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

Static and Dynamic Testing of a Concrete T-Beam Bridge before and after Carbon Fiber–Reinforced Polymer Retrofit

This paper summarizes the design and execution of field studies to improve the performance of a deteriorated bridge through the use of carbon fiber-reinforced polymer (CFRP) material. The objective of the CFRP retrofit was to extend the life of Bridge 2028 in Cayey, Puerto Rico, by increasing its load rating. Field testing before and after the retrofit was performed to evaluate objectively improvement in load capacity and stiffness. The field testing program included both static load tests and dynamic tests. The first set of field tests was conducted in November 2002 to capture baseline bridge performance characteristics before the retrofit The CFRP retrofit was installed in October 2003, and a second set of nearly identical field tests was performed in August 2004. The test results indicated that the retrofit increased the bending stiffness of the bridge by 15% and decreased the tensile strains in the bottom rebars of the concrete T-beams by about 13%. Furthermore, the maximum rebar strains under a heavy truck load case were only 10% of the yield strength after the retrofit The change in stiffness determined from static deflection measurements was well correlated with the stiffness change determined from the dynamic tests. The field testing program showed that the CFRP retrofit was successful in improving the mechanical behavior of the bridge. The long-term performance and durability of the CFRP retrofit could be affected by a number of parameters such as local environmental conditions. The field testing program is to be periodically repeated; alternatively, a continuous monitoring program could be implemented to evaluate objectively the long-term performance and durability of the CFRP retrofit

The Microstructural Characterization of Semi-Solid Slurries

Due to recent interest in semi-solid metal (SSM) processing, there is a need for fundamental knowledge on the formation and solidification of primary particles. The primary particle size, distribution, morphology, and percentage are the main concerns because particle quantity and size affect not only the mechanical properties of as-cast SSM parts but also the flow characteristics of SSM slurries during die filling. Microstructural characterization is a basic tool for measuring the critical parameters that influence the resulting properties. This article describes the tools and techniques available for structural analysis of SSM slurries. It also attempts to elucidate the ambiguities and interpretations of special structural features.Shahrooz Nafisi and Reza Ghomashch