An exploratory study of metformin (Met) with or without rapamycin (Rapa) as maintenance therapy after induction chemotherapy in patients (Pts) with metastatic pancreatic adenocarcinoma (PDA).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 700-700
Author(s):  
Katherine M. Bever ◽  
Erkut Hasan Borazanci ◽  
Elizabeth Thompson ◽  
Annie Wu ◽  
Jennifer N. Durham ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Stable Disease ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Open Label ◽  
Peripheral Blood Mononuclear ◽  
Mtor Inhibition ◽  
Oncogenic Pathways ◽  
Line Of Therapy ◽  
Ecog Ps

700 Background: Few studies have examined maintenance therapy in unselected pts with metastatic PDA (mPDA). mTOR signaling is central to several oncogenic pathways in PDA and also has a role in T cell differentiation and activation, and we hypothesized a role for mTOR inhibition (mTORi) in the maintenance setting. Methods: This was a randomized open-label study conducted at 2 sites. Eligible pts had mPDA with stable disease for ≥6 months on chemotherapy and ECOG PS 0/1. Pts were randomized 1:1 to Met 850mg BID alone (Arm A) or with Rapa 4mg daily (Arm B), stratified by prior FOLFIRINOX. Baseline and on-treatment PET scans and peripheral blood mononuclear cells were obtained for exploratory analyses. Results: 23 pts were randomized. Median age was 64 (range 34-77) and 82% had ECOG PS 1. 12 of 23 received prior FOLFIRINOX; 8 received >1 prior line of therapy. 22 subjects (11 per arm) were treated per protocol. Treatment related adverse events of Grade ≥3 were seen in 0% vs 27% of pts in Arm A vs B and were all asymptomatic hematologic or electrolyte abnormalities that were not clinically significant. Median PFS/OS were 3.5 (95% CI: 2.9-9.2)/13.2 mos (95% CI: 7.8 to not reached) respectively, with 2 yr OS rate of 37% (95% CI: 21-66%); there were no differences between treatment arms. As expected in the maximally debulked setting, no responses were observed by RECIST; however, decreases in FDG avidity and/or CA199 were observed in several long-term survivors. Better survival was associated with low baseline neutrophil to lymphocyte ratio, baseline lack of assessable disease by PET, and with expansion of dendritic cells following treatment. Compared to Met alone, Met + Rapa was associated with decreased mTOR activity on some immune cell subsets and decreased metabolic fitness, but this was not correlated with outcome. Conclusions: Met +/- rapa maintenance for mPDA was well-tolerated and several pts achieved stable disease associated with exceptionally long survival. Further prospective studies are needed to clarify the role of mTORi in the maintenance setting and to enhance pt selection for such approaches. Clinical trial information: NCT02048384.

IMPACT: Immunotherapy in patients with metastatic cancers and CDK12 mutations.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS5091-TPS5091 ◽  
Author(s):  
Melissa Andrea Reimers ◽  
Wassim Abida ◽  
Jonathan Chou ◽  
Daniel J. George ◽  
Elisabeth I. Heath ◽  
...  
Keyword(s):  
T Cell ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Histologic Diagnosis ◽  
Peripheral Blood Mononuclear ◽  
Diversity Assessment ◽  
Potential Biomarker

TPS5091 Background: Tumors with biallelic CDK12 loss have been identified as a distinct subtype in metastatic castration resistant prostate cancer (mCRPC) and other cancer types. The CDK12 biallelic loss mCRPC genomic signature, distinct from homologous recombination deficient (HRD) and ETS fusion signatures, is characterized by excessive tandem duplications, genomic instability, gene fusion-caused putative neoantigens, and increased tumor T cell infiltration. Early clinical experience with anti-PD-1 immunotherapy in CDK12 loss mCRPC patients (pts) is notable for deep and sustained PSA as well as radiographic responses. We hypothesize that CDK12 biallelic loss is a potential biomarker of immune checkpoint immunotherapy (ICI) efficacy in mCRPC and other cancers. Methods: IMPACT (NCT03570619) is a multi-center, open label, phase 2 study of pts with metastatic cancers that harbor CDK12 biallelic loss. mCRPC pts will be enrolled in cohort A (n = 25) in a Mini-Max Simon Two-Stage design, and all other pts in single-stage cohort B (n = 15). All pts will receive induction therapy with nivolumab 3 mg/kg IV and ipilimumab 1 mg/kg IV q3 weeks for up to 4 cycles, followed by maintenance nivolumab at 480 mg IV q4 weeks (up to 52 weeks in total). Eligible pts must have identified biallelic CDK12 loss on any CLIA/CAP approved next generation sequencing assay and a histologic diagnosis of metastatic prostate adenocarcinoma or other metastatic carcinoma. No prior ICI is allowed. The primary endpoint is the overall response rate (ORR) in cohort A per PCWG3 criteria. An ORR of 30% is targeted in cohort A. Secondary endpoints include safety, secondary efficacy measures, quality of life, and survival measures. Exploratory objectives include tumor whole exome analysis and changes in immune profiles with therapy. Comprehensive and serial monitoring of peripheral blood immune cell populations will be performed via T cell clonal diversity assessment and multi-parametric flow cytometry. Changes in myeloid and lymphoid populations will be assessed from whole blood. Polarization and effector function of T cells and activation of antigen presenting cells will be further characterized from isolated peripheral blood mononuclear cells. Study accrual is ongoing. Clinical trial information: NCT03570619.

scholarly journals Profiles of Peripheral Immune Cells of Uncomplicated COVID-19 Cases with Distinct Viral RNA Shedding Periods

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 514
Author(s):  
Denise Utami Putri ◽  
Cheng-Hui Wang ◽  
Po-Chun Tseng ◽  
Wen-Sen Lee ◽  
Fu-Lun Chen ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Cells ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Severe Disease ◽  
Viral Rna ◽  
Disease Course ◽  
Peripheral Blood Mononuclear ◽  
Peripheral Immune Cells ◽  
Cell Profile

The heterogeneity of immune response to COVID-19 has been reported to correlate with disease severity and prognosis. While so, how the immune response progress along the period of viral RNA-shedding (VRS), which determines the infectiousness of disease, is yet to be elucidated. We aim to exhaustively evaluate the peripheral immune cells to expose the interplay of the immune system in uncomplicated COVID-19 cases with different VRS periods and dynamic changes of the immune cell profile in the prolonged cases. We prospectively recruited four uncomplicated COVID-19 patients and four healthy controls (HCs) and evaluated the immune cell profile throughout the disease course. Peripheral blood mononuclear cells (PBMCs) were collected and submitted to a multi-panel flowcytometric assay. CD19+-B cells were upregulated, while CD4, CD8, and NK cells were downregulated in prolonged VRS patients. Additionally, the pro-inflammatory-Th1 population showed downregulation, followed by improvement along the disease course, while the immunoregulatory cells showed upregulation with subsequent decline. COVID-19 patients with longer VRS expressed an immune profile comparable to those with severe disease, although they remained clinically stable. Further studies of immune signature in a larger cohort are warranted.

scholarly journals Endogenous retrovirus-encoded Syncytin-2 contributes to exosome-mediated immunosuppression of T cells†

2019 ◽  
Author(s):  
Adjimon G Lokossou ◽  
Caroline Toudic ◽  
Phuong Trang Nguyen ◽  
Xavier Elisseeff ◽  
Amandine Vargas ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Map Kinases ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Endogenous Retrovirus ◽  
Jurkat Cells ◽  
Peripheral Blood Mononuclear ◽  
Interfering Rna

Abstract Modulation of the activation status of immune cell populations during pregnancy depends on placental villous cytotrophoblast (VCT) cells and the syncytiotrophoblast (STB). Failure in the establishment of this immunoregulatory function leads to pregnancy complications. Our laboratory has been studying Syncytin-2 (Syn-2), an endogenous retroviral protein expressed in placenta and on the surface of placental exosomes. This protein plays an important role not only in STB formation through its fusogenic properties, but also through its immunosuppressive domain (ISD). Considering that Syn-2 expression is importantly reduced in preeclamptic placentas, we were interested in addressing its possible immunoregulatory effects on T cells. Activated Jurkat T cells and peripheral blood mononuclear cells (PBMCs) were treated with monomeric or dimerized version of a control or a Syn-2 ISD peptide. Change in phosphorylation levels of ERK1/2 MAP kinases was selectively noted in Jurkat cells treated with the dimerized ISD peptide. Upon incubation with the dimerized Syn-2 ISD peptide, significant reduction in Th1 cytokine production was further demonstrated by ELISA and Human Th1/Th2 Panel Multi-Analyte Flow Assay. To determine if exosome-associated Syn-2 could also be immunosuppressive placental exosomes were incubated with activated Jurkat and PBMCs. Quantification of Th1 cytokines in the supernatants revealed severe reduction in T cell activation. Interestingly, exosomes from Syn-2-silenced VCT incubated with PBMCs were less suppressive when compared with exosome derived from VCT transfected with control small interfering RNA (siRNA). Our results suggest that Syn-2 is an important immune regulator both locally and systemically, via its association with placental exosomes.

scholarly journals Anticancer immunity induced by a synthetic tumor-targeted CD137 agonist

2021 ◽  
Vol 9 (1) ◽  
pp. e001762
Author(s):  
Punit Upadhyaya ◽  
Johanna Lahdenranta ◽  
Kristen Hurov ◽  
Sailaja Battula ◽  
Rachel Dods ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Tumor Antigens ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Human Peripheral Blood ◽  
Interleukin 2 ◽  
Cancer Therapeutics ◽  
Peripheral Blood Mononuclear ◽  
Tnf Superfamily

BackgroundIn contrast to immune checkpoint inhibitors, the use of antibodies as agonists of immune costimulatory receptors as cancer therapeutics has largely failed. We sought to address this problem using a new class of modular synthetic drugs, termed tumor-targeted immune cell agonists (TICAs), based on constrained bicyclic peptides (Bicycles).MethodsPhage libraries displaying Bicycles were panned for binders against tumor necrosis factor (TNF) superfamily receptors CD137 and OX40, and tumor antigens EphA2, Nectin-4 and programmed death ligand 1. The CD137 and OX40 Bicycles were chemically conjugated to tumor antigen Bicycles with different linkers and stoichiometric ratios of binders to obtain a library of low molecular weight TICAs (MW <8 kDa). The TICAs were evaluated in a suite of in vitro and in vivo assays to characterize their pharmacology and mechanism of action.ResultsLinking Bicycles against costimulatory receptors (e.g., CD137) to Bicycles against tumor antigens (e.g., EphA2) created potent agonists that activated the receptors selectively in the presence of tumor cells expressing these antigens. An EphA2/CD137 TICA (BCY12491) efficiently costimulated human peripheral blood mononuclear cells in vitro in the presence of EphA2 expressing tumor cell lines as measured by the increased secretion of interferon γ and interleukin-2. Treatment of C57/Bl6 mice transgenic for the human CD137 extracellular domain (huCD137) bearing EphA2-expressing MC38 tumors with BCY12491 resulted in the infiltration of CD8+ T cells, elimination of tumors and generation of immunological memory. BCY12491 was cleared quickly from the circulation (plasma t1/2 in mice of 1–2 hr), yet intermittent dosing proved effective.ConclusionTumor target-dependent CD137 agonism using a novel chemical approach (TICAs) afforded elimination of tumors with only intermittent dosing suggesting potential for a wide therapeutic index in humans. This work unlocks a new path to effective cancer immunotherapy via agonism of TNF superfamily receptors.

scholarly journals The effect of a short-term low-carbohydrate, high-fat diet with or without postmeal walks on glycemic control and inflammation in type 2 diabetes: a randomized trial

2018 ◽  
Vol 315 (6) ◽  
pp. R1210-R1219 ◽  
Author(s):  
Étienne Myette-Côté ◽  
Cody Durrer ◽  
Helena Neudorf ◽  
Tyler D. Bammert ◽  
José Diego Botezelli ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glycemic Control ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
High Fat ◽  
Peripheral Blood Mononuclear ◽  
Time Interaction ◽  
Low Carbohydrate

Lowering carbohydrate consumption effectively lowers glucose, but impacts on inflammation are unclear. The objectives of this study were to: 1) determine whether reducing hyperglycemia by following a low-carbohydrate, high-fat (LC) diet could lower markers of innate immune cell activation in type 2 diabetes (T2D) and 2) examine if the combination of an LC diet with strategically timed postmeal walking was superior to an LC diet alone. Participants with T2D ( n = 11) completed a randomized crossover study involving three 4-day diet interventions: 1) low-fat low-glycemic index (GL), 2) and 3) LC with 15-min postmeal walks (LC+Ex). Four-day mean glucose was significantly lower in the LC+Ex group as compared with LC (−5%, P < 0.05), whereas both LC+Ex (−16%, P < 0.001) and LC (−12%, P < 0.001) conditions were lower than GL. A significant main effect of time was observed for peripheral blood mononuclear cells phosphorylated c-Jun N-terminal kinase ( P < 0.001), with decreases in all three conditions (GL: −32%, LC: −45%, and LC+Ex: −44%). A significant condition by time interaction was observed for monocyte microparticles ( P = 0.040) with a significant decrease in GL (−76%, P = 0.035) and a tendency for a reduction in LC (−70%, P = 0.064), whereas there was no significant change in LC+Ex (0.5%, P = 0.990). Both LC (−27%, P = 0.001) and LC+Ex (−35%, P = 0.005) also led to significant reductions in circulating proinsulin. An LC diet improved 4-day glycemic control and fasting proinsulin levels when compared with GL, with added glucose-lowering benefits when LC was combined with postmeal walking.

scholarly journals Longitudinal high-dimensional analysis identifies biomarkers of response to anti-PD-1 immunotherapy

2021 ◽  
Author(s):  
Run-Ze Li ◽  
Xing-Xing Fan ◽  
Ze-Bo Jiang ◽  
Jumin Huang ◽  
Hu-Dan Pan ◽  
...  
Keyword(s):  
Clinical Response ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Response To Therapy ◽  
High Dimensional ◽  
Meso Scale Discovery ◽  
Peripheral Blood Mononuclear ◽  
Poor Outcomes ◽  
Nsclc Patients

Abstract The response to immunotherapy could be better predicted by using a wide set of biomarkers, including serum tumor markers; however, robust immune markers associated with efficacy have yet to be validated. In this study, changes in immune cell subsets from NSCLC patients treated with anti-PD1 therapy were longitudinally monitored by high-dimensional cytometry by time of flight (CyTOF) and Meso Scale Discovery (MSD) multi-cytokines kits. The frequencies of circulating CD8+ and CD8+CD101hiTIM3+ (CCT T) subsets were significantly correlated with clinical response and survival. Enrichment of these populations in peripheral blood mononuclear cells (PBMCs) indicated a poor clinical response to ICB therapy. Cell function assays revealed that these subsets were remarkably impaired, which supported the poor outcomes observed. Additionally, longitudinal analysis showed that KLRG1 expression and cytokines were associated with the response to therapy. Overall, our results provide novel potential biomarkers for guiding the management of NSCLC patients eligible to anti-PD-1 therapy, and contribute insights for new therapeutic strategies.

scholarly journals Acetate correlates with disability and immune response in multiple sclerosis

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e10220 ◽  
Author(s):  
Silvia Pérez-Pérez ◽  
María Inmaculada Domínguez-Mozo ◽  
Aitana Alonso-Gómez ◽  
Silvia Medina ◽  
Noelia Villarrubia ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Short Chain Fatty Acids ◽  
Liquid Chromatography Mass Spectrometry ◽  
Peripheral Blood Mononuclear ◽  
Healthy Donors ◽  
Disability Status

Background Gut microbiota has been related to multiple sclerosis (MS) etiopathogenesis. Short-chain fatty acids (SCFA) are compounds derived from microbial metabolism that have a role in gut-brain axis. Objectives To analyse SCFA levels in plasma of MS patients and healthy donors (HD), and the possible link between these levels and both clinical data and immune cell populations. Methods Ninety-five MS patients and 54 HD were recruited. Patients were selected according to their score in the Expanded Disability Status Scale (EDSS) (49 EDSS ≤ 1.5, 46 EDSS ≥ 5.0). SCFA were studied in plasma samples by liquid chromatography-mass spectrometry. Peripheral blood mononuclear cells were studied by flow cytometry. Gender, age, treatments, EDSS and Multiple Sclerosis Severity Score (MSSS) were evaluated at the recruitment. Results Plasma acetate levels were higher in patients than in HD (p = 0.003). Patients with EDSS ≥ 5.0 had higher acetate levels than those with EDSS≤ 1.5 (p = 0.029), and HD (p = 2.97e–4). Acetate levels correlated with EDSS (r = 0.387; p = 1.08e–4) and MSSS (r = 0.265; p = 0.011). In untreated MS patients, acetate levels correlated inversely with CD4+ naïve T cells (r =  − 0.550, p = 0.001) and directly with CD8+ IL-17+ cells (r = 0.557; p = 0.001). Conclusions Plasma acetate levels are higher in MS patients than in HD. In MS there exists a correlation between plasma acetate levels, EDSS and increased IL-17+ T cells. Future studies will elucidate the role of SCFA in the disease.

scholarly journals Molecular mechanisms governing circulating immune cell heterogeneity across different species revealed by single cell sequencing

2021 ◽  
Author(s):  
Zhibin Li ◽  
chengcheng Sun ◽  
Fei Wang ◽  
Xiran Wang ◽  
Jiacheng Zhu ◽  
...  
Keyword(s):  
Single Cell ◽  
Immune Cells ◽  
Evolutionary Biology ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Cell Types ◽  
Genetic Regulatory Networks ◽  
Peripheral Blood Mononuclear

Background: Immune cells play important roles in mediating immune response and host defense against invading pathogens. However, insights into the molecular mechanisms governing circulating immune cell diversity among multiple species are limited. Methods: In this study, we compared the single-cell transcriptomes of 77 957 immune cells from 12 species using single-cell RNA-sequencing (scRNA-seq). Distinct molecular profiles were characterized for different immune cell types, including T cells, B cells, natural killer cells, monocytes, and dendritic cells. Results: The results revealed the heterogeneity and compositions of circulating immune cells among 12 different species. Additionally, we explored the conserved and divergent cellular cross-talks and genetic regulatory networks among vertebrate immune cells. Notably, the ligand and receptor pair VIM-CD44 was highly conserved among the immune cells. Conclusions: This study is the first to provide a comprehensive analysis of the cross-species single-cell atlas for peripheral blood mononuclear cells (PBMCs). This research should advance our understanding of the cellular taxonomy and fundamental functions of PBMCs, with important implications in evolutionary biology, developmental biology, and immune system disorders

scholarly journals MicroRNA expression profiling of peripheral blood mononuclear cells associated with syphilis

2019 ◽  
Author(s):  
Tao Huang ◽  
Jun Zhang ◽  
Wujian Ke ◽  
Xiaohui Zhang ◽  
Wentao Chen ◽  
...  
Keyword(s):  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Treponema Pallidum ◽  
Target Sequence ◽  
Healthy Individuals ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

Abstract Background Treponema pallidum ( T. pallidum ) infection evokes significant immune responses, resulting in tissue damage. The immune mechanism underlying T. pallidum infection is still unclear, although microRNAs (miRNAs) have been shown to influence immune cell function and, consequently, the generation of antibody responses during other microbe infections. However, these mechanisms are unknown for T. pallidum . Methods In this study, we performed a comprehensive analysis of differentially expressed miRNAs in healthy individuals, untreated patients with syphilis, patients in the serofast state, and serologically cured patients. miRNAs were profiled from the peripheral blood of patients obtained at the time of serological diagnosis. Then, both the target sequence analysis of these different miRNAs and pathway analysis were performed to identify important immune and cell signaling pathways. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was performed for microRNA analysis. Results A total of 89 differentially regulated miRNAs were identified. Following RT-qPCR confirmation, three miRNAs (hsa-miR-195-5p, hsa-miR-223-3p, hsa-miR-589-3p) showed significant differences in the serofast and serologically cured states ( P <0.05). One miRNA (hsa-miR-195-5p) showed significant differences between untreated patients and healthy individuals. Conclusions This is the first study of miRNA expression differences in peripheral blood mononuclear cells (PBMCs) in different stages of T. pallium infection. Our study suggests that the combination of three miRNAs has great potential to serve as a non-invasive biomarker of T. pallium infections, which will facilitate better diagnosis and treatment of T. pallium infections.

scholarly journals Diagnosing Alzheimer’s Disease from Circulating Blood Leukocytes Using a Fluorescent Amyloid Probe

2021 ◽  
pp. 1-14
Author(s):  
Stefanie A.G. Black ◽  
Anastasiia A. Stepanchuk ◽  
George W. Templeton ◽  
Yda Hernandez ◽  
Tomoko Ota ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Misfolding ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Amyloid Β ◽  
Csf Biomarkers ◽  
Blood Leukocytes ◽  
Peripheral Blood Mononuclear ◽  
The Brain

Background: Toxic amyloid-β (Aβ) peptides aggregate into higher molecular weight assemblies and accumulate not only in the extracellular space, but also in the walls of blood vessels in the brain, increasing their permeability, and promoting immune cell migration and activation. Given the prominent role of the immune system, phagocytic blood cells may contact pathological brain materials. Objective: To develop a novel method for early Alzheimer’s disease (AD) detection, we used blood leukocytes, that could act as “sentinels” after trafficking through the brain microvasculature, to detect pathological amyloid by labelling with a conformationally-sensitive fluorescent amyloid probe and imaging with confocal spectral microscopy. Methods: Formalin-fixed peripheral blood mononuclear cells (PBMCs) from cognitively healthy control (HC) subjects, mild cognitive impairment (MCI) and AD patients were stained with the fluorescent amyloid probe K114, and imaged. Results were validated against cerebrospinal fluid (CSF) biomarkers and clinical diagnosis. Results: K114-labeled leukocytes exhibited distinctive fluorescent spectral signatures in MCI/AD subjects. Comparing subjects with single CSF biomarker-positive AD/MCI to negative controls, our technique yielded modest AUCs, which improved to the 0.90 range when only MCI subjects were included in order to measure performance in an early disease state. Combining CSF Aβ 42 and t-Tau metrics further improved the AUC to 0.93. Conclusion: Our method holds promise for sensitive detection of AD-related protein misfolding in circulating leukocytes, particularly in the early stages of disease.

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