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

State Under Siege: Development and Policy Making in Peru

Using a framework that highlights how societal and international factors have shaped state capacities, Philip Mauceri examines the volatile politics in Peru from the Velasco through the Fujimori regimes as the country has moved from a “developmentalist” state to neoliberalism. Dr. Mauceri begins by reassessing the reformist experiment of the Peruvian military regime (1968–1980), arguing that it led to the development of unexpected challenges to state authority, both from new social actors and international financial organizations. During the 1980s, these challenges intensified, made even worse by poor planning and limited policy choices. The author then argues that the attempt by the Fujimori regime, backed by a neoliberal coalition, to “retool” the state indicates the degree to which state capacities are determined by social and international conditions. Mauceri also gives special attention to the relation between changing state power and social control. Separate chapters on the evolution of a Lima shantytown and the Shining Path examine how changes in state-society relations have had impacts at the grassroots level. -- Provided by publisherhttps://scholarworks.uni.edu/facbook/1098/thumbnail.jp

Estado, élites y contrainsurgencia: una comparación preliminar entre colombia y perú.

En este artículo el autor compara la violencia insurgente en Colombia y Perú. Después de haber identificado un rasgo común, la debilidad del Estado, las diferentes estrategias empleadas en los dos países para luchar contra los movimientos armados son evaluados. Sobre la base de un análisis conceptual de las características del Estado en ambos casos, el autor sostiene que la diferencia entre la configuración de las élites socio-económicas y su WIIH la relación del Estado en cada país, explica las diferencias entre los modelos de contrainsurgencia de socio-céntricas " privatización "(aprobado en Colombia) y Estado-céntrica" autoritarismo "(en Perú). El estudio comparativo de estas estrategias pone de manifiesto que tanto los enormes costos representados por las respectivas sociedades de estos países y no fueron acompañados por transformaciones en sus respectivas estructuras políticas, diseñados para garantizar la estabilidad y la preservación del sistema democrátic