31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

The Power Board of the KM3NeT Digital Optical Module: Design, Upgrade, and Production

The KM3NeT Collaboration is building an underwater neutrino observatory at the bottom of the Mediterranean Sea, consisting of two neutrino telescopes, both composed of a three-dimensional array of light detectors, known as digital optical modules. Each digital optical module contains a set of 31 three-inch photomultiplier tubes distributed over the surface of a 0.44 m diameter pressure- resistant glass sphere. The module also includes calibration instruments and electronics for power, readout, and data acquisition. The power board was developed to supply power to all the elements of the digital optical module. The design of the power board began in 2013, and ten prototypes were produced and tested. After an exhaustive validation process in various laboratories within the KM3NeT Collaboration, a mass production batch began, resulting in the construction of over 1200 power boards so far. These boards were integrated in the digital optical modules that have already been produced and deployed, which total 828 as of October 2023. In 2017, an upgrade of the power board, to increase reliability and efficiency, was initiated. The validation of a pre-production series has been completed, and a production batch of 800 upgraded boards is currently underway. This paper describes the design, architecture, upgrade, validation, and production of the power board, including the reliability studies and tests conducted to ensure safe operation at the bottom of the Mediterranean Sea throughout the observatory’s lifespan

KM3NeT/ARCA sensitivity to transient neutrino sources

The KM3NeT Collaboration is constructing a km3-volume neutrino telescope in the Mediterranean sea, ARCA (Astroparticle Research with Cosmics in the Abyss), for the detection and subsequent study of high-energy cosmic neutrinos.This telescope will be able to reconstruct the arrival direction of the neutrinos with a precision of ~0.1 degrees. The configuration of ARCA makes it sensitive to neutrinos in a wide energy range, from sub-TeV up to tens of PeV. Moreover, this detector has a large field of view and a very high duty cycle, allowing a full-sky (and all-flavours) searches. All these features make ARCA an excellent candidate to study transient neutrino sources. Atmospheric muons and neutrinos, produced by primary cosmic rays, constitute the main background for ARCA. This background can be several orders of magnitude higher than the expected cosmic neutrino flux. In this work, we introduce an event selection which reduces the background up to a negligible level inside the region of interest and within the search time window. The ARCA performance to detect a transient neutrino flux, including the effective area, sensitivity and discovery potential, are provided for a given test source, and for different time windows

Indirect dark matter searches with neutrinos from the Galactic Centre region with the ANTARES and KM3NeT telescopes

An anomalous flux of neutrinos produced in hypothetical annihilations or decays of dark matter inside a source would produce a signal observable with neutrino telescopes. As suggested by observations, a conspicuous amount of dark matter is believed to accumulate in the centre of our Galaxy, which is in neat visibility for the Mediterranean underwater telescopes ANTARES and KM3NeT. Searches have been conducted with a maximum likelihood method to identify the presence of a dark matter signature in the neutrino flux measured by ANTARES. Results of all-flavour searches for WIMPs with masses from 50 GeV/c2 up to 100 TeV/c2 over the whole operation period from 2007 to 2020 are presented here. Alternative scenarios which propose a dark matter candidate in the heavy sector extensions of the Standard Model would produce a clear signature in the ANTARES telescope, that can exploit its view of the Galactic Centre up to high energies. The presentation of Galactic Centre searches is completed with ongoing analyses and future potential of the KM3NeT telescope, in phased construction in the Mediterranean Sea

Search for nuclearites with the KM3NeT detector

Strange quark matter (SQM) is a hypothetical type of matter composed of almost equal quantities of up, down and strange quarks. In [1], Edward Witten presented the SQM as a denser and more stable matter that could represent the ground state of Quantum Chromodynamics (QCD). Massive SQM particles are called nuclearites. These particles could have been produced in violent astrophysical processes, such as neutron star collisions and could be present in the cosmic radiation. Nuclearites with masses greater than 1013 GeV and velocities of about 250 km/s (typical galactic velocities) could reach the Earth and interact with atoms and molecules of sea water within the sensitive volume of the deep-sea neutrino telescopes. The SQM particles can be detected with the KM3NeT telescope (whose first lines are already installed and taking data in the Mediterranean Sea) through the visible blackbody radiation generated along their path inside or near the instrumented area. In this work the results of a study using Monte Carlo simulations of down-going nuclearites are discussed