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https://www.readbyqxmd.com/read/29791021/immtac-anti-pd-1-combination-to-enhance-killing-of-cancer-cells-by-reversing-treg-mediated-immunosuppression
#1
Huanling Zhang, Yanyan Li, Xiaoping Liu, Zhaoduan Liang, Mengyong Yan, Qiang Liu, Anan Chen, Yifeng Bao, Chengzhi Zhou, Shiyue Li, Cassian Yee, Yi Li
Recently, bi-functional molecules that can redirect immune effectors to tumor cells have emerged as potentially robust mediators of tumor regression in clinical trials. Two modalities, in particular, bi-specific antibodies for T cell redirection and activation (BiTe) and immune-mobilizing monoclonal T-cell receptors against cancer (ImmTAC) are being evaluated in efficacy studies as 'off-the-shelf' reagents. Optimal therapy will require an understanding and means to address regulatory mechanisms of limiting efficacy...
May 23, 2018: Immunology
https://www.readbyqxmd.com/read/29786422/mechanisms-regulating-the-association-of-protein-phosphatase-1-with-spinophilin-and-neurabin
#2
Michael C Edler, Asma B Salek, Darryl S Watkins, Harjot Kaur, Cameron W Morris, Bryan K Yamamoto, Anthony J Baucum
Protein phosphorylation is a key mediator of signal transduction, allowing for dynamic regulation of substrate activity. Whereas protein kinases obtain substrate specificity by targeting specific amino acid sequences, serine/threonine phosphatase catalytic subunits are much more promiscuous in their ability to dephosphorylate substrates. To obtain substrate specificity, serine/threonine phosphatases utilize targeting proteins to regulate phosphatase subcellular localization and catalytic activity. Spinophilin and its homolog neurabin are two of the most abundant dendritic spine-localized protein phosphatase 1 (PP1) targeting proteins...
May 22, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29781221/aberrant-expansion-and-function-of-t-follicular-helper-cell-subsets-in-igg4-related-disease
#3
Yu Chen, Wei Lin, Hongxian Yang, Mu Wang, Panpan Zhang, Ruie Feng, Hua Chen, Linyi Peng, Xuan Zhang, Yan Zhao, Xiaofeng Zeng, Fengchun Zhang, Wen Zhang, Peter E Lipsky
OBJECTIVE: To determine the number and function of Tfh cell subsets in IgG4-RD. METHODS: Mononuclear cells from peripheral blood and involved tissues of IgG4-RD patients were collected. Tfh cell subsets, mRNA levels of Bcl-6, Blimp-1 and IL-21 were tested. Immunohistochemistry and immunofluorescence techniques were used to assess the location of IL-21, Bcl-6, and (CD4+CXCR5+) Tfh cells in the involved tissues. Furthermore, by in vitro cell co-culture, the abilities of cTfh cell subsets to induce B cells proliferation, apoptosis, differentiation, and production of IgG4 were explored...
May 21, 2018: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/29780387/cd32-expressing-cd4-t-cells-are-phenotypically-diverse-and-can-contain-proviral-hiv-dna
#4
Genevieve E Martin, Matthew Pace, John P Thornhill, Chansavath Phetsouphanh, Jodi Meyerowitz, Morgane Gossez, Helen Brown, Natalia Olejniczak, Julianne Lwanga, Gita Ramjee, Pontiano Kaleebu, Kholoud Porter, Christian B Willberg, Paul Klenerman, Nneka Nwokolo, Julie Fox, Sarah Fidler, John Frater
Efforts to both characterize and eradicate the HIV reservoir have been limited by the rarity of latently infected cells and the absence of a specific denoting biomarker. CD32a (FcγRIIa) has been proposed to be a marker for an enriched CD4 T cell HIV reservoir, but this finding remains controversial. Here, we explore the expression of CD32 on CD3+ CD4+ cells in participants from two primary HIV infection studies and identify at least three distinct phenotypes (CD32low , CD32+ CD14+ , and CD32high ). Of note, CD4 negative enrichment kits remove the majority of CD4+ CD32+ T cells, potentially skewing subsequent analyses if used...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29777823/updated-efficacy-analysis-including-secondary-population-results-for-oak-a-randomized-phase-iii-study-of-atezolizumab-vs-docetaxel-in-patients-with-previously-treated-advanced-non-small-cell-lung-cancer
#5
L Fehrenbacher, J von Pawel, K Park, A Rittmeyer, D R Gandara, S Ponce Aix, J-Y Han, S M Gadgeel, T Hida, D L Cortinovis, M Cobo, D M Kowalski, F De Marinis, M Gandhi, B Danner, C Matheny, M Kowanetz, P He, F Felizzi, H Patel, A Sandler, M Ballinger, F Barlesi
INTRODUCTION: The efficacy and safety of atezolizumab vs docetaxel as second- or third-line treatment in patients with advanced non-small cell lung cancer in the primary (n=850; ITT850) and secondary (n=1225; ITT1225) efficacy populations of the randomized phase III OAK study at an updated data cutoff were assessed. METHODS: Patients received atezolizumab 1200mg or docetaxel 75mg/m2 intravenously every 3 weeks until loss of clinical benefit or disease progression, respectively...
May 16, 2018: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/29775689/biomarkers-for-checkpoint-inhibition-in-hematologic-malignancies
#6
REVIEW
Djordje Atanackovic, Tim Luetkens
In the past few years we have seen remarkable paradigm shifts in the treatment of many solid tumors due to the introduction of inhibitors targeting immune checkpoints such as PD-1/PD-L1 and CTLA-4. Recent results indicate that checkpoint inhibition also represents a very promising approach for certain types of hematologic malignancies. Unfortunately, treatment with checkpoint inhibitors is also associated with substantial toxicities and high costs and only a subset of patients appears to derive clinical benefit from these treatments...
May 15, 2018: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/29774031/il-10-producing-b-cells-ability-to-induce-regulatory-t-cells-is-maintained-in-rheumatoid-arthritis
#7
Julie Mielle, Rachel Audo, Michael Hahne, Laurence Macia, Bernard Combe, Jacques Morel, Claire Daien
Despite growing evidence highlighting the relevance of increasing IL-10-producing B cells (B10+ cells) in autoimmune diseases, their functions in patients are still unknown. The aim of this study was to evaluate the functions of CpG-induced B10+ cells isolated from healthy controls (HC) and rheumatoid arthritis (RA) patients, on naïve T cell differentiation. We demonstrated that CpG-induced B10+ cells from HC drove naïve T cell differentiation toward regulatory T cells (Treg cells) and IL-10-producing T cells (Tr1) through IL-10 secretion and cellular contacts...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29773068/pharmacokinetic-and-pharmacodynamic-relationship-of-blinatumomab-in-patients-with-non-hodgkin-lymphoma
#8
Youssef Hijazi, Matthias Klinger, Andrea Kratzer, Benjamin Wu, Patrick A Baeuerle, Peter Kufer, Andreas Wolf, Dirk Nagorsen, Min Zhu
OBJECTIVE: We describe the relationship between pharmacokinetics (PK) of blinatumomab and pharmacodynamic (PD) changes in peripheral lymphocytes, serum cytokines, and tumor size in patients with non-Hodgkin lymphoma (NHL). METHODS: In a phase 1 study, 76 patients with relapsed/refractory NHL received blinatumomab by continuous intravenous infusion at various doses (0.5 to 90 µg/m2/day). PD changes were analyzed with respect to dose, blinatumomab concentration at steady state (Css), and cumulative area under the concentration-versus-time curve (AUCcum)...
May 17, 2018: Current Clinical Pharmacology
https://www.readbyqxmd.com/read/29769249/spatial-distribution-and-function-of-t-follicular-regulatory-cells-in-human-lymph-nodes
#9
Ismail Sayin, Andrea J Radtke, Laura A Vella, Wenjie Jin, E John Wherry, Marcus Buggert, Michael R Betts, Ramin S Herati, Ronald N Germain, David H Canaday
T follicular regulatory (Tfr) cells are a population of CD4+ T cells that express regulatory T cell markers and have been shown to suppress humoral immunity. However, the precise mechanisms and location of Tfr-mediated suppression in the lymph node (LN) microenvironment are unknown. Using highly multiplexed quantitative imaging and functional assays, we examined the spatial distribution, suppressive function, and preferred interacting partners of Tfr cells in human mesenteric LNs. We find that the majority of Tfr cells express low levels of PD-1 and reside at the border between the T cell zone and B cell follicle, with very few found in the germinal centers (GCs)...
May 16, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29764494/precision-medicine-becomes-reality-tumor-type-agnostic-therapy
#10
REVIEW
Li Yan, Wei Zhang
Precision medicine just witnessed two breakthroughs in oncology in 2017. Pembrolizumab (Keytruda), Merck's anti-programmed cell death-1 (PD-1) monoclonal antibody (mAb), received accelerated approval in May 2017 by the US Food and Drug Administration for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having microsatellite instability-high (MSI-H) or deficient DNA mismatch repair (dMMR). Shortly after, nivolumab (Opdivo), Bristol-Myers Squibb's anti-PD-1 mAb, gained an accelerated approval in August 2017 for adult and pediatric patients with MSI-H or dMMR metastatic colorectal cancer that has progressed after standard chemotherapy...
March 31, 2018: Cancer communications
https://www.readbyqxmd.com/read/29762141/pd-1-expression-in-chronic-lymphocytic-leukemia-small-lymphocytic-lymphoma-cll-sll-and-large-b-cell-richter-transformation-dlbcl-rt-a-characteristic-feature-of-dlbcl-rt-and-potential-surrogate-marker-for-clonal-relatedness
#11
Rong He, Wei Ding, David S Viswanatha, Dong Chen, Min Shi, Daniel Van Dyke, Shulan Tian, Linda N Dao, Sameer A Parikh, Tait D Shanafelt, Timothy G Call, Stephen M Ansell, Jose F Leis, Ming Mai, Curtis A Hanson, Karen L Rech
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a low-grade B-cell neoplasm and ∼2% to 9% patients develop an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (Richter transformation, DLBCL-RT). Programmed death-1 (PD-1) pathway plays a crucial role in tumor host immunity evasion and its blockade has emerged as an effective anti-cancer immunotherapy. PD-L1 and PD-1 expression has shown predictive value in anti-PD cancer immunotherapy; however, it has not been well documented in CLL/SLL and DLBCL-RT...
May 14, 2018: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/29761938/lactoferricin-b-reverses-cisplatin-resistance-in-head-and-neck-squamous-cell-carcinoma-cells-through-targeting-pd-l1
#12
Pei Zhang, Jinzhong Liu, Wenlu Li, Shanshan Li, Xinguang Han
Head and neck squamous cell carcinoma (HNSCC) ranks among the top most common cancers with a poor prognosis. The mechanism of chemoresistance is still not well known. This study is to investigate the programmed death-ligand 1 (PD-L1) expression in HNSCC, and test the effect of lactoferricin B (LfcinB) on chemoresistance and its mechanism. We analyzed 510 HNSCC patients in TCGA database and investigated how CD274 expression was related to patient prognosis. PD-L1 was verified from HNSCC samples at local hospital with immunohistochemistry...
May 15, 2018: Cancer Medicine
https://www.readbyqxmd.com/read/29758333/hepatitis-b-virus-specific-t-cell-responses-after-stopping-nucleos-t-ide-analogue-therapy-in-hbeag-negative-chronic-hepatitis-b
#13
Franziska Rinker, Christine L Zimmer, Christoph Höner Zu Siederdissen, Michael P Manns, Anke R M Kraft, Heiner Wedemeyer, Niklas K Björkström, Markus Cornberg
BACKGROUND AND AIMS: Treatment with nucleos(t)ide analogues (NA) leads to HBV DNA suppression in most patients with chronic hepatitis B (CHB), but HBsAg loss rates are low. Upon NA discontinuation, HBV DNA can return rapidly with ensuing ALT flares and induction of cytokines. Several studies reported higher HBsAg loss rates after stopping therapy, but at present, it is unclear if cell-mediated immune responses are altered after treatment discontinuation. The aim of this study was to characterise T cell responses during the early phase of virological relapse following discontinuation of NA therapy in HBeAg-negative patients...
May 11, 2018: Journal of Hepatology
https://www.readbyqxmd.com/read/29748856/cd3-cd8-t-cell-density-and-tumoral-pd-l1-predict-survival-irrespective-of-rituximab-treatment-in-chinese-diffuse-large-b-cell-lymphoma-patients
#14
Yunfei Shi, Lijuan Deng, Yuqin Song, Dongmei Lin, Yumei Lai, LiXin Zhou, Lei Yang, Xianghong Li
To investigate the prognostic value of tumor-infiltrating T-cell density and programmed cell death ligand-1 (PD-L1) expression in diffuse large B cell lymphoma (DLBCL). One-hundred-twenty-five Chinese DLBCL patients were enrolled in our study and provided samples; 76 of all cases were treated with rituximab (R). Tumor tissues were immunostained and analyzed for CD3+ and CD8+ tumor-infiltrating T-cell density, tumoral PD-L1, and microenvironmental PD-L1 (mPD-L1). The density of CD3 was rated as high in 33.6% cases, while 64...
May 10, 2018: International Journal of Hematology
https://www.readbyqxmd.com/read/29746148/vitrification-assessment-thermal-analysis-of-cryoprotective-aqueous-solutions-1-2-propanediol-and-ethylene-glycol
#15
Muhamad Abidalla, Pio F Roversi
Cryopreservation of viable cells and cell materials is being developed for biological and biopharmaceutical applications. The inhibition of ice formation during the cooling and warming phase of vitrified living biological samples is important for their survival. The tendency to form glasses (glass transition temperature, Tg ) upon cooling in the vitrification solution and the stability of the amorphous state upon warming to determine the critical cooling rate (Vccr ) and critical warming rates (Vcwr ) are evaluated...
May 10, 2018: Biopreservation and Biobanking
https://www.readbyqxmd.com/read/29745928/cancer-immunotherapy-and-the-pd-1-pd-l1-checkpoint-pathway
#16
Jonathan Barclay, Joanne Creswell, Juan León
Long-term survival for patients with advanced bladder cancer is precarious, with a 5-year survival of just 5% in metastatic cases. Normally, the binding of PD-L1 to PD-1 alters the immune activity by modulating it to inhibit autoimmune diseases or chronic inflammation. However, some cancers use this route to block the immune response of the patient and continue growing. The new immunotherapy against bladder cancer aims to block the ability of tumor cells to resist patient' immune response by acting on the checkpoints of immune cells...
May 2018: Archivos Españoles de Urología
https://www.readbyqxmd.com/read/29739909/a-high-frequency-of-hiv-specific-circulating-follicular-helper-t-cells-is-associated-with-preserved-memory-b-cell-responses-in-hiv-controllers
#17
M Claireaux, M Galperin, D Benati, A Nouël, M Mukhopadhyay, J Klingler, P de Truchis, D Zucman, S Hendou, F Boufassa, C Moog, O Lambotte, L A Chakrabarti
Follicular helper T cells (Tfh) play an essential role in the affinity maturation of the antibody response by providing help to B cells. To determine whether this CD4+ T cell subset may contribute to the spontaneous control of HIV infection, we analyzed the phenotype and function of circulating Tfh (cTfh) in patients from the ANRS CO21 CODEX cohort who naturally controlled HIV-1 replication to undetectable levels and compared them to treated patients with similarly low viral loads. HIV-specific cTfh (Tet+ ), detected by Gag-major histocompatibility complex class II (MHC-II) tetramer labeling in the CD45RA- CXCR5+ CD4+ T cell population, proved more frequent in the controller group ( P = 0...
May 8, 2018: MBio
https://www.readbyqxmd.com/read/29739341/hbv-and-hiv-viral-load-but-not-microbial-translocation-or-immune-activation-are-associated-with-liver-fibrosis-among-patients-in-south-africa
#18
Tongai Gibson Maponga, Monique I Andersson, Christoffel J van Rensburg, Joop E Arends, Jantjie Taljaard, Wolfgang Preiser, Richard H Glashoff
BACKGROUND: Co-infection with HIV negatively impacts the progression of chronic hepatitis B virus (HBV) infection, including causing rapid progression to liver fibrosis. Sub-Saharan Africa represents arguably the most important intersection of high endemicity of both chronic hepatitis B virus (HBV) infection and HIV infection. METHODS: We recruited 46 HBV/HIV-co-infected; 47 HBV-monoinfected; 39 HIV-monoinfected; and 37 HBV/HIV-uninfected patients from Tygerberg Hospital, Cape Town, South Africa...
May 8, 2018: BMC Infectious Diseases
https://www.readbyqxmd.com/read/29735433/glycosphingolipid-levels-and-glucocerebrosidase-activity-are-altered-in-normal-aging-of-the-mouse-brain
#19
Penelope J Hallett, Mylene Huebecker, Oeystein R Brekk, Elizabeth B Moloney, Emily M Rocha, David A Priestman, Frances M Platt, Ole Isacson
Aging is the predominant risk factor for both genetic and sporadic Parkinson's disease (PD). The majority of PD cases are nonfamilial, and the connection between aging and PD-associated genes is not well understood. Haploinsufficiency of the GBA gene, leading to a reduction in glucocerebrosidase (GCase) activity, is one of the most common genetic risk factors for PD. Furthermore, GCase activity is also reduced in brain regions of sporadic PD patients, with a corresponding accumulation of its glycosphingolipid (GSL) substrates...
March 29, 2018: Neurobiology of Aging
https://www.readbyqxmd.com/read/29729204/outcome-of-anti-viral-immunity-in-the-liver-is-shaped-by-the-level-of-antigen-expressed-in-infected-hepatocytes
#20
Katrin Manske, Nina Kallin, Verena König, Annika Schneider, Sandra Kurz, Miriam Bosch, Meike Welz, Ru-Lin Cheng, Bertram Bengsch, Katja Steiger, Ulrike Protzer, Robert Thimme, Percy A Knolle, Dirk Wohlleber
The liver bears unique immune-properties supporting both immune tolerance and immunity, but the mechanisms responsible for clearance versus persistence of virus-infected hepatocytes remains unclear. Here, we dissect the factors determining the outcome of anti-viral immunity using novel recombinant adenoviruses reflecting the hepatropism and -trophism of hepatitis viruses. We generated replication-deficient adenoviruses with equimolar ovalbumin, luciferase and GFP-expression driven by strong ubiquitous CMV-promoter (Ad-CMV-GOL) or by 100-fold weaker, yet hepatocyte-specific Transthyretin(TTR)-promoter (Ad-TTR-GOL)...
May 5, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
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