Safety and Toxicity of Catheter Gene Delivery to the Pulmonary Vasculature in a Patient with Metastatic Melanoma

Overview summary Transcatheter delivery of HLA-B7 DNA and cationic liposomes into a segment of a pulmonary artery was safely performed in 1 patient with tumor nodules in the lung. No immunologic or organ toxicities were observed. Percutaneous catheter gene delivery has been performed in humans. Further refinements of this approach may lead to useful treatments for a variety of human diseases.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63196/1/hum.1994.5.9-1089.pd

Multi-stakeholder consensus on a target product profile for an HIV cure

Developing a cure for HIV is a global priority. Target product profiles are a tool commonly used throughout the drug development process to align interested parties around a clear set of goals or requirements for a potential product. Three distinct therapeutic modalities (combination therapies, ex-vivo gene therapy, and in-vivo gene therapy) for a target product profile for an HIV cure were identified. Using a process of expert face-to-face consultation and an online Delphi consultation, we found a high degree of agreement regarding the criteria for the optimum target product profile. Although the minimum attributes for a cure were debated, the broad consensus was that an acceptable cure need not be as safe and effective as optimally delivered antiretroviral therapy. An intervention that successfully cured a reasonable fraction of adults would be sufficient to advance to the clinic. These target product profiles will require further discussion and ongoing revisions as the field matures

Trispecific antibody targeting HIV-1 and T cells activates and eliminates latently-infected cells in HIV/SHIV infections.

Agents that can simultaneously activate latent HIV, increase immune activation and enhance the killing of latently-infected cells represent promising approaches for HIV cure. Here, we develop and evaluate a trispecific antibody (Ab), N6/αCD3-αCD28, that targets three independent proteins: (1) the HIV envelope via the broadly reactive CD4-binding site Ab, N6; (2) the T cell antigen CD3; and (3) the co-stimulatory molecule CD28. We find that the trispecific significantly increases antigen-specific T-cell activation and cytokine release in both CD4 <sup>+</sup> and CD8 <sup>+</sup> T cells. Co-culturing CD4 <sup>+</sup> with autologous CD8 <sup>+</sup> T cells from ART-suppressed HIV <sup>+</sup> donors with N6/αCD3-αCD28, results in activation of latently-infected cells and their elimination by activated CD8 <sup>+</sup> T cells. This trispecific antibody mediates CD4 <sup>+</sup> and CD8 <sup>+</sup> T-cell activation in non-human primates and is well tolerated in vivo. This HIV-directed antibody therefore merits further development as a potential intervention for the eradication of latent HIV infection

Transcriptional profiles reveal a stepwise developmental program of memory CD8(+) T cell differentiation.

The generation of CD8(+) T-cell memory is a major aim of vaccination. While distinct subsets of CD8(+) T-cells are generated following immunization that differ in their ability to confer long-term immunity against infection, the transcriptional profiles of these subsets within endogenous vaccine-induced CD8(+) T cell responses have not been resolved. Here, we measure global transcriptional profiles of endogenous effector (TEFF), effector memory (TEM) and central memory (TCM) CD8(+) T-cells arising from immunization with three distinct prime-boost vaccine regimens. While a proportion of transcripts were uniquely regulated within distinct CD8(+) T cell populations, we observed progressive up- or down-regulation in the expression of a majority of differentially expressed transcripts when subsets were compared in the order TN>TCM>TEM>TEFF. Strikingly, when we compared global differences in gene expression between TN, TCM, TEM and TEFF cells with known transcriptional changes that result when CD8(+) T cells repetitively encounter antigen, our analysis overwhelmingly favored a model whereby cumulative antigen stimulation drives differentiation specifically from TN>TCM>TEM>TEFF and this was common to all vaccines tested. These findings provide insight into the molecular basis of immunological memory and identify potential biomarkers for characterization of vaccine-induced responses and prediction of vaccine efficacy

First scientific review article on multi-gas GHG budgets : Delivarable D5.9

European anthropogenic AFOLU greenhouse gas emissions: a review and benchmark data (Petrescu et al, 2020, published in ESSD)Emission of greenhouse gases (GHGs) and removals from land, including both anthropogenic and natural fluxes, require reliable quantification, including estimates of uncertainties, to support credible mitigation action under the Paris Agreement. This study provides a state-of-the-art scientific overview of bottom-up anthropogenic emissions data from agriculture, forestry and other land use (AFOLU) in the European Union (EU281). The data integrates recent AFOLU emission inventories with ecosystem data and land carbon models and summarizes GHG emissions and removals over the period 1990-2016. This compilation of bottom-up estimates of the AFOLU GHG emissions of European national greenhouse gas inventories (NGHGI) with those of land carbon models and observation-based estimates of large-scale GHG fluxes, aims at improving the overall estimates of the GHG balance in Europe with respect to land GHG emissions and removals. Whenever available, we present uncertainties, its propagation and role in the comparison of different estimates. While NGHGI data for EU28 provides consistent quantification of uncertainty following the established IPCC guidelines, uncertainty in the estimates produced with other methods needs to account for both within model uncertainty and the spread from different model results. The largest inconsistencies between EU28 estimates are mainly due to different sources of data related to human activity, referred here as activity data (AD) and methodologies (Tiers) used for calculating emissions and removals from AFOLU sectors. The referenced datasets related to figures are visualised at http://doi.org/doi:10.5281/zenodo.3662371 (Petrescu et al., 2020)