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.

Project description:Autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination is a promising immunotherapy for patients with high grade gliomas, but responses have not been demonstrated in all patients. Pre-clinical studies demonstrate that toll-like receptor (TLR) agonists can enhance the anti-tumor immune response from cancer vaccines. To determine the most effective combination of autologous tumor lysate-pulsed DC vaccination, with or without the adjuvant toll-like receptor (TLR) agonists poly-ICLC or resiquimod, we conducted a randomized, open-label multi-arm Phase 2 clinical trial to evaluate immune responses and survival in 23 patients with newly diagnosed or recurrent WHO Grade III-IV malignant gliomas. Patients were randomized to receive ATL-DC vaccination with either a placebo, a TLR-7/8 agonist (resiquimod, topical 0.2%), or a TLR-3 agonist (poly-ICLC, 20 mcg/kg intramuscular). Peripheral blood was obtained at baseline and following the vaccination cycle for immune monitoring. Mass cytometry, bulk and single-cell RNA sequencing analyses were performed. Analysis of the bulk RNAseq data (pre-treatment vs. post-treatment) demonstrated highly significant upregulation of type 1 and type 2 interferon gene expression selectively in patients who received adjuvant TLR agonist (either poly-ICLC or resiquimod) together with ATL-DC. CyTOF analysis of patient peripheral blood mononuclear cells (PBMCs) showed increased levels of memory PD-1+ T-cell and monocyte populations after ATL-DC + TLR agonist administration. In addition, scRNA-seq demonstrated a higher expression fold change of IFN-induced genes with poly-ICLC treatment in both peripheral blood monocytes and T lymphocytes. Median progression-free survival (PFS) was 8.1 months (5.5 placebo vs. 8.1 resiquimod vs. 31.4 poly-ICLC), and median overall survival (OS) was 26.6 months (7.7 placebo vs. 16.7 resiquimod vs. 52.5 poly-ICLC). Patients who had higher expression of interferon response genes lived significantly longer and had longer time to progression compared to those with lower expression. The results suggest that ATL-DC in conjunction with adjuvant poly-ICLCTL induces a polarized interferon response in circulating monocytes and specific activation of a CD8+ T cell population. This combination was associated with extended survival in this patient population. This interferon response signature may represent an important blood biomarker for immunotherapy in patients with malignant glioma.

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DC immunotherapy in HIV-1 infection induces a major blood transcriptome shift

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