distinct mechanisms...
April 24, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28433543/phenformin-inhibits-myeloid-derived-suppressor-cells-and-enhances-the-anti-tumor-activity-of-pd-1-blockade-in-melanoma
#7
Sun Hye Kim, Man Li, Sebastian Trousil, Yaqing Zhang, Marina Pasca di Magliano, Kenneth D Swanson, Bin Zheng
Biguanides, such as the diabetes therapeutics metformin and phenformin, have demonstrated antitumor activity both in vitro and in vivo. However, their potential effects on the tumor microenvironment are largely unknown. Here we report that phenformin selectively inhibits granulocytic myeloid-derived suppressor cells (G-MDSCs) in spleens of tumor bearing mice and ex vivo. Phenformin induces production of reactive oxygen species in G-MDSC, whereas the antioxidant N-acetylcysteine attenuates the inhibitory effects of phenformin...
April 19, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28432648/rationale-for-new-checkpoint-inhibitor-combinations-in-melanoma-therapy
#8
Mario Mandalà, Carlo Tondini, Barbara Merelli, Daniela Massi
The use of monoclonal antibodies that block immunologic checkpoints, which mediate adaptive immune resistance, has revolutionized the treatment of metastatic melanoma patients. Specifically, targeting single immune suppressive molecules such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4), or programmed cell death protein 1 (PD-1) expressed on T cells or its primary ligand, programmed cell death ligand 1 (PD-L1), resulted in pronounced clinical benefit for a subset of melanoma patients. Although single-agent immune checkpoint inhibitor therapy has demonstrated promising clinical activity in metastatic melanoma patients, there is still a significant proportion of patients who show primary resistance to these therapies...
April 21, 2017: American Journal of Clinical Dermatology
https://www.readbyqxmd.com/read/28430587/parkin-regulates-translesion-dna-synthesis-in-response-to-uv-radiation
#9
Xuefei Zhu, Xiaolu Ma, Yingfeng Tu, Min Huang, Hongmei Liu, Fengli Wang, Juanjuan Gong, Jiuqiang Wang, Xiaoling Li, Qian Chen, Hongyan Shen, Shu Zhu, Yun Wang, Yang Liu, Caixia Guo, Tie-Shan Tang
Deficiency of Parkin is a major cause of early-onset Parkinson's disease (PD). Notably, PD patients also exhibit a significantly higher risk in melanoma and other skin tumors, while the mechanism remains largely unknown. In this study, we show that depletion of Parkin causes compromised cell viability and genome stability after ultraviolet (UV) radiation. We demonstrate that Parkin promotes efficient Rad18-dependent proliferating cell nuclear antigen (PCNA) monoubiquitination by facilitating the formation of Replication protein A (RPA)-coated ssDNA upon UV radiation...
April 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28428883/response-after-treatment-with-pembrolizumab-in-a-patient-with-myelophthisis-due-to-melanoma-the-role-of-checkpoint-inhibition-in-the-bone
#10
Samuel Rosner, Filiz Sen, Michael Postow
BACKGROUND: Myelophthisis due to melanoma is a rare phenomenon. Treatment strategies for patients with this serious complication of malignancy have not been well documented, and none have previously reported efficacy of immune checkpoint inhibition. Since bone metastases are not measurable lesions per standard response criteria, the efficacy of immune checkpoint inhibition in the bones is also not well described. CASE PRESENTATION: We describe a patient with widespread melanoma metastases involving the bone marrow causing myelophthisis and pancytopenia who responded to immune checkpoint inhibition with the anti-programmed cell death-1 (PD-1) inhibitor pembrolizumab...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28428193/pd-l1-expression-in-melanoma-a-quantitative-immunohistochemical-antibody-comparison
#11
Joel C Sunshine, Peter Nguyen, Genevieve Kaunitz, Tricia Cottrell, Sneha Berry, Jessica Esandrio, Haiying Xu, Aleksandra Ogurtsova, Karen R Bleich, Toby C Cornish, Evan J Lipson, Robert A Anders, Janis Taube
PD-L1 expression in the pre-treatment tumor microenvironment enriches for response to anti-PD-1/PD-L1 therapies. The purpose of this study was to quantitatively compare the performance of five monoclonal anti-PD-L1 antibodies used in recent landmark publications.  <br /><br />Experimental Design: PD-L1 immunohistochemistry (IHC) was performed on thirty-four formalin-fixed paraffin-embedded archival melanoma samples using the 5H1, SP142, 28-8, 22C3 and SP263 clones.  The percentage of total cells (including melanocytes and immune cells) demonstrating cell surface PD-L1 staining, as well as intensity measurements/H-scores, were assessed for each melanoma specimen using a computer-assisted platform...
April 20, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28427522/the-role-of-anti-pd-1-and-anti-pd-l1-agents-in-the-treatment-of-diffuse-large-b-cell-lymphoma-the-future-is-now
#12
REVIEW
Luis Miguel Juárez-Salcedo, Jose Sandoval-Sus, Lubomir Sokol, Julio C Chavez, Samir Dalia
Immune checkpoints inhibitors have been incorporated into standard treatment protocols for advanced solid tumors. The aim of T-cell-based immune therapy in cancer has been to generate durable clinical benefits for patients, paired with enhanced side effect profiles. The beneficial antitumoral activity of programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) has been thoroughly demonstrated in certain metastatic malignancies (e.g. melanoma, non-small cell lung cancer, renal cell carcinoma); however, the therapeutic role in lymphoid cancers is complex...
May 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/28426103/neurotoxicity-from-immune-checkpoint-inhibition-in-the-treatment-of-melanoma-a-single-centre-experience-and-review-of-the-literature
#13
L Spain, G Walls, M Julve, K O'Meara, T Schmid, E Kalaitzaki, S Turajlic, M Gore, J Rees, J Larkin
Background: Treatment with immune checkpoint inhibitors (ICPi) has greatly improved survival for patients with advanced melanoma in recent years. Anti-CTLA-4 and anti-PD1 antibodies have been approved following large Phase III trials. Immune-related neurological toxicity of varying severity has been reported in the literature. The cumulative incidence of neurotoxicity among ipilimumab, nivolumab and pembrolizumab is reported as <1% in published clinical trials. We aimed to identify the incidence of neurotoxicity in our institution across anti-CTLA4 and anti-PD-1 antibodies, including the combination of ipilimumab with nivolumab...
February 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28419059/late-onset-nivolumab-mediated-pneumonitis-in-a-patient-with-melanoma-and-multiple-immune-related-adverse-events
#14
Panagiotis T Diamantopoulos, Maria Gaggadi, Eva Kassi, Olga Benopoulou, Amalia Anastasopoulou, Helen Gogas
Immune-related adverse effects (AEs) of PD-1 inhibitors can affect almost every organ, but the skin, intestine, lung, eye, and liver are the most commonly affected organs. Here, we present the case of a 62-year-old female patient with stage IIIc melanoma treated with nivolumab in an adjuvant setting who sequentially developed hyperthyroidism, hypothyroidism, acute hepatitis, and pneumonitis. Six months before the emergence of pneumonitis, the patient had discontinued treatment with nivolumab because of acute hepatitis...
April 17, 2017: Melanoma Research
https://www.readbyqxmd.com/read/28417343/adjuvant-therapy-for-melanoma
#15
REVIEW
Aya Agha, Ahmad A Tarhini
Systemic adjuvant therapy for surgically resected cutaneous melanoma that is at high risk for disease recurrence and death targets residual micrometastatic disease which is the source of future local or distant relapse. Interferon-alfa (IFNα) has been the most extensively studied in regimens that varied by dosage, route of administration, formulation, and duration of therapy. Most regimens have demonstrated improvements in relapse-free survival (RFS), while the regimen administered at high dosage (HDI) showed improvements in overall survival (OS) in two out of three RCTs...
May 2017: Current Oncology Reports
https://www.readbyqxmd.com/read/28416578/quantitative-mass-spectrometry-analysis-of-pd-l1-protein-expression-n-glycosylation-and-expression-stoichiometry-with-pd-1-and-pd-l2-in-human-melanoma
#16
Carlos A Morales-Betanzos, Hyoungjoo Lee, Paula I Gonzalez-Ericsson, Justin M Balko, Douglas B Johnson, Lisa J Zimmerman, Daniel C Liebler
Quantitative assessment of key proteins that control the tumor-immune interface is one of the most formidable analytical challenges in immunotherapeutics. We developed a targeted mass spectrometry (MS) platform to quantify programmed cell death-1 (PD-1), programmed cell death 1 ligand 1 (PD-L1), and programmed cell death 1 ligand 2 (PD-L2) at fmol/microgram protein levels in formalin fixed, paraffin-embedded sections from 22 human melanomas. PD-L1 abundance ranged 50-fold, from approximately 0.03 to 1.5 fmol/microgram protein and the PRM data were largely concordant with total PD-L1-positive cell content, as analyzed by immunohistochemistry (IHC) with the E1L3N antibody...
April 17, 2017: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/28412591/baseline-%C3%AE-catenin-programmed-death-ligand-1-expression-and-tumour-infiltrating-lymphocytes-predict-response-and-poor-prognosis-in-braf-inhibitor-treated-melanoma-patients
#17
Daniela Massi, Emanuela Romano, Eliana Rulli, Barbara Merelli, Romina Nassini, Francesco De Logu, Ivan Bieche, Gianna Baroni, Laura Cattaneo, Gongda Xue, Mario Mandalà
BACKGROUND: The activation of oncogenic Wnt/β-catenin pathway in melanoma contributes to a lack of T-cell infiltration. Whether baseline β-catenin expression in the context of tumour-infiltrating lymphocytes (TILs) and programmed death ligand-1 (PD-L1) overexpression correlates with prognosis of metastatic melanoma patients (MMPs) treated with mitogen-activated protein kinase, MAPK inhibitor (MAPKi) monotherapy, however, has not been fully clarified. PATIENTS AND METHODS: Sixty-four pre-treatment formalin-fixed and paraffin embedded melanoma samples from MMP treated with a BRAF inhibitor (n = 39) or BRAF and MEK inhibitors (n = 25) were assessed for presence of β-catenin, PD-L1, cluster of differentiation (CD)8, CD103 and forkhead box protein P3 (FOXP3) expression by immunohistochemistry, and results were correlated with clinical outcome...
April 13, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28411193/liver-metastasis-and-treatment-outcome-with-anti-pd-1-monoclonal-antibody-in-patients-with-melanoma-and-nsclc
#18
Paul C Tumeh, Matthew D Hellmann, Omid Hamid, Katy K Tsai, Kimberly L Loo, Matthew A Gubens, Michael Rosenblum, Christina L Harview, Janis Taube, Nathan Handley, Neharika Khurana, Adi Nosrati, Matthew F Krummel, Andrew Tucker, Eduardo Sosa, Philip J Sanchez, Nooriel Banayan, Juan Osorio, Dan L Nguyen-Kim, Jeremy Chang, I Peter Shintaku, Peter Boasberg, Emma J Taylor, Pamela N Munster, Alain P Algazi, Bartosz Chmielowski, Reinhard Dummer, Tristan R Grogan, David A Elashoff, Jimmy Hwang, Simone Goldinger, Edward Garon, Robert H Pierce, Adil I Daud
We explored the association between liver metastases, tumor CD8+ T cell count, and response in patients with melanoma or lung cancer treated with the anti-PD-1 antibody, pembrolizumab. The melanoma discovery cohort was drawn from the Phase I Keynote 001 trial, whereas the melanoma validation cohort was drawn from Keynote 002, 006, and EAP trials and the non-small cell lung cancer (NSCLC) cohort from Keynote 001. Liver metastasis was associated with reduced response and shortened progression-free survival (PFS); [objective response rate (ORR), 30...
April 14, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28410988/fc-optimized-anti-cd25-depletes-tumor-infiltrating-regulatory-t-cells-and-synergizes-with-pd-1-blockade-to-eradicate-established-tumors
#19
Frederick Arce Vargas, Andrew J S Furness, Isabelle Solomon, Kroopa Joshi, Leila Mekkaoui, Marta H Lesko, Enrique Miranda Rota, Rony Dahan, Andrew Georgiou, Anna Sledzinska, Assma Ben Aissa, Dafne Franz, Mariana Werner Sunderland, Yien Ning Sophia Wong, Jake Y Henry, Tim O'Brien, David Nicol, Ben Challacombe, Stephen A Beers, Samra Turajlic, Martin Gore, James Larkin, Charles Swanton, Kerry A Chester, Martin Pule, Jeffrey V Ravetch, Teresa Marafioti, Karl S Peggs, Sergio A Quezada
CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models...
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28405524/therapeutic-efficacy-of-combined-vaccination-against-tumor-pericyte-associated-antigens-dlk1-and-dlk2-in-mice
#20
Kellsye Paula L Fabian, Nina Chi-Sabins, Jennifer L Taylor, Ronald Fecek, Aliyah Weinstein, Walter J Storkus
When compared with vascular cells in normal tissues, pericytes and vascular endothelial cells (VEC) in tumor blood vessels exhibit altered morphology and epigenetic programming that leads to the expression of unique antigens that allow for differential recognition by CD8(+) T cells. We have previously shown that the Notch antagonist delta-like homolog 1 (DLK1) is a tumor pericyte-associated antigen expressed in setting of melanoma and a range of carcinomas. In this report, we show that therapeutic vaccination against DLK1 in murine models results in slowed tumor growth, but also to the compensatory expression of the DLK1 homolog, DLK2, by tumor-associated pericytes...
2017: Oncoimmunology
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