Gene expression of PBMC and isolated CD4 T cells from participants in Part A REDUC clinical trial
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE185027 | GEO | 2022/03/28
REPOSITORIES: GEO
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Project description:The BCN02 (NCT02616874) was a pilot study to evaluate the kick and kill therapy on 15 early-treated individuals that were rolled-over from the BCN01 Study. The participants in the study received two MVA.HIVconsv vaccination before and after the 3-cycle infusion of Romidepsin, an inhibitor of histone deacetylases that act as a latency reversing agent. Additionally, the inclusion of a monitored antiretroviral pause (MAP) allowed tthe identification of 8 individuals with an Early Rebound (pVL > 2,000 HIV RNA copies/mL, < 4 weeks of MAP initiation) and 4, with a Late Rebound (pVL > 2,000 HIV RNA copies/mL, > 4 weeks of MAP initiation). In the present study we studied gene expression at 3 different timepoints: w0 (Bsl), w1 (Vacc), w6 (Vacc+RMD) and applied pairwise comparisons.
2022-03-28 | GSE184653 | GEO
Project description:BCN02 was an exploratory, single arm study designed to evaluate a kick-and-kill therapeutic vaccine strategy in early-treated HIV infected individuals. The participants in the study received a MVA.HIVconsv vaccination before and after three cycles of infusion of romidepsin (RMD), an inhibitor of histone deacetylases that acts as a viral latency reversing agent. The inclusion of a monitored antiretroviral pause (MAP) identified 8 individuals with an early viral rebound (pVL > 2,000 HIV RNA copies/mL, < 4 weeks of MAP initiation) and 4, with a late viral rebound (pVL > 2,000 HIV RNA copies/mL, > 4 weeks of MAP initiation). In the present study, a systems biology analysis was conducted to identify the pathways modulated at transcriptomic and epigenetic level during the clinical intervention, involving vaccination and RMD, and to identify biomarkers predictive of HIV viral rebound during MAP. To this end, we studied gene expression and whole-genome DNA methylation in longitudinal PBMC samples prior and after the intervention. The main impact on host transcriptional and epigenetic signatures was observed after vaccination and RMD infusion (Vacc+RMD) with multiple pathways related to HIV infection and immune response showing changes at gene expression and DNA methylation level. Analysis of an independent cohort of individuals treated with RMD alone, showed that these changes were mainly driven by CD4 T cells. DNA methylation patterns in full PBMC obtained after full intervention (Vacc+RMD) allowed to discriminate individuals with an Early versus Late viral rebound. These individuals also showed a differential enrichment on chromatin accessibility and transcription factor binding sites. Intriguingly, 30 of the DMPs between Early and Late rebounders at Vacc+RMD were present already at baseline and were more accentuated after RMD infusion. Overall, this study provides with a deeper understanding of the mechanisms modulated during the BCN02 study and highlights the importance of DNA methylation profiles in HIV cure.
2022-03-28 | GSE185389 | GEO
Project description:BCN02 was an exploratory, single arm study designed to evaluate a kick-and-kill therapeutic vaccine strategy in early-treated HIV infected individuals. The participants in the study received a MVA.HIVconsv vaccination before and after three cycles of infusion of romidepsin (RMD), an inhibitor of histone deacetylases that acts as a viral latency reversing agent. The inclusion of a monitored antiretroviral pause (MAP) identified 8 individuals with an early viral rebound (pVL > 2,000 HIV RNA copies/mL, < 4 weeks of MAP initiation) and 4, with a late viral rebound (pVL > 2,000 HIV RNA copies/mL, > 4 weeks of MAP initiation). In the present study, a systems biology analysis was conducted to identify the pathways modulated at transcriptomic and epigenetic level during the clinical intervention, involving vaccination and RMD, and to identify biomarkers predictive of HIV viral rebound during MAP. To this end, we studied gene expression and whole-genome DNA methylation in longitudinal PBMC samples prior and after the intervention. The main impact on host transcriptional and epigenetic signatures was observed after vaccination and RMD infusion (Vacc+RMD) with multiple pathways related to HIV infection and immune response showing changes at gene expression and DNA methylation level. Analysis of an independent cohort of individuals treated with RMD alone, showed that these changes were mainly driven by CD4 T cells. DNA methylation patterns in full PBMC obtained after full intervention (Vacc+RMD) allowed to discriminate individuals with an Early versus Late viral rebound. These individuals also showed a differential enrichment on chromatin accessibility and transcription factor binding sites. Intriguingly, 30 of the DMPs between Early and Late rebounders at Vacc+RMD were present already at baseline and were more accentuated after RMD infusion. Overall, this study provides with a deeper understanding of the mechanisms modulated during the BCN02 study and highlights the importance of DNA methylation profiles in HIV cure.
2022-03-28 | GSE185390 | GEO
Project description:Microarray analysis of total RNA isolated from samples of circulating tumor cells from 7 patients before romidepsin infusion (0 hours), at 4 h after initiation of the infusion (4 hours) and 24 h after initiation of the infusion (24 hours). MAPK pathway related genes were selected to see differences between patient blood samples after roomidepsin treatment at 0 hour, 4 hour and 24 hour.
2013-06-03 | E-GEOD-45405 | biostudies-arrayexpress
Project description:Microarray analysis of total RNA isolated from samples of circulating tumor cells from 7 patients before romidepsin infusion (0 hours), at 4 h after initiation of the infusion (4 hours) and 24 h after initiation of the infusion (24 hours).
2013-06-03 | GSE45405 | GEO
Project description:Gene expression of PBMC and isolated CD4 T cells from participants in Part A REDUC clinical trial
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Project description:PBMC Gene expression of participants in the kick and kill clinical trial BCN02
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Project description:Phase I Safety, Pharmacokinetic and Pharmacogenomic Trial of ES-285, a Novel Marine Cytotoxic Agent Administered as an Infusion over 24 h Every 21 Days in Patients with Solid Tumors Purpose: A dose-escalation, phase I study evaluated the safety, pharmacokinetics, pharmacogenomics and efficacy of ES-285, a novel agent isolated from a marine mollusc, in adult cancer patients. Experimental design: Patients received a 24-hour i.v. infusion of ES-285 once every 3 weeks until disease progression or unacceptable toxicity. The starting dose was 4mg/m2. Dose escalation proceeded according to the worst toxicity observed in the previous cohort. Results: 28 patients were treated with 72 courses of ES-285 across 8 dose levels. No doselimiting toxicities (DLTs) were seen between 4mg/m2 and 128mg/m2. Two out of 4 patients treated at 256mg/m2 had dose-limiting reversible grade 3 transaminitis; one patient at 256mg/m2 also had transient grade 3 central neurotoxicity. One of 3 patients subsequently treated at 200mg/m2 died following drug-related central neurotoxicity. Pharmacokinetic studies indicated dose-proportionality with high volume of distribution (median Vss at 256mg/m2 was 2389L, range 1615-4051L) and long elimination half life (median t1/2 at 256mg/m2 was 29h, range 21-32h). The 3 patients with DLT had the highest drug exposure. Pharmacogenomic studies of paired surrogate tissue samples identified changes in gene expression following treatment that correlated with increasing dose. Pre-treatment 59- and 49-gene sets were identified in blood and skin respectively, that may predict DLT. Disease stabilisation for 6 to 18 weeks was recorded in 9 patients. Conclusion: Using this schedule, 128 mg/m2 was considered safe and feasible. At this dose, pharmacologically relevant concentrations of drug were safely achieved with pharmacogenomic studies indicating changes in the expression of genes of potential biological relevance. Keywords: dose response
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