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Anti-PD1

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https://www.readbyqxmd.com/read/29762855/real-world-treatment-practice-in-patients-with-advanced-melanoma-in-the-nivolumab-era-five-novel-italian-case-reports-and-a-literature-review
#1
R Depenni, C De Rossi, M De Tursi, R Marconcini, T Troiani
OBJECTIVE: The approval of the anti-PD1 antibody nivolumab has provided a significant therapeutic opportunity in the landscape of metastatic melanoma. In pivotal clinical trials, nivolumab improved clinical outcomes with a great safety profile. However, in real-world practice, the majority of the population with metastatic melanoma does meet one or more eligibility criteria of pivotal trials, since they have an ECOG-PS ≥ 2 or active/untreated known brain metastases. Waiting for larger real-wold studies that are currently lacking, but would be crucial to confirm the efficacy of nivolumab in challenging patients and to detect rare adverse events that could not be noticed in pivotal trials, this review collects both literature and unpublished case reports on nivolumab treatment in metastatic melanoma...
April 2018: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/29760383/outlier-response-to-anti-pd1-in-uveal-melanoma-reveals-germline-mbd4-mutations-in-hypermutated-tumors
#2
Manuel Rodrigues, Lenha Mobuchon, Alexandre Houy, Alice Fiévet, Sophie Gardrat, Raymond L Barnhill, Tatiana Popova, Vincent Servois, Aurore Rampanou, Aurore Mouton, Stéphane Dayot, Virginie Raynal, Michèle Galut, Marc Putterman, Sarah Tick, Nathalie Cassoux, Sergio Roman-Roman, François-Clément Bidard, Olivier Lantz, Pascale Mariani, Sophie Piperno-Neumann, Marc-Henri Stern
Metastatic uveal melanoma is a deadly disease with no proven standard of care. Here we present a metastatic uveal melanoma patient with an exceptional high sensitivity to a PD-1 inhibitor associated with outlier CpG>TpG mutation burden, MBD4 germline deleterious mutation, and somatic MBD4 inactivation in the tumor. We identify additional tumors in The Cancer Genome Atlas (TCGA) cohorts with similar hypermutator profiles in patients carrying germline deleterious MBD4 mutations and somatic loss of heterozygosity...
May 14, 2018: Nature Communications
https://www.readbyqxmd.com/read/29758196/temozolomide-combined-with-pd-1-antibody-therapy-for-mouse-orthotopic-glioma-model
#3
Bailing Dai, Na Qi, Junchao Li, Guilong Zhang
PURPOSE: Temozolomide (TMZ) is the most frequent adjuvant chemotherapy drug in gliomas. PDL1 expresses on various tumors, including gliomas, and anti-PD-1 antibodies have been approved for treating some tumors by FDA. This study was to evaluate the therapeutical potential of combined TMZ with anti-PD-1 antibody therapy for mouse orthotopic glioma model. METHODS: We performed C57BL/6 mouse orthotopic glioma model by stereotactic intracranial implantation of glioma cell line GL261, mice were randomly divided into four groups: (1) control group; (2) TMZ group; (3) anti-PD-1 antibody group; (4) TMZ combined with anti-PD-1 antibody group...
May 11, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29755699/sequential-immunotherapy-in-a-patient-with-primary-refractory-hodgkin-lymphoma-and-novel-mutations
#4
Richard Greil, Lisa Pleyer, Bettina Jansko, Carmen Feierabend, Lukas Rettenbacher, Olga Stiefel, Christoph Rass, Patrick Morre, Daniel Neureiter, Sigrun Greil-Ressler
Primary resistant Hodgkin lymphoma is an aggressive disease with few treatment options and short survival. Neoplastic cells of classical Hodgkin lymphoma are heavily dependent on microenvironmental stimuli, regularly express PD-L1, and a relevant proportion of relapsed patients is sensitive to blocking of the PD1/PD-L1 axis. However, response duration is limited and further treatment options are unknown but urgently needed. We report a case of a patient without relevant response to five subsequent chemotherapy regimens who immediately and dramatically responded to an anti-PD1 mab...
April 17, 2018: Oncotarget
https://www.readbyqxmd.com/read/29746927/indoleamine-2-3-dioxygenase-1-inhibition-targets-anti-pd1-resistant-lung-tumors-by-blocking-myeloid-derived-suppressor-cells
#5
Ailin Li, Hampartsoum B Barsoumian, Jonathan E Schoenhals, Taylor R Cushman, Mauricio S Caetano, Xiaohong Wang, David R Valdecanas, Sharareh Niknam, Ahmed I Younes, Guang Li, Wendy A Woodward, Maria Angelica Cortez, James W Welsh
Indoleamine 2,3-dioxygenase 1 (IDO1), involved in the catabolism of tryptophan (Trp) to kynurenine (Kyn) is an important regulator of tumor-mediated immunosuppression implicated in resistance to anti-PD1 immunotherapy. We investigated the role of IDO1 in an anti-PD1-resistant lung cancer model (344SQ_R) compared to the parental 344SQ tumors (344SQ_P). IDO1 was overexpressed in tumor-infiltrating leukocytes, and plasma Kyn levels were increased, in 344SQ_R vs. 344SQ_P. The IDO1 inhibitor INCB023843 retarded tumor growth and reduced lung metastases in 344SQ_R...
May 7, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29743521/e2f1-inhibition-mediates-cell-death-of-metastatic-melanoma
#6
Florian Rouaud, Nedra Hamouda-Tekaya, Michaël Cerezo, Patricia Abbe, Joséphine Zangari, Veronique Hofman, Mickaël Ohanna, Baharia Mograbi, Najla El-Hachem, Zohra Benfodda, Alexandre Lebeau, Meri K Tulic, Paul Hofman, Corine Bertolotto, Thierry Passeron, Jean-Sébastien Annicotte, Robert Ballotti, Stéphane Rocchi
Melanoma is one of the most lethal cancers when it reaches a metastatic stage. Despite advancements in targeted therapies (BRAF inhibitors) or immunotherapies (anti-CTLA-4 or anti-PD1), most patients with melanoma will need additional treatment. Thus, there is an urgent need to develop new therapeutical approaches to bypass resistance and achieve more prolonged responses. In this context, we were interested in E2F1, a transcription factor that plays a major role in the control of cell cycle under physiological and pathological conditions...
May 9, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29738824/radiologic-pseudoprogression-during-anti-pd1-therapy-for-advanced-non-small-cell-lung-cancer
#7
Sharyn I Katz, Mark Hammer, Stephen Bagley, Charu Aggarwal, Joshua Bauml, Jeffrey C Thompson, Arun C Nachiappan, Charles B Simone, Corey Langer
INTRODUCTION: Anti-PD1 (programmed cell death protein 1) therapy can lead to unconventional tumor responses including radiologic pseudoprogression. Here we determine the real-world incidence of radiologic pseudoprogression in advanced non-small cell lung cancer (NSCLC) and compare radiologic response criteria for disease response assessment. METHODS: Electronic medical records of all NSCLC patients receiving anti-PD1 therapy at our institution over a 3-year period were retrospectively reviewed and patients with clinically suspected radiologic pseudoprogression identified...
May 5, 2018: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/29733528/anti-pd-1-therapy-redirects-macrophages-from-an-m2-to-an-m1-phenotype-inducing-regression-of-os-lung-metastases
#8
Pooja Dhupkar, Nancy Gordon, John Stewart, Eugenie S Kleinerman
Osteosarcoma (OS) pulmonary metastasis translates into poor patient survival. The implication of PD-1-PD-L1 pathway in the context of NK cells and/or macrophages in OS is unknown. We investigated the effect of anti-PD-1 in OS lung metastasis and the role of NK cells and/or macrophages in anti-PD-1 responses. A human LM7 OS mouse model was used. Immunohistochemistry for tissues (PD-L1, caspase-3, Ki-67, NK cells, macrophages), and Western blotting for OS lung tumors (p-Stat3, p-Erk1/2) was performed. NK and macrophages were assessed using flow cytometry...
May 7, 2018: Cancer Medicine
https://www.readbyqxmd.com/read/29724901/prolonged-remissions-after-anti-pd1-discontinuation-in-patients-with-hodgkin-lymphoma
#9
Guillaume Manson, Charles Herbaux, Pauline Brice, Krimo Bouabdallah, Aspasia Stamatoullas, Jean-Marc Schiano, Hervé Ghesquieres, Laurent Dercle, Roch Houot
No abstract text is available yet for this article.
May 3, 2018: Blood
https://www.readbyqxmd.com/read/29721388/circulating-tumor-dna-evaluated-by-next-generation-sequencing-is-predictive-of-tumor-response-and-prolonged-clinical-benefit-with-nivolumab-in-advanced-non-small-cell-lung-cancer
#10
Etienne Giroux Leprieur, Guillaume Herbretau, Coraline Dumenil, Catherine Julie, Violaine Giraud, Sylvie Labrune, Jennifer Dumoulin, Julie Tisserand, Jean-François Emile, Hélène Blons, Thierry Chinet
Nivolumab is an anti-PD1 antibody, given in second-line or later treatment in advanced non-small cell lung cancer (NSCLC). The objective of this study was to describe the predictive value of circulating tumor DNA (ctDNA) on the efficacy of nivolumab in advanced NSCLC. We prospectively included all consecutive patients with advanced NSCLC treated with nivolumab in our Department between June 2015 and October 2016. Plasma samples were obtained before the first injection of nivolumab and at the first tumor evaluation with nivolumab...
2018: Oncoimmunology
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
#11
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/29707124/-brca1-2-and-tp53-mutation-status-associates-with-pd-1-and-pd-l1-expression-in-ovarian-cancer
#12
Verena Wieser, Inge Gaugg, Martina Fleischer, Giridhar Shivalingaiah, Soeren Wenzel, Susanne Sprung, Sigurd F Lax, Alain G Zeimet, Heidelinde Fiegl, Christian Marth
Checkpoint molecules such as programmed cell death protein-1 (PD-1) and its ligand PD-L1 are critically required for tumor immune escape. The objective of this study was to investigate tumoral PD-1 and PD-L1 mRNA-expression in a cohort of ovarian cancer (OC) patients in relation to tumor mutations. We analyzed mRNA expression of PD-1 , PD-L1 and IFNG by quantitative real-time PCR in tissue of 170 patients with low grade-serous (LGSOC), high-grade serous (HGSOC), endometrioid and clear cell OC compared to 28 non-diseased tissues (ovaries and fallopian tubes) in relation to tumor protein 53 ( TP53 ) and breast cancer gene 1/2 ( BRCA1/2 ) mutation status...
April 3, 2018: Oncotarget
https://www.readbyqxmd.com/read/29704931/-novel-strategy-in-oncoimmunology
#13
REVIEW
François Ghiringhelli
Recent advances in immuno-oncology with the development of anti-PD1/PD-L1 antibodies are revolutionizing oncological management. Immuno-oncology I currently developing in most histological types of cancer. However, the rate of success of anti-PD1/PD-L1 antibodies in monotherapy is limited by a limited to a subpopulation of patients accounting for about 25-30 % of patients in most indications. The development of new strategies is based on this observation with the aim to predict response or enhancing response rate...
April 25, 2018: Bulletin du Cancer
https://www.readbyqxmd.com/read/29704674/pd-l1-expression-heterogeneity-in-non-small-cell-lung-cancer-defining-criteria-for-harmonization-between-biopsies-and-whole-sections
#14
E Munari, G Zamboni, G Lunardi, L Marchionni, M Marconi, M Sommaggio, M Brunelli, G Martignoni, G J Netto, M O Hoque, F Moretta, M C Mingari, M C Pegoraro, A Inno, S Paiano, A Terzi, A Cavazza, G Rossi, F R Mariotti, P Vacca, L Moretta, G Bogina
BACKGROUND: PD-L1 expression determination defines eligibility for treatment with pembrolizumab in patients with advanced non-small cell lung cancer (NSCLC). This study was designed to better define which value across core biopsies from the same case more closely reflects the PD-L1 expression status on whole sections and how many biopsies are needed for confident classification of tumors in terms of PD-L1 expression. MATERIALS AND METHODS: We built tissue microarrays as surrogate of biopsies collecting 5 cores per case from 268 cases and compared PD-L1 staining results using validated clone SP263 with tumor whole sections...
April 25, 2018: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/29698933/detection-of-immune-related-adverse-events-by-medical-imaging-in-patients-treated-with-anti-programmed-cell-death-1
#15
Ahmed Mekki, Laurent Dercle, Philip Lichtenstein, Aurélien Marabelle, Jean-Marie Michot, Olivier Lambotte, Jérôme Le Pavec, Eleonora De Martin, Corinne Balleyguier, Stéphane Champiat, Samy Ammari
BACKGROUND: Programmed death receptor-1 blocking antibodies (anti-PD1) are a new standard of care in many cancer types. Patients benefit from improved survival but have the risk of immune-related adverse events (irAE). We evaluated if medical imaging procedures, used for anti-tumour response assessment, can detect irAEs. MATERIALS AND METHODS: All consecutive patients treated with anti-PD1 and with a medical imaging acquisition performed within 2 weeks with irAEs ≥2 were retrospectively included...
April 23, 2018: European Journal of Cancer
https://www.readbyqxmd.com/read/29682332/gender-and-outcomes-in-non-small-cell-lung-cancer-an-old-prognostic-variable-comes-back-for-targeted-therapy-and-immunotherapy
#16
Joseph A Pinto, Carlos S Vallejos, Luis E Raez, Luis A Mas, Rossana Ruiz, Junior S Torres-Roman, Zaida Morante, Jhajaira M Araujo, Henry L Gómez, Alfredo Aguilar, Denisse Bretel, Claudio J Flores, Christian Rolfo
Background: There are well-known differences in gender outcome in non-small cell lung cancer (NSCLC) and other cancers. In this work, we evaluated several randomised clinical trials to explore the gender influence in the outcome of patients with NSCLC treated with targeted therapy and immunotherapy. Methods: We performed a series of meta-analysis to compare the gender outcome in the routine setting for overall survival and progression-free survival (PFS) in phase III randomised clinical trials comparing EGFR inhibitors versus chemotherapy (OPTIMAL, LUX-lung 3, LUX-lung 6, EURTAC, ENSURE and WTJOG); ALK inhibitors versus chemotherapy (ASCEND 4, ASCEND 5, PROFILE 1014 and NCT009323893) and anti-PD1 checkpoint inhibitors versus chemotherapy (CheckMate 017, CheckMate 026, CheckMate 057, KEYNOTE 010 and KEYNOTE 024)...
2018: ESMO Open
https://www.readbyqxmd.com/read/29679556/a-novel-smac-mimetic-apg-1387-exhibited-dual-antitumor-effect-on-hbv-positive-hepatocellular-carcinoma-with-high-expression-of-ciap2-by-inducing-apoptosis-and-enhancing-innate-anti-tumor-immunity
#17
Wentao Pan, Qiuyun Luo, Xianglei Yan, Luping Yuan, Hanjie Yi, Lin Zhang, Baoxia Li, Yuxin Zhang, Jian Sun, Miao-Zhen Qiu, Da-Jun Yang
Check point inhibitor anti-PD1 antibody produced some efficacy in Hepatocellular Carcinoma (HCC) patients previously treated with sorafenib. Unfortunately, HCC patients with hepatitis B virus (HBV) infection did not respond as well as uninfected patients. Previously, SMAC mimetics-the antagonist for inhibitor of apoptosis proteins (IAPs) can rapidly reduce serum hepatitis B virus DNA in animal model. APG-1387 is a novel SMAC-mimetic, small molecule inhibitor targeting inhibitor of apoptosis proteins (IAPs)...
April 18, 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29669604/confirm-a-double-blind-placebo-controlled-phase-iii-clinical-trial-investigating-the-effect-of-nivolumab-in-patients-with-relapsed-mesothelioma-study-protocol-for-a-randomised-controlled-trial
#18
Dean A Fennell, Emma Kirkpatrick, Kelly Cozens, Mavis Nye, Jason Lester, Gerard Hanna, Nicola Steele, Peter Szlosarek, Sarah Danson, Joanne Lord, Christian Ottensmeier, Daniel Barnes, Stephanie Hill, Mihalis Kalevras, Tom Maishman, Gareth Griffiths
BACKGROUND: Mesothelioma is an incurable, apoptosis-resistant cancer caused in most cases by previous exposure to asbestos and is increasing in incidence. It represents a growing health burden but remains under-researched, with limited treatment options. Early promising signals of activity relating to both PD-L1- and PD-1-targeted treatment in mesothelioma implicate a dependency of mesothelioma on this immune checkpoint. There is a need to evaluate checkpoint inhibitors in patients with relapsed mesothelioma where treatment options are limited...
April 18, 2018: Trials
https://www.readbyqxmd.com/read/29669244/better-together-b7s1-checkpoint-blockade-synergizes-with-anti-pd1
#19
Melissa A Meyer, David G DeNardo
T cell checkpoint blockades can produce durable clinical responses, but only some patients and cancer types respond. In this issue of Immunity, Li et al. (2018) show B7S1-B7S1R signaling additionally regulates CD8+ T cell responses by working with the PD1-PDL1 checkpoint to block anti-tumor immunity.
April 17, 2018: Immunity
https://www.readbyqxmd.com/read/29650750/braf-and-mek-inhibitors-increase-pd1-positive-melanoma-cells-leading-to-a-potential-lymphocyte-independent-synergism-with-anti-pd1-antibody
#20
Martina Sanlorenzo, Igor Vujic, Arianna Floris, Mauro Novelli, Loretta Gammaitoni, Lidia Giraudo, Marco Macagno, Valeria Leuci, Ramona Rotolo, Chiara Donini, Marco Basiricò, Pietro Quaglino, Maria Teresa Fierro, Silvia Giordano, Maria Sibilia, Fabrizio Carnevale-Schianca, Massimo Aglietta, Dario Sangiolo
PURPOSE: BRAF and MEK inhibitors (BRAF/MEKi) favor melanoma-infiltrating lymphocytes, providing the rationale for current combinatorial trials with anti-PD1 antibody. A portion of melanoma cells may express PD1, and anti-PD1 antibody could have a direct anti-tumor effect. Here, we explore if BRAF/MEKi modulate rates of PD1+ melanoma cells, supporting an additional - lymphocyte-independent - basis for their therapeutic combination with anti-PD1 antibody. EXPERIMENTAL DESIGN: With data mining and flow cytometry, we assessed PD1, PDL1/2 expression on melanoma cell lines (CCLE, N=61; validation cell lines, N=7) and melanoma tumors (TCGA, N=214)...
April 12, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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