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PD1 cancer

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https://www.readbyqxmd.com/read/29760383/outlier-response-to-anti-pd1-in-uveal-melanoma-reveals-germline-mbd4-mutations-in-hypermutated-tumors
#1
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/29746927/indoleamine-2-3-dioxygenase-1-inhibition-targets-anti-pd1-resistant-lung-tumors-by-blocking-myeloid-derived-suppressor-cells
#2
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
#3
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
#4
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/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
#5
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
#6
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/29719621/histogram-analysis-of-adc-in-rectal-cancer-associations-with-different-histopathological-findings-including-expression-of-egfr-hif1-alpha-vegf-p53-pd1-and-ki-67-a-preliminary-study
#7
Hans Jonas Meyer, Annekathrin Höhn, Alexey Surov
Functional imaging modalities like Diffusion-weighted imaging are increasingly used to predict tumor behavior like cellularity and vascularity in different tumors. Histogram analysis is an emergent imaging analysis, in which every voxel is used to obtain a histogram and therefore statistically information about tumors can be provided. The purpose of this study was to elucidate possible associations between ADC histogram parameters and several immunhistochemical features in rectal cancer. Overall, 11 patients with histologically proven rectal cancer were included into the study...
April 6, 2018: Oncotarget
https://www.readbyqxmd.com/read/29707124/-brca1-2-and-tp53-mutation-status-associates-with-pd-1-and-pd-l1-expression-in-ovarian-cancer
#8
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/29705787/immune-checkpoint-inhibition-in-gastro-oesophageal-cancer
#9
Elizabeth Smyth, Peter C Thuss-Patience
Recently some progress has been made in the palliative treatment of gastric cancer. It was shown that second-line chemotherapy and VEGF-R2-directed treatment can prolong survival. Despite these advances most patients with metastatic gastric cancer live for less than 2 years. Immune-checkpoint blockade with anti-CTLA4, anti-PD-1 and anti-PD-L1 antibodies has revolutionised the treatment of many cancers. Significant benefit was also proven in gastric adenocarcinomas. Nivolumab improves overall survival as third-line treatment in Asian gastric cancer patients and is already registered in Japan...
2018: Oncology Research and Treatment
https://www.readbyqxmd.com/read/29704931/-novel-strategy-in-oncoimmunology
#10
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
#11
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/29702148/immunomodulatory-effects-of-cd38-targeting-antibodies
#12
REVIEW
Niels W C J van de Donk
The fist in class CD38-targeting antibody, daratumumab, is currently approved as single agent and in combination with standards of care for the treatment of relapsed and refractory multiple myeloma. Based on the high activity and favorable toxicity profile of daratumumab, other CD38 antibodies, such as isatuximab, MOR202, and TAK-079, are being evaluated in MM and other malignancies. The CD38-targeting antibodies have classic Fc-dependent immune effector mechanisms, including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC)...
April 24, 2018: Immunology Letters
https://www.readbyqxmd.com/read/29698933/detection-of-immune-related-adverse-events-by-medical-imaging-in-patients-treated-with-anti-programmed-cell-death-1
#13
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/29695749/oncolytic-viruses-as-engineering-platforms-for-combination-immunotherapy
#14
REVIEW
Kwame Twumasi-Boateng, Jessica L Pettigrew, Y Y Eunice Kwok, John C Bell, Brad H Nelson
To effectively build on the recent successes of immune checkpoint blockade, adoptive T cell therapy and cancer vaccines, it is critical to rationally design combination strategies that will increase and extend efficacy to a larger proportion of patients. For example, the combination of anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and anti-programmed cell death protein 1 (PD1) immune checkpoint inhibitors essentially doubles the response rate in certain patients with metastatic melanoma. However, given the heterogeneity of cancer, it seems likely that even more complex combinations of immunomodulatory agents may be required to obtain consistent, durable therapeutic responses against a broad spectrum of cancers...
April 25, 2018: Nature Reviews. 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
#15
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/29679564/frequencies-and-expression-levels-of-programmed-death-ligand-1-pd-l1-in-circulating-tumor-rna-ctrna-in-various-cancer-types
#16
Toshiyuki Ishiba, Andreas-Claudius Hoffmann, Joshua Usher, Yahya Elshimali, Todd Sturdevant, Mai Dang, Yolanda Jaimes, Rama Tyagi, Ronald Gonzales, Mary Grino, Jacek K Pinski, Afsaneh Barzi, Luis E Raez, Wilfried E Eberhardt, Dirk Theegarten, Heinz-Josef Lenz, Hiroyuki Uetake, Peter V Danenberg, Kathleen Danenberg
BACKGROUND: Precision medicine and prediction of therapeutic response requires monitoring potential biomarkers before and after treatment. Liquid biopsies provide noninvasive prognostic markers such as circulating tumor DNA and RNA. Circulating tumor RNA (ctRNA) in blood is also used to identify mutations in genes of interest, but additionally, provides information about relative expression levels of important genes. In this study, we analyzed PD-L1 expression in ctRNA isolated from various cancer types...
April 27, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29675979/senescent-cells-re-engineered-to-express-spd-1-for-inhibiting-pd-1-pd-l1-as-a-vaccination-approach-against-breast-cancer
#17
Zehong Chen, Kang Hu, Lieting Feng, Ruxiong Su, Nan Lai, Zike Yang, Shijun Kang
Various types of vaccines have been proposed as approaches for prevention or delay of the onset of cancer by boosting the endogenous immune system. We previously developed a senescent-cell-based vaccine, induced by radiation and veliparib, as a preventive and therapeutic tool against triple-negative breast cancer. However, the PD-1/PD-L1 pathway was found to play an important role in vaccine failure. Hence, we further developed sPD1-expressing senescent cells to overcome PD-L1/PD1-mediated immune suppression while vaccinating to promote dendritic cells (DCs) maturity, thereby amplifying T cell activation...
April 20, 2018: Cancer Science
https://www.readbyqxmd.com/read/29669806/targeting-merkel-cell-carcinoma-by-engineered-t-cells-specific-to-t-antigens-of-merkel-cell-polyomavirus
#18
Ioannis Gavvovidis, Matthias Leisegang, Gerald Willimsky, Natalie J Miller, Paul Nghiem, Thomas Blankenstein
PURPOSE: The causative agent of most cases of Merkel cell carcinoma (MCC) has been identified as the Merkel cell polyomavirus (MCV). MCV-encoded T-antigens (Tags) are essential not only for virus-mediated tumorigenesis but also for maintaining MCC cell lines in vitro. MCV Tags are thus an appealing target for viral oncoprotein-directed T cell therapy for MCC. With this study, we aimed to isolate and characterize Tag-specific T cell receptors (TCR) for potential use in gene therapy clinical trials...
April 18, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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
#19
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
#20
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
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