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https://www.readbyqxmd.com/read/28193624/transcriptional-mechanisms-of-resistance-to-anti-pd-1-therapy
#1
Maria Libera Ascierto, Alvin Makohon-Moore, Evan J Lipson, Janis M Taube, Tracee L McMiller, Alan E Berger, Jinshui Fan, Genevieve Kaunitz, Tricia Cottrell, Zachary 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 pre-mortem, 22 post-mortem) were subjected to whole-exome sequencing. Candidate immunologic markers and gene expression were assessed in ten cutaneous metastases showing response or progression during therapy...
February 13, 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
#2
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 H Sharfman, Christos Georgiades, Franco Verde, Peter Illei, Qing Kay Li, Edward Gabrielson, Malcolm V Brock, Cynthia A Zahnow, Stephen B Baylin, Robert 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 non-small cell lung cancer patients after initial response to immune checkpoint blockade with anti-PD1 or anti-PD-1/anti-CTLA4 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...
December 28, 2016: Cancer Discovery
https://www.readbyqxmd.com/read/28008146/autologous-reconstitution-of-human-cancer-and-immune-system-in-vivo
#3
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
#4
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
#5
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
#6
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
https://www.readbyqxmd.com/read/27822377/erratum-to-agonist-anti-gitr-monoclonal-antibody-and-stereotactic-radiation-induce-immune-mediated-survival-advantage-in-murine-intracranial-glioma
#7
Mira A Patel, Jennifer E Kim, Debebe Theodros, Ada Tam, Esteban Velarde, Christina M Kochel, Brian Francica, Thomas R Nirschl, Ali Ghasemzadeh, Dimitrios Mathios, Sarah Harris-Bookman, Christopher C Jackson, Christina Jackson, Xiaobu Ye, Phuoc T Tran, Betty Tyler, Vladimir Coric, Mark Selby, Henry Brem, Charles G Drake, Drew M Pardoll, Michael Lim
[This corrects the article DOI: 10.1186/s40425-016-0132-2.].
2016: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/27736323/the-scaffold-immune-microenvironment-biomaterial-mediated-immune-polarization-in-traumatic-and-non-traumatic-applications
#8
Kaitlyn Sadtler, Brian W Allen, Kenneth Estrellas, Franck Housseau, Drew M Pardoll, Jennifer H Elisseeff
The immune system mediates tissue growth and homeostasis and is the first responder to injury or biomaterial implantation. Recently, it has been appreciated that immune cells play a critical role in wound healing and tissue repair and should thus be considered as potentially beneficial particularly in the context of scaffolds for regenerative medicine. Here, we present a flow cytometric analysis of cellular recruitment to tissue-derived extracellular matrix scaffolds where we quantitatively describe the infiltration and polarization of several immune subtypes including macrophages, dendritic cells, neutrophils, monocytes, T cells, and B cells...
October 13, 2016: Tissue Engineering. Part A
https://www.readbyqxmd.com/read/27683557/tgf%C3%AE-1-mediated-smad3-enhances-pd-1-expression-on-antigen-specific-t-cells-in-cancer
#9
Benjamin V Park, Zachary T Freeman, Ali Ghasemzadeh, Michael A Chattergoon, Alleluiah Rutebemberwa, Jordana Steigner, Matthew E Winter, Thanh V Huynh, Suzanne M Sebald, Se-Jin Lee, Fan Pan, Drew M Pardoll, Andrea L Cox
: Programmed death-1 (PD-1) is a coinhibitory receptor that downregulates the activity of tumor-infiltrating lymphocytes (TIL) in cancer and of virus-specific T cells in chronic infection. The molecular mechanisms driving high PD-1 expression on TILs have not been fully investigated. We demonstrate that TGFβ1 enhances antigen-induced PD-1 expression through SMAD3-dependent, SMAD2-independent transcriptional activation in T cells in vitro and in TILs in vivo The PD-1(hi) subset seen in CD8(+) TILs is absent in Smad3-deficient tumor-specific CD8(+) TILs, resulting in enhanced cytokine production by TILs and in draining lymph nodes and antitumor activity...
December 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27491898/the-intratumoral-balance-between-metabolic-and-immunologic-gene-expression-is-associated-with-anti-pd-1-response-in-patients-with-renal-cell-carcinoma
#10
Maria Libera Ascierto, Tracee L McMiller, Alan E Berger, Ludmila Danilova, Robert A Anders, George J Netto, Haiying Xu, Theresa S Pritchard, Jinshui Fan, Chris Cheadle, Leslie Cope, Charles G Drake, Drew M Pardoll, Janis M Taube, Suzanne L Topalian
Pretreatment tumor PD-L1 expression has been shown to correlate with response to anti-PD-1/PD-L1 therapies. Yet, most patients with PD-L1(+) tumors do not respond to treatment. The current study was undertaken to investigate mechanisms underlying the failure of PD-1-targeted therapies in patients with advanced renal cell carcinoma (RCC) whose tumors express PD-L1. Formalin-fixed, paraffin-embedded pretreatment tumor biopsies expressing PD-L1 were derived from 13 RCC patients. RNA was isolated from PD-L1(+) regions and subjected to whole genome microarray and multiplex quantitative (q)RT-PCR gene expression analysis...
September 2, 2016: Cancer Immunology Research
https://www.readbyqxmd.com/read/27438767/microrna-17-modulates-regulatory-t-cell-function-by-targeting-co-regulators-of-the-foxp3-transcription-factor
#11
Huang-Yu Yang, Joseph Barbi, Chao-Yi Wu, Ying Zheng, Paolo D A Vignali, Xingmei Wu, Jin-Hui Tao, Benjamin V Park, Shashika Bandara, Lewis Novack, Xuhao Ni, Xiaoping Yang, Kwang-Yu Chang, Ren-Chin Wu, Junran Zhang, Chih-Wei Yang, Drew M Pardoll, Huabin Li, Fan Pan
Regulatory T (Treg) cells are important in maintaining self-tolerance and immune homeostasis. The Treg cell transcription factor Foxp3 works in concert with other co-regulatory molecules, including Eos, to determine the transcriptional signature and characteristic suppressive phenotype of Treg cells. Here, we report that the inflammatory cytokine interleukin-6 (IL-6) actively repressed Eos expression through microRNA-17 (miR-17). miR-17 expression increased in Treg cells in the presence of IL-6, and its expression negatively correlated with that of Eos...
July 19, 2016: Immunity
https://www.readbyqxmd.com/read/27358487/combination-therapy-with-anti-pd-1-anti-tim-3-and-focal-radiation-results-in-regression-of-murine-gliomas
#12
Jennifer E Kim, Mira A Patel, Antonella Mangraviti, Eileen S Kim, Debebe Theodros, Esteban Velarde, Ann Liu, Eric W Sankey, Ada Tam, Haiying Xu, Dimitrios Mathios, Christopher M Jackson, Sarah Harris-Bookman, Tomas Garzon-Muvdi, Mary Sheu, Allison M Martin, Betty M Tyler, Phuoc T Tran, Xiaobu Ye, Alessandro Olivi, Janis M Taube, Peter C Burger, Charles G Drake, Henry Brem, Drew M Pardoll, Michael Lim
PURPOSE: Checkpoint molecules like programmed death-1 (PD-1) and T-cell immunoglobulin mucin-3 (TIM-3) are negative immune regulators that may be upregulated in the setting of glioblastoma multiforme. Combined PD-1 blockade and stereotactic radiosurgery (SRS) have been shown to improve antitumor immunity and produce long-term survivors in a murine glioma model. However, tumor-infiltrating lymphocytes (TIL) can express multiple checkpoints, and expression of ≥2 checkpoints corresponds to a more exhausted T-cell phenotype...
June 29, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27301879/the-myeloid-immune-signature-of-enterotoxigenic-bacteroides-fragilis-induced-murine-colon-tumorigenesis
#13
E Thiele Orberg, H Fan, A J Tam, C M Dejea, C E Destefano Shields, S Wu, L Chung, B B Finard, X Wu, P Fathi, S Ganguly, J Fu, D M Pardoll, C L Sears, F Housseau
Enterotoxigenic Bacteroides fragilis (ETBF), a human commensal and candidate pathogen in colorectal cancer (CRC), is a potent initiator of interleukin-17 (IL-17)-dependent colon tumorigenesis in Min(Apc+/-) mice. We examined the role of IL-17 and ETBF on the differentiation of myeloid cells into myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages, which are known to promote tumorigenesis. The myeloid compartment associated with ETBF-induced colon tumorigenesis in Min mice was defined using flow cytometry and gene expression profiling...
June 15, 2016: Mucosal Immunology
https://www.readbyqxmd.com/read/27190629/agonist-anti-gitr-monoclonal-antibody-and-stereotactic-radiation-induce-immune-mediated-survival-advantage-in-murine-intracranial-glioma
#14
Mira A Patel, Jennifer E Kim, Debebe Theodros, Ada Tam, Esteban Velarde, Christina M Kochel, Brian Francica, Thomas R Nirschl, Ali Ghasemzadeh, Dimitrios Mathios, Sarah Harris-Bookman, Christopher C Jackson, Christina Jackson, Xiaobu Ye, Phuoc T Tran, Betty Tyler, Vladimir Coric, Mark Selby, Henry Brem, Charles G Drake, Drew M Pardoll, Michael Lim
BACKGROUND: Glioblastoma (GBM) is a poorly immunogenic neoplasm treated with focused radiation. Immunotherapy has demonstrated synergistic survival effects with stereotactic radiosurgery (SRS) in murine GBM. GITR is a co-stimulatory molecule expressed constitutively on regulatory T-cells and by effector T-cells upon activation. We tested the hypothesis that anti-GITR monoclonal antibody (mAb) and SRS together would confer an immune-mediated survival benefit in glioma using the orthotopic GL261 glioma model...
2016: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/27161248/erratum-to-pd-1-pd-l1-pd-l2-expression-in-the-chordoma-microenvironment
#15
Dimitrios Mathios, Jacob Ruzevick, Christopher M Jackson, Haiying Xu, Sagar R Shah, Janis M Taube, Peter C Burger, Edward F McCarthy, Alfredo Quinones-Hinojosa, Drew M Pardoll, Michael Lim
No abstract text is available yet for this article.
May 2016: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/27093365/pd-1-blockade-with-pembrolizumab-in-advanced-merkel-cell-carcinoma
#16
MULTICENTER STUDY
Paul T Nghiem, Shailender Bhatia, Evan J Lipson, Ragini R Kudchadkar, Natalie J Miller, Lakshmanan Annamalai, Sneha Berry, Elliot K Chartash, Adil Daud, Steven P Fling, Philip A Friedlander, Harriet M Kluger, Holbrook E Kohrt, Lisa Lundgren, Kim Margolin, Alan Mitchell, Thomas Olencki, Drew M Pardoll, Sunil A Reddy, Erica M Shantha, William H Sharfman, Elad Sharon, Lynn R Shemanski, Michi M Shinohara, Joel C Sunshine, Janis M Taube, John A Thompson, Steven M Townson, Jennifer H Yearley, Suzanne L Topalian, Martin A Cheever
BACKGROUND: Merkel-cell carcinoma is an aggressive skin cancer that is linked to exposure to ultraviolet light and the Merkel-cell polyomavirus (MCPyV). Advanced Merkel-cell carcinoma often responds to chemotherapy, but responses are transient. Blocking the programmed death 1 (PD-1) immune inhibitory pathway is of interest, because these tumors often express PD-L1, and MCPyV-specific T cells express PD-1. METHODS: In this multicenter, phase 2, noncontrolled study, we assigned adults with advanced Merkel-cell carcinoma who had received no previous systemic therapy to receive pembrolizumab (anti-PD-1) at a dose of 2 mg per kilogram of body weight every 3 weeks...
June 30, 2016: New England Journal of Medicine
https://www.readbyqxmd.com/read/27081073/developing-a-pro-regenerative-biomaterial-scaffold-microenvironment-requires-t-helper-2-cells
#17
Kaitlyn Sadtler, Kenneth Estrellas, Brian W Allen, Matthew T Wolf, Hongni Fan, Ada J Tam, Chirag H Patel, Brandon S Luber, Hao Wang, Kathryn R Wagner, Jonathan D Powell, Franck Housseau, Drew M Pardoll, Jennifer H Elisseeff
Immune-mediated tissue regeneration driven by a biomaterial scaffold is emerging as an innovative regenerative strategy to repair damaged tissues. We investigated how biomaterial scaffolds shape the immune microenvironment in traumatic muscle wounds to improve tissue regeneration. The scaffolds induced a pro-regenerative response, characterized by an mTOR/Rictor-dependent T helper 2 pathway that guides interleukin-4-dependent macrophage polarization, which is critical for functional muscle recovery. Manipulating the adaptive immune system using biomaterials engineering may support the development of therapies that promote both systemic and local pro-regenerative immune responses, ultimately stimulating tissue repair...
April 15, 2016: Science
https://www.readbyqxmd.com/read/27079802/mechanism-driven-biomarkers-to-guide-immune-checkpoint-blockade-in-cancer-therapy
#18
Suzanne L Topalian, Janis M Taube, Robert A Anders, Drew M Pardoll
With recent approvals for multiple therapeutic antibodies that block cytotoxic T lymphocyte associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) in melanoma, non-small-cell lung cancer and kidney cancer, and additional immune checkpoints being targeted clinically, many questions still remain regarding the optimal use of drugs that block these checkpoint pathways. Defining biomarkers that predict therapeutic effects and adverse events is a crucial mandate, highlighted by recent approvals for two PDL1 diagnostic tests...
May 2016: Nature Reviews. Cancer
https://www.readbyqxmd.com/read/27064190/inhibiting-dna-methylation-causes-an-interferon-response-in-cancer-via-dsrna-including-endogenous-retroviruses
#19
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.
February 25, 2016: Cell
https://www.readbyqxmd.com/read/26962927/tumor-regression-and-allograft-rejection-after-administration-of-anti-pd-1
#20
LETTER
Evan J Lipson, Serena M Bagnasco, Jack Moore, Sekwon Jang, Manisha J Patel, Andrea A Zachary, Drew M Pardoll, Janis M Taube, Charles G Drake
No abstract text is available yet for this article.
March 3, 2016: New England Journal of Medicine
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