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

Simulation of an explosion-proof bin made of relaxation material

The article discusses the numerical simulation of a blast wave interaction with a relaxation multiphase material used in design of the destructible protection bin with combined method of suppression of the blast damage effects. Numerical simulation of shock-wave systems and processes occurring during the detonation of a condensed high explosive (HE) in semi-open (open at the top) explosion-proof bins was obtained, including when one which uses multiphase gas-liquid material (at a first approximation – water-bubble mechanical foam) as relaxation substance that absorbs the explosion energy and thus reduces the damaging effect of the blast waves

Approximate Analytical Models of Shock-Wave Structure at Steady Mach Reflection

In this study, we obtain the comparative analysis of methods of quick approximate analytical prediction of Mach shock height in planar steady supersonic flows (for example, in supersonic jet flow and in narrowing channel between two wedges), that are developed since the 1980s and being actively modernized now. A new analytical model based on flow averaging downstream curved Mach shock is proposed, which seems more accurate than preceding models, comparing with numerical and experimental data

Blast suppression with water barriers

The article presents the results of numerical simulation of an explosive of interaction between air blast wave and water barrier. To find the best spape of relaxation material and to evaluate the suppression degree resulted from the interaction of the blast wave with protective liquid barriers, calculations for various shapes and sizes of water barriers were provided. Keywords: high explosive blast, blast protection, shock-wave structures, relaxation media, water barrie

Stationary Mach Configurations with Pulsed Energy Release on the Normal Shock

We obtained a theoretical analysis of stationary Mach configurations of shock waves with a pulsed energy release at the main (normal) shock and a corresponding change in gas thermodynamic properties. As formation of the stationary Mach configuration corresponds to one of two basic, well-known criteria of regular/Mach shock reflection transition, we studied here how the possibility of pulsed energy release at the normal Mach stem shifts the von Neumann criterion, and how it correlates then with another transition criterion (the detachment one). The influence of a decrease in the &ldquo;equilibrium&rdquo; gas adiabatic index at the main shock on a shift of the solution domain was also investigated analytically and numerically. Using a standard detonation model for a normal shock in stationary Mach configuration, and ordinary Hugoniot relations for other oblique shocks, we estimated influence of pulsed energy release and real gas effects (expressed by decrease of gas adiabatic index) on shift of von Neumann criterion, and derived some analytical relations that describe those dependencies

A mitochondrial pathway for biosynthesis of lipid mediators

The central role of mitochondria in metabolic pathways and in cell death mechanisms requires sophisticated signaling systems. Essential in this signaling process is an array of lipid mediators derived from polyunsaturated fatty acids. However, the molecular machinery for the production of oxygenated polyunsaturated fatty acids is localized in the cytosol and their biosynthesis has not been identified in mitochondria. Here we report that a range of diversified polyunsaturated molecular species derived from a mitochondria-specific phospholipid, cardiolipin, are oxidized by the intermembrane space hemoprotein, cytochrome c. We show that an assortment of oxygenated cardiolipin species undergoes phospholipase A2-catalyzed hydrolysis thus generating multiple oxygenated fatty acids, including well known lipid mediators. This represents a new biosynthetic pathway for lipid mediators. We demonstrate that this pathway including oxidation of polyunsaturated cardiolipins and accumulation of their hydrolysis products – oxygenated linoleic, arachidonic acids and monolyso-cardiolipins – is activated in vivo after acute tissue injury