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

Numerical and Experimental models of postoperative realistic flows in a stenosed coronary bypasses

By means of both experimental and finite element methods, we simulated three-dimensional unsteady flows through coronory bypass anastomosis. The host artery includes a stenosis shape located at two different distances of grafting. The inflow rates are issued from in vivo measurements in patients who had undergone coronary bypass surgery a few days before. We provide a comparison between experimental and numerical velocity profiles coupled with the numerical analysis of spatial and temporal wall shear stress evolution. The interaction between the graft and coronary flows has been demonstrated. The phase inflow difference can partly be responsible for specific flow phenomena: jet deflection towards a preferential wall or feedback phenomenon that causes the flapping of the post-stenotic jet during the cardiac cycle. In conclusion, we showed the sensitivity of these typical flows to distance of grafting, inflows waveforms but also to their phase differenc

Assessment of the trackability, flexibility, and conformability of coronary stents: A comparative analysis

The efficacy and safety of coronary stent implantation depend on the mechanical features of these devices when deployed in atheromatous lesions of various morphologies. We evaluated the trackability, flexibility, and conformability of 17 coronary stents using specific mechanical bench tests. The quantifications used a dynamometer for assessment of trackability (maximal strength) and flexibility (stiffness) and a 3D optical gauging machine for assessment of conformability (distance between stent and arterial wall in a curvature). The maximal strength (measuring the trackability) ranged respectively from 0.24 ± 0.06 and 0.38 ± 0.03 N (Seaquest) to 1.31 ± 0.42 and 1.34 ± 0.35 N (Carbostent), concerning respectively curvatures of 90° (P < 0.0001) and 135° (P < 0.0001). The stiffness (measuring the flexibility) ranged from 0.53 ± 0.16 (Seaquest) to 1.28 ± 0.10 N/mm (NIR Royal; P < 0.0001). The mean distance between stent and external curvature (external conformability) ranged from 0.15 ± 0.06 mm (S7) to 0.57 ± 0.4 mm (NIR Royal; P < 0.0001). The mean distance between stent and internal curve (internal conformability) ranged from 0.26 ± 0.13 (S7) to 0.44 ± 0.12 mm (S670; P < 0.0001). These results may influence the choice of a particular stent adapted to a specific coronary anatomy

Système d'étude du comportement cellulaire en condition de flux

International audienc