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https://www.readbyqxmd.com/read/29755681/dendritic-cell-activation-enhances-anti-pd-1-mediated-immunotherapy-against-glioblastoma
#1
Tomas Garzon-Muvdi, Debebe Theodros, Andrew S Luksik, Russell Maxwell, Eileen Kim, Christopher M Jackson, Zineb Belcaid, Sudipto Ganguly, Betty Tyler, Henry Brem, Drew M Pardoll, Michael Lim
Introduction: The glioblastoma (GBM) immune microenvironment is highly suppressive as it targets and hinders multiple components of the immune system. Checkpoint blockade (CB) is being evaluated for GBM patients. However, biomarker analyses suggest that CB monotherapy may be effective only in a small fraction of GBM patients. We hypothesized that activation of antigen presentation would increase the therapeutic response to PD-1 blockade. Results: We show that activating DCs through TLR3 agonists enhances the anti-tumor immune response to CB and increases survival in GBM...
April 17, 2018: Oncotarget
https://www.readbyqxmd.com/read/29721192/pd-l1-expression-in-medulloblastoma-an-evaluation-by-subgroup
#2
Allison M Martin, Christopher J Nirschl, Magda J Polanczyk, W Robert Bell, Thomas R Nirschl, Sarah Harris-Bookman, Jillian Phallen, Jessica Hicks, Daniel Martinez, Aleksandra Ogurtsova, Haiying Xu, Lisa M Sullivan, Alan K Meeker, Eric H Raabe, Kenneth J Cohen, Charles G Eberhart, Peter C Burger, Mariarita Santi, Janis M Taube, Drew M Pardoll, Charles G Drake, Michael Lim
Background: This study evaluated the expression of PD-L1 and markers of immune mediated resistance in human medulloblastoma (MB), the most common malignant pediatric brain tumor. Results: Overall levels of PD-L1 in human MB were low; however, some cases demonstrated robust focal expression associated with increased immune infiltrates. The case with highest PD-L1 expression was a sonic hedgehog (SHH) MB. In cell lines, SHH MB, which are low-MYC expressing, demonstrated both constitutive and inducible expression of PD-L1 while those in Group 3/4 that expressed high levels of MYC had only inducible expression...
April 10, 2018: Oncotarget
https://www.readbyqxmd.com/read/29658848/neoadjuvant-pd-1-blockade-in-resectable-lung-cancer
#3
Patrick M Forde, Jamie E Chaft, Kellie N Smith, Valsamo Anagnostou, Tricia R Cottrell, Matthew D Hellmann, Marianna Zahurak, Stephen C Yang, David R Jones, Stephen Broderick, Richard J Battafarano, Moises J Velez, Natasha Rekhtman, Zachary Olah, Jarushka Naidoo, Kristen A Marrone, Franco Verde, Haidan Guo, Jiajia Zhang, Justina X Caushi, Hok Yee Chan, John-William Sidhom, Robert B Scharpf, James White, Edward Gabrielson, Hao Wang, Gary L Rosner, Valerie Rusch, Jedd D Wolchok, Taha Merghoub, Janis M Taube, Victor E Velculescu, Suzanne L Topalian, Julie R Brahmer, Drew M Pardoll
Background Antibodies that block programmed death 1 (PD-1) protein improve survival in patients with advanced non-small-cell lung cancer (NSCLC) but have not been tested in resectable NSCLC, a condition in which little progress has been made during the past decade. Methods In this pilot study, we administered two preoperative doses of PD-1 inhibitor nivolumab in adults with untreated, surgically resectable early (stage I, II, or IIIA) NSCLC. Nivolumab (at a dose of 3 mg per kilogram of body weight) was administered intravenously every 2 weeks, with surgery planned approximately 4 weeks after the first dose...
April 16, 2018: New England Journal of Medicine
https://www.readbyqxmd.com/read/29544099/bacteroides-fragilis-toxin-coordinates-a-pro-carcinogenic-inflammatory-cascade-via-targeting-of-colonic-epithelial-cells
#4
Liam Chung, Erik Thiele Orberg, Abby L Geis, June L Chan, Kai Fu, Christina E DeStefano Shields, Christine M Dejea, Payam Fathi, Jie Chen, Benjamin B Finard, Ada J Tam, Florencia McAllister, Hongni Fan, Xinqun Wu, Sudipto Ganguly, Andriana Lebid, Paul Metz, Sara W Van Meerbeke, David L Huso, Elizabeth C Wick, Drew M Pardoll, Fengyi Wan, Shaoguang Wu, Cynthia L Sears, Franck Housseau
No abstract text is available yet for this article.
March 14, 2018: Cell Host & Microbe
https://www.readbyqxmd.com/read/29509750/the-intestinal-microbiome-influences-checkpoint-blockade
#5
Cynthia L Sears, Drew M Pardoll
No abstract text is available yet for this article.
March 6, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29472271/tnf%C3%AE-and-radioresistant-stromal-cells-are-essential-for-therapeutic-efficacy-of-cyclic-dinucleotide-sting-agonists-in-nonimmunogenic-tumors
#6
Brian J Francica, Ali Ghasemzadeh, Anthony L Desbien, Debebe Theodros, Kelsey E Sivick, Gabrielle L Reiner, Laura Hix Glickman, Ariel E Marciscano, Andrew B Sharabi, Meredith L Leong, Sarah M McWhirter, Thomas W Dubensky, Drew M Pardoll, Charles G Drake
The cGAS-STING cytosolic DNA sensing pathway may play an integral role in the initiation of antitumor immune responses. Studies evaluating the immunogenicity of various cyclic dinucleotide (CDN) STING agonists administered by intratumoral (i.t.) injection showed potent induction of inflammation, tumor necrosis, and, in some cases, durable tumor-specific adaptive immunity. However, the specific immune mechanisms underlying these responses remain incompletely defined. The majority of these studies have focused on the effect of CDNs on immune cells but have not conclusively interrogated the role of stromal cells in the acute rejection of the CDN-injected tumor...
April 2018: Cancer Immunology Research
https://www.readbyqxmd.com/read/29420293/patients-with-familial-adenomatous-polyposis-harbor-colonic-biofilms-containing-tumorigenic-bacteria
#7
Christine M Dejea, Payam Fathi, John M Craig, Annemarie Boleij, Rahwa Taddese, Abby L Geis, Xinqun Wu, Christina E DeStefano Shields, Elizabeth M Hechenbleikner, David L Huso, Robert A Anders, Francis M Giardiello, Elizabeth C Wick, Hao Wang, Shaoguang Wu, Drew M Pardoll, Franck Housseau, Cynthia L Sears
Individuals with sporadic colorectal cancer (CRC) frequently harbor abnormalities in the composition of the gut microbiome; however, the microbiota associated with precancerous lesions in hereditary CRC remains largely unknown. We studied colonic mucosa of patients with familial adenomatous polyposis (FAP), who develop benign precursor lesions (polyps) early in life. We identified patchy bacterial biofilms composed predominately of Escherichia coli and Bacteroides fragilis Genes for colibactin ( clbB ) and Bacteroides fragilis toxin ( bft ), encoding secreted oncotoxins, were highly enriched in FAP patients' colonic mucosa compared to healthy individuals...
February 2, 2018: Science
https://www.readbyqxmd.com/read/29398651/bacteroides-fragilis-toxin-coordinates-a-pro-carcinogenic-inflammatory-cascade-via-targeting-of-colonic-epithelial-cells
#8
Liam Chung, Erik Thiele Orberg, Abby L Geis, June L Chan, Kai Fu, Christina E DeStefano Shields, Christine M Dejea, Payam Fathi, Jie Chen, Benjamin B Finard, Ada J Tam, Florencia McAllister, Hongni Fan, Xinqun Wu, Sudipto Ganguly, Andriana Lebid, Paul Metz, Sara W Van Meerbeke, David L Huso, Elizabeth C Wick, Drew M Pardoll, Fengyi Wan, Shaoguang Wu, Cynthia L Sears, Franck Housseau
Pro-carcinogenic bacteria have the potential to initiate and/or promote colon cancer, in part via immune mechanisms that are incompletely understood. Using ApcMin mice colonized with the human pathobiont enterotoxigenic Bacteroides fragilis (ETBF) as a model of microbe-induced colon tumorigenesis, we show that the Bacteroides fragilis toxin (BFT) triggers a pro-carcinogenic, multi-step inflammatory cascade requiring IL-17R, NF-κB, and Stat3 signaling in colonic epithelial cells (CECs). Although necessary, Stat3 activation in CECs is not sufficient to trigger ETBF colon tumorigenesis...
February 14, 2018: Cell Host & Microbe
https://www.readbyqxmd.com/read/29296775/th17-immune-microenvironment-in-epstein-barr-virus-negative-hodgkin-lymphoma-implications-for-immunotherapy
#9
Amy S Duffield, Maria Libera Ascierto, Robert A Anders, Janis M Taube, Alan K Meeker, Shuming Chen, Tracee L McMiller, Neil A Phillips, Haiying Xu, Aleksandra Ogurtsova, Alan E Berger, Drew M Pardoll, Suzanne L Topalian, Richard F Ambinder
Classical Hodgkin lymphoma (CHL) is a neoplasm characterized by robust inflammatory infiltrates and heightened expression of the immunosuppressive PD-1/PD-L1 pathway. Although anti-PD-1 therapy can be effective in >60% of patients with refractory CHL, improved treatment options are needed for CHLs which are resistant to anti-PD-1 or relapse after this form of immunotherapy. A deeper understanding of immunologic factors in the CHL microenvironment might support the design of more effective treatment combinations based on anti-PD-1...
July 25, 2017: Blood Advances
https://www.readbyqxmd.com/read/29127039/biodegradable-sting-agonist-nanoparticles-for-enhanced-cancer-immunotherapy
#10
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...
February 2018: Nanomedicine: Nanotechnology, Biology, and Medicine
https://www.readbyqxmd.com/read/28970196/stereotactic-radiotherapy-increases-functionally-suppressive-regulatory-t-cells-in-the-tumor-microenvironment
#11
Yuki Muroyama, Thomas R Nirschl, Christina M Kochel, Zoila Lopez-Bujanda, Debebe Theodros, Wendy Mao, Maria A Carrera-Haro, Ali Ghasemzadeh, Ariel E Marciscano, Esteban Velarde, Ada J Tam, Christopher J Thoburn, Muniza Uddin, Alan K Meeker, Robert A Anders, Drew M Pardoll, Charles G Drake
Radiotherapy (RT) enhances innate and adaptive antitumor immunity; however, the effects of radiation on suppressive immune cells, such as regulatory T cells (Treg), in the tumor microenvironment (TME) are not fully elucidated. Although previous reports suggest an increased Treg infiltration after radiation, whether these Tregs are functionally suppressive remains undetermined. To test the hypothesis that RT enhances the suppressive function of Treg in the TME, we selectively irradiated implanted tumors using the small animal radiation research platform (SARRP), which models stereotactic radiotherapy in human patients...
November 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28596308/mismatch-repair-deficiency-predicts-response-of-solid-tumors-to-pd-1-blockade
#12
Dung T Le, Jennifer N Durham, Kellie N Smith, Hao Wang, Bjarne R Bartlett, Laveet K Aulakh, Steve Lu, Holly Kemberling, Cara Wilt, Brandon S Luber, Fay Wong, Nilofer S Azad, Agnieszka A Rucki, Dan Laheru, Ross Donehower, Atif Zaheer, George A Fisher, Todd S Crocenzi, James J Lee, Tim F Greten, Austin G Duffy, Kristen K Ciombor, Aleksandra D Eyring, Bao H Lam, Andrew Joe, S Peter Kang, Matthias Holdhoff, Ludmila Danilova, Leslie Cope, Christian Meyer, Shibin Zhou, Richard M Goldberg, Deborah K Armstrong, Katherine M Bever, Amanda N Fader, Janis Taube, Franck Housseau, David Spetzler, Nianqing Xiao, Drew M Pardoll, Nickolas Papadopoulos, Kenneth W Kinzler, James R Eshleman, Bert Vogelstein, Robert A Anders, Luis A Diaz
The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients...
July 28, 2017: Science
https://www.readbyqxmd.com/read/28388418/inhibiting-dna-methylation-causes-an-interferon-response-in-cancer-via-dsrna-including-endogenous-retroviruses
#13
Katherine B Chiappinelli, Pamela L Strissel, Alexis Desrichard, Huili Li, Christine Henke, Benjamin Akman, Alexander Hein, Neal S Rote, Leslie M Cope, Alexandra Snyder, Vladimir Makarov, Sadna Budhu, Dennis J Slamon, Jedd D Wolchok, Drew M Pardoll, Matthias W Beckmann, Cynthia A Zahnow, Taha Merghoub, Timothy A Chan, Stephen B Baylin, Reiner Strick
No abstract text is available yet for this article.
April 6, 2017: Cell
https://www.readbyqxmd.com/read/28360208/prediction-of-response-to-immune-checkpoint-inhibitor-therapy-using-early-time-point-18-f-fdg-pet-ct-imaging-in-patients-with-advanced-melanoma
#14
Steve Y Cho, Evan J Lipson, Hyung-Jun Im, Steven P Rowe, Esther Mena Gonzalez, Amanda Blackford, Alin Chirindel, Drew M Pardoll, Suzanne L Topalian, Richard L Wahl
The purpose of this study was to evaluate 18 F-FDG PET/CT scanning as an early predictor of response to immune checkpoint inhibitors (ICIs) in patients with advanced melanoma. Methods: Twenty patients with advanced melanoma receiving ICI prospectively underwent 18 F-FDG PET/CT at 3 scan intervals: before treatment initiation (SCAN-1), at days 21-28 (SCAN-2), and at 4 mo (SCAN-3). This study was approved by the institutional review board, and informed consent was received from all patients who were enrolled between April 2012 and December 2013...
September 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/28193624/transcriptional-mechanisms-of-resistance-to-anti-pd-1-therapy
#15
Maria L Ascierto, Alvin Makohon-Moore, Evan J Lipson, Janis M Taube, Tracee L McMiller, Alan E Berger, Jinshui Fan, Genevieve J Kaunitz, Tricia R Cottrell, Zachary A Kohutek, Alexander Favorov, Vladimir Makarov, Nadeem Riaz, Timothy A Chan, Leslie Cope, Ralph H Hruban, Drew M Pardoll, Barry S Taylor, David B Solit, Christine A Iacobuzio-Donahue, Suzanne L Topalian
Purpose: To explore factors associated with response and resistance to anti-PD-1 therapy, we analyzed multiple disease sites at autopsy in a patient with widely metastatic melanoma who had a heterogeneous response. Materials and Methods: Twenty-six melanoma specimens (four premortem, 22 postmortem) were subjected to whole exome sequencing. Candidate immunologic markers and gene expression were assessed in 10 cutaneous metastases showing response or progression during therapy. Results: The melanoma was driven by biallelic inactivation of NF1 All lesions had highly concordant mutational profiles and copy number alterations, indicating linear clonal evolution...
June 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28031159/evolution-of-neoantigen-landscape-during-immune-checkpoint-blockade-in-non-small-cell-lung-cancer
#16
Valsamo Anagnostou, Kellie N Smith, Patrick M Forde, Noushin Niknafs, Rohit Bhattacharya, James White, Theresa Zhang, Vilmos Adleff, Jillian Phallen, Neha Wali, Carolyn Hruban, Violeta B Guthrie, Kristen Rodgers, Jarushka Naidoo, Hyunseok Kang, William Sharfman, Christos Georgiades, Franco Verde, Peter Illei, Qing Kay Li, Edward Gabrielson, Malcolm V Brock, Cynthia A Zahnow, Stephen B Baylin, Robert B Scharpf, Julie R Brahmer, Rachel Karchin, Drew M Pardoll, Victor E Velculescu
Immune checkpoint inhibitors have shown significant therapeutic responses against tumors containing increased mutation-associated neoantigen load. We have examined the evolving landscape of tumor neoantigens during the emergence of acquired resistance in patients with non-small cell lung cancer after initial response to immune checkpoint blockade with anti-PD-1 or anti-PD-1/anti-CTLA-4 antibodies. Analyses of matched pretreatment and resistant tumors identified genomic changes resulting in loss of 7 to 18 putative mutation-associated neoantigens in resistant clones...
March 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28008146/autologous-reconstitution-of-human-cancer-and-immune-system-in-vivo
#17
Juan Fu, Rupashree Sen, David L Masica, Rachel Karchin, Drew Pardoll, Vonn Walter, D Neil Hayes, Christine H Chung, Young J Kim
Correlative studies from checkpoint inhibitor trials have indicated that better understanding of human leukocytic trafficking into the human tumor microenvironment can expedite the translation of future immune-oncologic agents. In order to directly characterize signaling pathways that can regulate human leukocytic trafficking into the tumor, we have developed a completely autologous xenotransplantation method to reconstitute the human tumor immune microenvironment in vivo. We were able to genetically mark the engrafted CD34+ bone marrow cells as well as the tumor cells, and follow the endogenous leukocytic infiltration into the autologous tumor...
January 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28003545/anti-pd-1-antitumor-immunity-is-enhanced-by-local-and-abrogated-by-systemic-chemotherapy-in-gbm
#18
Dimitrios Mathios, Jennifer E Kim, Antonella Mangraviti, Jillian Phallen, Chul-Kee Park, Christopher M Jackson, Tomas Garzon-Muvdi, Eileen Kim, Debebe Theodros, Magdalena Polanczyk, Allison M Martin, Ian Suk, Xiaobu Ye, Betty Tyler, Chetan Bettegowda, Henry Brem, Drew M Pardoll, Michael Lim
The immunosuppressive effects of chemotherapy present a challenge for designing effective cancer immunotherapy strategies. We hypothesized that although systemic chemotherapy (SC) exhibits negative immunologic effects, local chemotherapy (LC) can potentiate an antitumor immune response. We show that LC combined with anti-programmed cell death protein 1 (PD-1) facilitates an antitumor immune response and improves survival (P < 0.001) in glioblastoma. LC-treated mice had increased infiltration of tumor-associated dendritic cells and clonal expansion of antigen-specific T effector cells...
December 21, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27903500/primary-resistance-to-pd-1-blockade-mediated-by-jak1-2-mutations
#19
Daniel Sanghoon Shin, Jesse M Zaretsky, Helena Escuin-Ordinas, Angel Garcia-Diaz, Siwen Hu-Lieskovan, Anusha Kalbasi, Catherine S Grasso, Willy Hugo, Salemiz Sandoval, Davis Y Torrejon, Nicolaos Palaskas, Gabriel Abril Rodriguez, Giulia Parisi, Ariel Azhdam, Bartosz Chmielowski, Grace Cherry, Elizabeth Seja, Beata Berent-Maoz, I Peter Shintaku, Dung T Le, Drew M Pardoll, Luis A Diaz, Paul C Tumeh, Thomas G Graeber, Roger S Lo, Begoña Comin-Anduix, Antoni Ribas
Loss-of-function mutations in JAK1/2 can lead to acquired resistance to anti-programmed death protein 1 (PD-1) therapy. We reasoned that they may also be involved in primary resistance to anti-PD-1 therapy. JAK1/2-inactivating mutations were noted in tumor biopsies of 1 of 23 patients with melanoma and in 1 of 16 patients with mismatch repair-deficient colon cancer treated with PD-1 blockade. Both cases had a high mutational load but did not respond to anti-PD-1 therapy. Two out of 48 human melanoma cell lines had JAK1/2 mutations, which led to a lack of PD-L1 expression upon interferon gamma exposure mediated by an inability to signal through the interferon gamma receptor pathway...
February 2017: Cancer Discovery
https://www.readbyqxmd.com/read/27837027/association-of-pd-1-pd-l-axis-expression-with-cytolytic-activity-mutational-load-and-prognosis-in-melanoma-and-other-solid-tumors
#20
Ludmila Danilova, Hao Wang, Joel Sunshine, Genevieve J Kaunitz, Tricia R Cottrell, Haiying Xu, Jessica Esandrio, Robert A Anders, Leslie Cope, Drew M Pardoll, Charles G Drake, Janis M Taube
Programmed cell death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) checkpoint blockade has led to remarkable and durable objective responses in a number of different tumor types. A better understanding of factors associated with the PD-1/PD-L axis expression is desirable, as it informs their potential role as prognostic and predictive biomarkers and may suggest rational treatment combinations. In the current study, we analyzed PD-L1, PD-L2, PD-1, and cytolytic activity (CYT) expression, as well as mutational density from melanoma and eight other solid tumor types using The Cancer Genome Atlas database...
November 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
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