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https://www.readbyqxmd.com/read/29127039/biodegradable-sting-agonist-nanoparticles-for-enhanced-cancer-immunotherapy
#1
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...
November 7, 2017: Nanomedicine: Nanotechnology, Biology, and Medicine
https://www.readbyqxmd.com/read/28970196/stereotactic-radiotherapy-increases-functionally-suppressive-regulatory-t-cells-in-the-tumor-microenvironment
#2
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...
October 2, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28596308/mismatch-repair-deficiency-predicts-response-of-solid-tumors-to-pd-1-blockade
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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-nontraumatic-applications
#13
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 potentially beneficial, particularly in the context of scaffolds for regenerative medicine. In this study, 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 2017: 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
#14
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
#15
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
#16
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
#17
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
#18
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...
March 2017: 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
#19
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
#20
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
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