Safety and immunogenicity of novel 5T4 viral vectored vaccination regimens in early stage prostate cancer: a phase I clinical trial.

Prostate cancer (PCa) has been under investigation as a target for antigen-specific immunotherapies in metastatic disease settings for the last two decades leading to a licensure of the first therapeutic cancer vaccine, Sipuleucel-T, in 2010. However, neither Sipuleucel-T nor other experimental PCa vaccines that emerged later induce strong T-cell immunity. In this first-in-man study, VANCE, we evaluated a novel vaccination platform based on two replication-deficient viruses, chimpanzee adenovirus (ChAd) and MVA (Modified Vaccinia Ankara), targeting the oncofetal self-antigen 5T4 in early stage PCa. Forty patients, either newly diagnosed with early-stage PCa and scheduled for radical prostatectomy or patients with stable disease on an active surveillance protocol, were recruited to the study to assess the vaccine safety and T-cell immunogenicity. Secondary and exploratory endpoints included immune infiltration into the prostate, prostate-specific antigen (PSA) change, and assessment of phenotype and functionality of antigen-specific T cells. The vaccine had an excellent safety profile. Vaccination-induced 5T4-specific T-cell responses were measured in blood by ex vivo IFN-γ ELISpot and were detected in the majority of patients with a mean level in responders of 198 spot-forming cells per million peripheral blood mononuclear cells. Flow cytometry analysis demonstrated the presence of both CD8+ and CD4+ polyfunctional 5T4-specific T cells in the circulation. 5T4-reactive tumor-infiltrating lymphocytes were isolated from post-treatment prostate tissue. Some of the patients had a transient PSA rise 2-8 weeks following vaccination, possibly indicating an inflammatory response in the target organ. An excellent safety profile and T-cell responses elicited in the circulation and also detected in the prostate gland support the evaluation of the ChAdOx1-MVA 5T4 vaccine in efficacy trials. It remains to be seen if this vaccination strategy generates immune responses of sufficient magnitude to mediate clinical efficacy and whether it can be effective in late-stage PCa settings, as a monotherapy in advanced disease or as part of multi-modality PCa therapy. To address these questions, the phase I/II trial, ADVANCE, is currently recruiting patients with intermediate-risk PCa, and patients with advanced metastatic castration-resistant PCa, to receive this vaccine in combination with nivolumab. The trial was registered with the U.S. National Institutes of Health (NIH) Clinical Trials Registry (ClinicalTrials.gov identifier NCT02390063)

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Constraints on mantle plumes from the helium isotopic composition of basalts from the British Tertiary Igneous Province

Helium isotopes have been measured in olivines from igneous rocks spanning the history of the Palaeocene volcanic centre at the Isle of Skye, northwest of Scotland. He-3/He-4 in olivine phenocrysts from basalts from the Skye Lava Field are up to 22 times the atmospheric ratio which is consistent with their origin from the proto-Iceland mantle plume despite being erupted 1300 km from the plume axis. The He-3-anomaly of the Palaeocene starting plume in the North Atlantic appears to have been up to three times greater, for the same distance from the plume axis, than the modern Iceland plume. The Pb isotope and trace element (Delta Nb) composition of the least crustally contaminated Skye magmas resemble North Atlantic MORB rather than Iceland basalts. The proto-Iceland plume head appears to have been dominated by upper mantle material with a small deep mantle He contribution rather than undiluted deep mantle material as predicted in the classic plume model

Reconciling and improving formulations for thermodynamics and conservation principles in Earth System Models (ESMs)

International audienceThis paper provides a comprehensive derivation of the total energy equations for the atmospheric components of Earth system models (ESMs). The assumptions and approximations made in this derivation are motivated and discussed. In particular, it is emphasized that closing the energy budget is conceptually challenging and hard to achieve in practice without resorting to ad hoc fixers. As a concrete example, the energy budget terms are diagnosed in a realistic climate simulation using a global atmosphere model. The largest total energy errors in this example are spurious dynamical core energy dissipation, thermodynamic inconsistencies (e.g. coupling parameterizations with the host model) and missing processes/terms associated with falling precipitation and evaporation (e.g. enthalpy flux between components). The latter two errors are not, in general, reduced by increasing horizontal resolution. They are due to incomplete thermodynamic and dynamic formulations. Future research directions are proposed to reconcile and improve thermodynamics formulations and conservation principles