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https://www.readbyqxmd.com/read/28621686/pseudoprogression-in-microsatellite-instability-high-colorectal-cancer-during-treatment-with-combination-t-cell-mediated-immunotherapy-a-case-report-and-literature-review
#1
Young Kwang Chae, Si Wang, Halla Nimeiri, Aparna Kalyan, Francis J Giles
Evading tumor-mediated immunosuppression through antibodies to immune checkpoints has shown clinical benefit in patients with select solid tumors. There is a heterogeneity of responses in patients receiving immunotherapy, including pseudoprogression in which the tumor burden increases initially before decreasing to reach disease control. The characteristics and basis of pseudoprogression, however, remains poorly understood. We hereby report a case of microsatellite instability (MSI)-high metastatic colorectal cancer treated with combination of OX40 agonist and programmed death ligand-1 (PD-L1) antagonist that demonstrated pseudoprogression reaching 163% increase from baseline tumor burden...
June 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28612217/ox40-promotes-obesity-induced-adipose-inflammation-and-insulin-resistance
#2
Bing Liu, Hengchi Yu, Guangyong Sun, Xiaojing Sun, Hua Jin, Chunpan Zhang, Wen Shi, Dan Tian, Kai Liu, Hufeng Xu, Xinmin Li, Jie Yin, Xu Hong, Dong Zhang
Adaptive immunity plays a critical role in IR and T2DM development; however, the biological mechanisms linking T cell costimulation and glucose metabolism have not been fully elucidated. In this study, we demonstrated that the costimulatory molecule OX40 controls T cell activation and IR development. Inflammatory cell accumulation and enhanced proinflammatory gene expression, as well as high OX40 expression levels on CD4(+) T cells, were observed in the adipose tissues of mice with diet-induced obesity. OX40-KO mice exhibited significantly less weight gain and lower fasting glucose levels than those of WT mice, without obvious adipose tissue inflammation...
June 13, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28578991/oncolytic-vsv-primes-differential-responses-to-immuno-oncology-therapy
#3
Nicholas M Durham, Kathy Mulgrew, Kelly McGlinchey, Noel R Monks, Hong Ji, Ronald Herbst, JoAnn Suzich, Scott A Hammond, Elizabeth J Kelly
Vesicular stomatitis virus encoding the IFNβ transgene (VSV-IFNβ) is a mediator of potent oncolytic activity and is undergoing clinical evaluation for the treatment of solid tumors. Emerging preclinical and clinical data suggest treatment of tumors with oncolytic viruses may sensitize tumors to checkpoint inhibitors and increase the anti-tumor immune response. New generations of immuno-oncology molecules including T cell agonists are entering clinical development and could be hypothesized to enhance the activity of oncolytic viruses, including VSV-IFNβ...
June 1, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28566332/oncolytic-adenovirus-and-tumor-targeting-immune-modulatory-therapy-improve-autologous-cancer-vaccination
#4
Hong Jiang, Yisel Rivera-Molina, Karen Clise-Dwyer, Laura Bover, Luis Vence, Ying Yuan, Frederick F Lang, Carlo Toniatti, Mohammad B Hossain, Candelaria Gomez-Manzano, Juan Fueyo
Oncolytic viruses selectively lyse tumor cells, disrupt immunosuppression within the tumor and reactivate anti-tumor immunity, but they have yet to live up to their therapeutic potential. Immune checkpoint modulation has been efficacious in a variety of cancer with an immunogenic microenvironment, but is associated with toxicity due to nonspecific T-cell activation. Therefore, combining these two strategies would likely result in both effective and specific cancer therapy. To test the hypothesis, we first constructed oncolytic adenovirus Delta-24-RGDOX expressing the immune co-stimulator OX40 ligand (OX40L)...
May 31, 2017: Cancer Research
https://www.readbyqxmd.com/read/28556418/phase-i-randomized-study-of-khk4083-an-anti-ox40-monoclonal-antibody-in-patients-with-mild-to-moderate-plaque-psoriasis
#5
K A Papp, M J Gooderham, G Girard, M Raman, V Strout
BACKGROUND: OX40 (CD134) is expressed in lesional but not healthy skin of patients with psoriasis. KHK4083 is a fully human monoclonal antibody against OX40. OBJECTIVE: The primary aim of this first-in-human phase 1 study was to determine the safety and tolerability of ascending single doses of KHK4083 in patients with mild to moderate plaque psoriasis. Secondary aims were to determine the pharmacokinetics and immunogenicity of KHK4083, and an exploratory objective was to assess clinical activity...
May 27, 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/28537889/immune-signature-of-metastatic-breast-cancer-identifying-predictive-markers-of-immunotherapy-response
#6
Ji-Yeon Kim, Eunjin Lee, Kyunghee Park, Woong-Yang Park, Hae Hyun Jung, Jin Seok Ahn, Young-Hyuck Im, Yeon Hee Park
In breast cancer (BC), up to 10-20% patients were known to have clinical benefit with immune checkpoint inhibitors, and biomarkers are needed for optimal use of this multi-potential therapeutic strategy. Accordingly, we conducted an experiment to identify expression of genes associated with immune checkpoints that represent potential targets of cancer immunotherapy. We performed whole-transcriptome sequencing and whole-exome sequencing using 37 refractory BC specimens. In the immune pathway gene set expression analysis, we found that HER2 expression and previous taxane treatment were positively correlated with high expression of immune gene set expression (p = 0...
May 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28485382/single-cell-profiling-of-lineage-determining-transcription-factors-in-antigen-specific-cd4-t-cells-reveals-unexpected-complexity-in-recall-responses-during-immune-reconstitution
#7
Chansavath Phetsouphanh, Yin Xu, Mee Ling Munier, John J Zaunders, Anthony D Kelleher
Recent studies of protein and gene expression at the single-cell level have revealed that the memory T-cell compartment is more heterogeneous than previously acknowledged. Identifying different T helper subsets involved in memory responses at the single-cell level is thus necessary to understand the level of heterogeneity within this population. Antigen-specific CD4(+) T cells were measured using the CD25/OX40 assay together with a qualitative multiplex single-cell RT-PCR assay. Transcription profiles and subset proportions within the antigen-specific CD4(+) T-cell population were dissected...
May 9, 2017: Immunology and Cell Biology
https://www.readbyqxmd.com/read/28483787/a-sting-agonist-given-with-ox40-receptor-and-pd-l1-modulators-primes-immunity-and-reduces-tumor-growth-in-tolerized-mice
#8
Jeremy B Foote, Marleen Kok, James M Leatherman, Todd D Armstrong, Bridget C Marcinkowski, Laureen S Ojalvo, David B Kanne, Elizabeth M Jaffee, Thomas W Dubensky, Leisha A Emens
Stimulator of interferon genes (STING) signaling induces IFNβ production by intratumoral dendritic cells (DC), driving T-cell priming and recruitment into the tumor microenvironment (TME). We examined to what extent preexisting antigen-specific tolerance influenced the efficacy of in situ delivery of a potent STING-activating cyclic dinucleotide (CDN), ADU S-100, against established HER-2(+) breast tumors. ADU S-100 induced HER-2-specific CD8(+) T-cell priming and durable tumor clearance in 100% of nontolerant parental FVB/N mice...
June 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28436935/tnf-superfamily-receptor-ox40-triggers-invariant-nkt-cell-pyroptosis-and-liver-injury
#9
Peixiang Lan, Yihui Fan, Yue Zhao, Xiaohua Lou, Howard P Monsour, Xiaolong Zhang, Yongwon Choi, Yaling Dou, Naoto Ishii, Rafik M Ghobrial, Xiang Xiao, Xian Chang Li
Tissue-resident immune cells play a key role in local and systemic immune responses. The liver, in particular, hosts a large number of invariant natural killer T (iNKT) cells, which are involved in diverse immune responses. However, the mechanisms that regulate survival and homeostasis of liver iNKT cells are poorly defined. Here we have found that liver iNKT cells constitutively express the costimulatory TNF superfamily receptor OX40 and that OX40 stimulation results in massive pyroptotic death of iNKT cells, characterized by the release of potent proinflammatory cytokines that induce liver injury...
June 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28428203/tslp-activated-dendritic-cells-induce-human-t-follicular-helper-cell-differentiation-through-ox40-ligand
#10
Lucia Pattarini, Coline Trichot, Sofia Bogiatzi, Maximilien Grandclaudon, Stephan Meller, Zela Keuylian, Melanie Durand, Elisabetta Volpe, Stefania Madonna, Andrea Cavani, Andrea Chiricozzi, Marco Romanelli, Toshiyuki Hori, Alain Hovnanian, Bernhard Homey, Vassili Soumelis
T follicular helper cells (Tfh) are important regulators of humoral responses. Human Tfh polarization pathways have been thus far associated with Th1 and Th17 polarization pathways. How human Tfh cells differentiate in Th2-skewed environments is unknown. We show that thymic stromal lymphopoietin (TSLP)-activated dendritic cells (DCs) promote human Tfh differentiation from naive CD4 T cells. We identified a novel population, distinct from Th2 cells, expressing IL-21 and TNF, suggestive of inflammatory cells...
May 1, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28413428/transcriptomic-evidence-of-a-para-inflammatory-state-in-the-middle-aged-lumbar-spinal-cord
#11
William Galbavy, Yong Lu, Martin Kaczocha, Michelino Puopolo, Lixin Liu, Mario J Rebecchi
BACKGROUND: We have previously reported elevated expression of multiple pro-inflammatory markers in the lumbar spinal cord (LSC) of middle-aged male rats compared to young adults suggesting a para-inflammatory state develops in the LSC by middle age, a time that in humans is associated with the greatest pain prevalence and persistence. The goal of the current study was to examine the transcriptome-wide gene expression differences between young and middle aged LSC. METHODS: Young (3 month) and middle-aged (17 month) naïve Fisher 344 rats (n = 5 per group) were euthanized, perfused with heparinized saline, and the LSC were removed...
2017: Immunity & Ageing: I & A
https://www.readbyqxmd.com/read/28370072/expression-profiling-of-sudanese-visceral-leishmaniasis-patients-pre-and-post-treatment-with-sodium-stibogluconate
#12
M A M Salih, M Fakiola, P A Lyons, B M Younis, A M Musa, A M Elhassan, D Anderson, G Syn, M E Ibrahim, J M Blackwell, H S Mohamed
Visceral leishmaniasis (VL) in Sudan caused by Leishmania donovani is fatal in susceptible individuals if untreated. Treatment with sodium stibogluconate (SSG) leads to post-kala-azar dermal leishmaniasis (PKDL) in 58% of patients. Here, Affymetrix microarrays were used to identify genes differentially expressed in lymph nodes (N=9 paired samples) pre- and post-treatment with SSG. Using the Bioconductor package limma, 438 genes from 28 869 post-quality-control probe sets were differentially expressed (Pnominal ≤...
March 31, 2017: Parasite Immunology
https://www.readbyqxmd.com/read/28369782/immune-checkpoint-proteins-exploring-their-therapeutic-potential-to-regulate-atherosclerosis
#13
REVIEW
A C Foks, J Kuiper
The immune system provides a large variety of immune checkpoint proteins, which involve both costimulatory and inhibitory proteins. Costimulatory proteins can promote cell survival, cell cycle progression and differentiation to effector and memory cells, whereas inhibitory proteins terminate these processes to halt ongoing inflammation. Immune checkpoint proteins play a pivotal role in atherosclerosis by regulating the activation and proliferation of various immune and non-immune cells, such as T-cells, macrophages and platelets...
March 30, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28349869/modulation-of-regulatory-t-cells-by-intranasal-allergen-immunotherapy-in-an-experimental-rat-model-of-airway-allergy
#14
Saibal Moitra, Ankur Datta, Somnath Mondal, Iman Hazra, Sk Md Omar Faruk, Prasanta K Das, Anjan K Basu, Santanu K Tripathi, Swapna Chaudhuri
Allergic airway diseases such as asthma and allergic rhinitis are increasing in prevalence worldwide. The theory of an altered Th1/Th2 balance in allergic diathesis has recently been termed a "procrustean paradigm" as it failed to explain many preclinical findings. Regulatory T cells (Treg) have now been shown to be critical in T-cell homeostasis and in the maintenance of peripheral tolerance to allergens. Allergen specific immunotherapy (SIT) has been shown to induce regulatory T cells in allergic patients...
March 24, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28335888/second-and-third-generation-drugs-for-immuno-oncology-treatment-the-more-the-better
#15
REVIEW
Wolfram C M Dempke, Klaus Fenchel, Peter Uciechowski, Stephen P Dale
Recent success in cancer immunotherapy (anti-CTLA-4, anti-PD1/PD-L1) has confirmed the hypothesis that the immune system can control many cancers across various histologies, in some cases producing durable responses in a way not seen with many small-molecule drugs. However, only less than 25% of all patients do respond to immuno-oncology drugs and several resistance mechanisms have been identified (e.g. T-cell exhaustion, overexpression of caspase-8 and β-catenin, PD-1/PD-L1 gene amplification, MHC-I/II mutations)...
March 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28320444/ox40-signaling-is-involved-in-the-autoactivation-of-cd4-cd28-t-cells-and-contributes-to-the-pathogenesis-of-autoimmune-arthritis
#16
Juean Jiang, Cuiping Liu, Mi Liu, Yu Shen, Xiaohan Hu, Qin Wang, Jian Wu, Min Wu, Qi Fang, Xueguang Zhang
BACKGROUND: CD4(+)CD28(-) T cells exhibit autoreactive potential in autoimmune disorders, including rheumatoid arthritis (RA). It is not well known which costimulator functions as an alternative second signal in the activation of this subset after CD28 expression is downregulated. Tumor necrosis factor receptor superfamily member OX40 is a key costimulator in the activation of T cells. The aim of this study was to investigate the costimulatory effects of OX40 on CD4(+)CD28(-) T cells in autoimmune arthritis...
March 21, 2017: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/28300714/biomarkers-and-immunotherapeutic-targets-in-glioblastoma
#17
REVIEW
Alice L Hung, Tomas Garzon-Muvdi, Michael Lim
Glioblastoma (GBM) is an aggressive central nervous system cancer with poor prognosis despite maximal therapy. The recent advent of immunotherapy holds great promise for improving GBM survival and has already made great strides toward changing management strategies. A diverse set of biomarkers have been implicated as immunotherapeutic targets and prognostic indicators in other cancers. Some of the more extensively studied examples include cytokines (IL-4, IL-13, and TGF-β), checkpoint molecules (PD-1, CTLA-4, TIM-3, LAG-3, CD137, GITR, OX40), and growth/angiogenesis proteins (endoglin and EGFR)...
June 2017: World Neurosurgery
https://www.readbyqxmd.com/read/28289708/interruption-of-ox40l-signaling-prevents-costimulation-blockade-resistant-allograft-rejection
#18
William H Kitchens, Ying Dong, David V Mathews, Cynthia P Breeden, Elizabeth Strobert, Maria E Fuentes, Christian P Larsen, Mandy L Ford, Andrew B Adams
The potential of costimulation blockade to serve as a novel transplant immunosuppression strategy has been explored for over 20 years, culminating in the recent clinical approval of belatacept for renal transplant patients. Despite improving long-term graft function and survival compared with calcineurin inhibitors, clinical acceptance of belatacept has been hindered by elevated rates of acute rejection. We examined the signaling pathways required to activate costimulation blockade-resistant alloreactive T cells and identified the OX40/OX40L secondary costimulatory pathway as a promising target...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28283653/antibody-drug-conjugates-bearing-pyrrolobenzodiazepine-or-tubulysin-payloads-are-immunomodulatory-and-synergize-with-multiple-immunotherapies
#19
Jonathan Rios-Doria, Jay Harper, Raymond Rothstein, Leslie Wetzel, Jon Chesebrough, Allison M Marrero, Cui Chen, Patrick Strout, Kathy Mulgrew, Kelly A McGlinchey, Ryan Fleming, Binyam Bezabeh, John Meekin, David Stewart, Maureen Kennedy, Philip Martin, Andrew Buchanan, Nazzareno Dimasi, Emil F Michelotti, Robert E Hollingsworth
Immunogenic cell death (ICD) is the process by which certain cytotoxic drugs induce apoptosis of tumor cells in a manner that stimulates the immune system. In this study, we investigated whether antibody-drug conjugates (ADC) conjugated with pyrrolobenzodiazepine dimer (PBD) or tubulysin payloads induce ICD, modulate the immune microenvironment, and could combine with IO drugs to enhance antitumor activity. We show that these payloads on their own induced an immune response that prevented the growth of tumors following subsequent tumor cell challenge...
March 10, 2017: Cancer Research
https://www.readbyqxmd.com/read/28283419/circulating-gluten-specific-foxp3-cd39-regulatory-t-cells-have-impaired-suppressive-function-in-celiac-disease
#20
Laura Cook, C Mee Ling Munier, Nabila Seddiki, David van Bockel, Noé Ontiveros, Melinda Y Hardy, Jana K Gillies, Megan K Levings, Hugh Reid, Jan Peterson, Jamie Rossjohn, Robert P Anderson, John Zaunders, Jason A Tye-Din, Anthony D Kelleher
BACKGROUND: Celiac disease is a chronic immune-mediated inflammatory disorder of the gut triggered by dietary gluten. Although the effector T-cell response in celiac disease has been well characterized, the role of regulatory T-cells (Tregs) in the loss of tolerance to gluten remains poorly understood. OBJECTIVE: To define if celiac disease patients have a dysfunction or lack of gluten-specific FOXP3(+) Tregs. METHODS: Treated celiac disease patients underwent oral wheat challenge to stimulate re-circulation of gluten-specific T-cells...
March 7, 2017: Journal of Allergy and Clinical Immunology
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