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

Gênero, o público e o privado Gender, the Public and the Private

Neste artigo, a filósofa política Susan Moller Okin discute as configurações históricas da dicotomia público/privado, analisando seus significados a partir de uma perspectiva de gênero. A ausência de reflexão sobre o gênero - especialmente sob duas formas, a negligência à realidade política das relações familiares e a linguagem 'neutra' - tem levado muitos teóricos, do passado e do presente, a reafirmar essa dicotomia sem levar em conta sua natureza patriarcal. Para Okin, os domínios da vida doméstica (pessoal) e da vida não-doméstica (pública) não podem ser interpretados isoladamente, o que demanda uma revisão profunda dos fundamentos de grande parte da teoria política liberal. A autora enfrenta essa tarefa, abordando problemas importantes, como o valor da privacidade.<br>In this article, the political philosopher Susan Moller Okin discusses the dichotomy public-private from a gendered perspective. Overlooking gender - especially as it assumes the form of overlooking the political reality of the family and gender 'neutral' language - has become, in many past and present authors, a reinforcement of that dichotomy, silencing about its patriarchal nature. As Okin understands it, domestic (personal) sphere and non-domestic (public) sphere can not be interpreted isolatedly, what demands a deep revision of the base of most liberal political theory. The author faces this demand, discussing important problems such as the value of privacy