Elucidating immunologic mechanisms of PROSTVAC cancer immunotherapy

BACKGROUND: PROSTVAC®, an active immunotherapy currently studied for the treatment of metastatic castration-resistant prostate cancer (mCRPC), consists of a heterologous prime-boost regimen with two different poxvirus-based vectors to provoke productive immune responses against prostate specific antigen (PSA) as the target tumor antigen. A Phase 2 study of PROSTVAC immunotherapy showed significantly improved median overall survival by 8.5 months and is currently being validated in a global Phase 3 study (PROSPECT; NCT01322490). Here, preclinical models were explored to investigate the mechanism of action and immune signatures of anti-tumor efficacy with PROSTVAC immunotherapy with the goal to identify potential immune correlates of clinical benefit. METHODS: PROSTVAC-induced immune responses and anti-tumor efficacy were studied in male BALB/c mice. Functionality of the induced T cell response was characterized by interferon-gamma (IFNγ) ELISPOT, cytotoxic degranulation, multi-cytokine intracellular staining, and in vivo T cell depletion. Tumor infiltrating lymphocytes (TILs) were evaluated phenotypically by flow cytometry. RESULTS: The heterologous prime-boost regimen of the two PROSTVAC vectors significantly enhanced the magnitude and quality of activated PSA-specific CD4 and CD8 T cell responses compared to homologous, single vector regimens. PROSTVAC-activated CD4 and CD8 T cells were highly functional as evidenced by expression of activation markers, production of multiple cytokines, and amplified cytotoxic T cell activity. Importantly, PROSTVAC immunotherapy resulted in significant anti-tumor efficacy in a transplantable prostate cancer mouse model. Antigen-spreading occurred in PROSTVAC-treated animals that rejected PSA-expressing tumors, as shown by subsequent rejection of PSA-negative tumors. In vivo CD4 and CD8 depletion revealed that both T cell subsets contributed to anti-tumor efficacy. Characterization of TILs demonstrated that PROSTVAC immunotherapy greatly increased the intra-tumoral ratio of activated effector to regulatory T cells. CONCLUSIONS: PROSTVAC immunotherapy activates broad, highly functional T cell immunity to PSA and to endogenous tumor antigens via immune-mediated antigen spreading. These preclinical results further elucidate the mode of action of PROSTVAC immunotherapy and its potential causal relationship to extended overall survival as observed in the PROSTVAC Phase 2 study. The clinical validation is ongoing in the PROSPECT Phase 3 clinical study. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40425-014-0034-0) contains supplementary material, which is available to authorized users

Young Stars and Protostellar Cores near NGC 2023

We investigate the young (proto)stellar population in NGC 2023 and the L 1630 molecular cloud bordering the HII region IC 434, using Spitzer IRAC and MIPS archive data, JCMT SCUBA imaging and spectroscopy as well as targeted BIMA observations of one of the Class 0 protostars, NGC 2023 MM1. We have performed photometry of all IRAC and MIPS images, and used color-color diagrams to identify and classify all young stars seen within a 22'x26' field along the boundary between IC 434 and L 1630. For some stars, which have sufficient optical, IR, and/or sub-millimeter data we have also used the online SED fitting tool for a large 2D archive of axisymmetric radiative transfer models to perform more detailed modeling of the observed SEDs. We identify 5 sub-millimeter cores in our 850 and 450 micron SCUBA images, two of which have embedded class 0 or I protostars. Observations with BIMA are used to refine the position and characteristics of the Class 0 source NGC 2023 MM 1. These observations show that it is embedded in a very cold cloud core, which is strongly enhanced in NH2D. We find that HD 37903 is the most massive member of a cluster with 20 -- 30 PMS stars. We also find smaller groups of PMS stars formed from the Horsehead nebula and another elephant trunk structure to the north of the Horsehead. We refine the spectral classification of HD 37903 to B2 Ve. Our study shows that the expansion of the IC 434 HII region has triggered star formation in some of the dense elephant trunk structures and compressed gas inside the L 1630 molecular cloud. This pre-shock region is seen as a sub-millimeter ridge in which stars have already formed. The cluster associated with NGC 2023 is very young, and has a large fraction of Class I sources.Comment: 21 pages, 11 figures. Accepted for publication in A&A Replaced with higher resolution figure

A Study of the Residual 39Ar Content in Argon from Underground Sources

The discovery of argon from underground sources with significantly less 39Ar than atmospheric argon was an important step in the development of direct-detection dark matter experiments using argon as the active target. We report on the design and operation of a low background detector with a single phase liquid argon target that was built to study the 39Ar content of the underground argon. Underground argon from the Kinder Morgan CO2 plant in Cortez, Colorado was determined to have less than 0.65% of the 39Ar activity in atmospheric argon.Comment: 21 pages, 10 figure

New experimental limits on the Pauli forbidden transitions in 12^{12}C nuclei obtained with 485 days Borexino data

The Pauli exclusion principle (PEP) has been tested for nucleons ($n,p$) in $^{12}C$ with the Borexino detector.The approach consists of a search for $\gamma$, $n$, $p$ and $\beta^\pm$ emitted in a non-Paulian transition of 1$P_{3/2}$- shell nucleons to the filled 1$S_{1/2}$ shell in nuclei. Due to the extremely low background and the large mass (278 t) of the Borexino detector, the following most stringent up-to-date experimental bounds on PEP violating transitions of nucleons have been established: $\tau({^{12}\rm{C}}\to{^{12}\widetilde{\rm{C}}}+\gamma) \geq 5.0\cdot10^{31}$ y, $\tau({^{12}\rm{C}}\to{^{11}\widetilde{\rm{B}}}+ p) \geq 8.9\cdot10^{29}$ y, $\tau({^{12}\rm{C}}\to{^{11}\widetilde{\rm{C}}}+ n) \geq 3.4 \cdot 10^{30}$ y, $\tau({^{12}\rm{C}}\to{^{12}\widetilde{\rm{N}}}+ e^- + \widetilde{\nu_e}) \geq 3.1\cdot 10^{30}$ y and $\tau({^{12}\rm{C}}\to{^{12}\widetilde{\rm{B}}}+ e^+ + \nu_e) \geq 2.1 \cdot 10^{30}$ y, all at 90% C.L. The corresponding upper limits on the relative strengths for the searched non-Paulian electromagnetic, strong and weak transitions have been estimated: $\delta^2_{\gamma} \leq 2.2\cdot10^{-57}$, $\delta^2_{N} \leq 4.1\cdot10^{-60}$ and $\delta^2_{\beta} \leq 2.1\cdot10^{-35}$.Comment: 9 pages, 6 figure

Muon and Cosmogenic Neutron Detection in Borexino

Borexino, a liquid scintillator detector at LNGS, is designed for the detection of neutrinos and antineutrinos from the Sun, supernovae, nuclear reactors, and the Earth. The feeble nature of these signals requires a strong suppression of backgrounds below a few MeV. Very low intrinsic radiogenic contamination of all detector components needs to be accompanied by the efficient identification of muons and of muon-induced backgrounds. Muons produce unstable nuclei by spallation processes along their trajectory through the detector whose decays can mimic the expected signals; for isotopes with half-lives longer than a few seconds, the dead time induced by a muon-related veto becomes unacceptably long, unless its application can be restricted to a sub-volume along the muon track. Consequently, not only the identification of muons with very high efficiency but also a precise reconstruction of their tracks is of primary importance for the physics program of the experiment. The Borexino inner detector is surrounded by an outer water-Cherenkov detector that plays a fundamental role in accomplishing this task. The detector design principles and their implementation are described. The strategies adopted to identify muons are reviewed and their efficiency is evaluated. The overall muon veto efficiency is found to be 99.992% or better. Ad-hoc track reconstruction algorithms developed are presented. Their performance is tested against muon events of known direction such as those from the CNGS neutrino beam, test tracks available from a dedicated External Muon Tracker and cosmic muons whose angular distribution reflects the local overburden profile. The achieved angular resolution is 3-5 deg and the lateral resolution is 35-50 cm, depending on the impact parameter of the crossing muon. The methods implemented to efficiently tag cosmogenic neutrons are also presented.Comment: 42 pages. 32 figures on 37 files. Uses JINST.cls. 1 auxiliary file (defines.tex) with TEX macros. submitted to Journal of Instrumentatio

Borexino calibrations: Hardware, Methods, and Results

Borexino was the first experiment to detect solar neutrinos in real-time in the sub-MeV region. In order to achieve high precision in the determination of neutrino rates, the detector design includes an internal and an external calibration system. This paper describes both calibration systems and the calibration campaigns that were carried out in the period between 2008 and 2011. We discuss some of the results and show that the calibration procedures preserved the radiopurity of the scintillator. The calibrations provided a detailed understanding of the detector response and led to a significant reduction of the systematic uncertainties in the Borexino measurements