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

BeiDou Augmented Navigation from Low Earth Orbit Satellites

Currently, the Global Navigation Satellite System (GNSS) mainly uses the satellites in Medium Earth Orbit (MEO) to provide position, navigation, and timing (PNT) service. The weak navigation signals limit its usage in deep attenuation environments, and make it easy to interference and counterfeit by jammers or spoofers. Moreover, being far away to the Earth results in relatively slow motion of the satellites in the sky and geometric change, making long time needed for achieved centimeter positioning accuracy. By using the satellites in Lower Earth Orbit (LEO) as the navigation satellites, these disadvantages can be addressed. In this contribution, the advantages of navigation from LEO constellation has been investigated and analyzed theoretically. The space segment of global Chinese BeiDou Navigation Satellite System consisting of three GEO, three IGSO, and 24 MEO satellites has been simulated with a LEO constellation with 120 satellites in 10 orbit planes with inclination of 55 degrees in a nearly circular orbit (eccentricity about 0.000001) at an approximate altitude of 975 km. With simulated data, the performance of LEO constellation to augment the global Chinese BeiDou Navigation Satellite System (BeiDou-3) has been assessed, as one of the example to show the promising of using LEO as navigation system. The results demonstrate that the satellite visibility and position dilution of precision have been significantly improved, particularly in mid-latitude region of Asia-Pacific region, once the LEO data were combined with BeiDou-3 for navigation. Most importantly, the convergence time for Precise Point Positioning (PPP) can be shorted from about 30 min to 1 min, which is essential and promising for real-time PPP application. Considering there are a plenty of commercial LEO communication constellation with hundreds or thousands of satellites, navigation from LEO will be an economic and promising way to change the heavily relay on GNSS systems

Analysis on BDS-3 Autonomous Navigation Performance Based on the LEO Constellation and Regional Stations

The global navigation satellite system (GNSS) is developing rapidly, and the related market applications and scientific research are increasing. Studies based on large low Earth orbit (LEO) satellite constellations have become research hotspots. The global coverage of the LEO constellation can reduce the dependence of navigation satellites on ground-monitoring stations and improve the precise orbit determination (POD) accuracy of navigation satellites. In this paper, we simulate various LEO satellite constellations (with 12, 30, and 60 satellites), along with ground stations’ observation data, to examine the impact of LEO satellites on the precision of the BeiDou-3 Global Navigation Satellite System (BDS-3) in terms of its POD accuracy. Using the simulated observation data of both LEO satellites and ground-monitoring stations, we analyze the integrated orbit determination for the LEO and BDS-3 satellites. The findings reveal that the 3D orbital accuracy of BDS-3 is 9.51 dm by using only seven ground-monitoring stations, and it is improved to a centimeter level after adding the LEO constellations. As the number of LEO constellation satellites increases, the impact on improving accuracy gradually diminishes. In terms of time synchronization accuracy in the BDS-3, compared to the results of clock offset using only ground stations, the addition of 12 LEO satellites resulted in an improvement of 49% for RMS1(root mean square) and 52% for RMS2 (standard deviation), the addition of 30 LEO satellites resulted in an improvement of 66% for RMS1 and 70% for RMS2, and the addition of 60 LEO satellites resulted in an improvement of 87% for RMS1 and 90% for RMS2. The integrated orbit determination of the LEO and BDS-3 satellites constellation greatly improves the accuracy of time synchronization. In addition, we also use simulated inter-satellite link (ISL) data to perform enhanced BDS-3 satellites POD and time synchronization experiments. The experiments showed that the orbit determination accuracy of the seven sta (seven stations) and ISL scheme is comparable to that of the seven sta and LEO12 scheme, and that the time synchronization accuracy of the seven sta and ISL scheme is slightly worse. The preliminary experiments showed that the LEO satellite could enhance the orbit determination accuracy of BDS-3 and obtain a higher time synchronization accuracy