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

Life before birth: abortion and prenatal personhood in morality and law

This thesis is about the legal and moral status of abortion. It is primarily concerned with the metaphysical status of the foetus, with particular attention to the question whether the foetus is properly characterised as a person in the philosophical sense. The argument of the thesis proceeds in two parts. The first part surveys certain lines of argument to the effect that the question of prenatal personhood is immaterial to the moral and legal permissibility of abortion. Against these claims, it argues that the personhood status of the foetus is indeed central to the moral and legal appraisal of abortion practice. The second part focuses on the metaphysical question in its own right. The thesis proposes a theoretical underpinning for the ‘gradualist’ view of human life before birth, according to which the human foetus is a fuller instantiation of a person the more biologically developed it is. It sets out to defend the kernel of the gradualist thesis against a cluster of criticisms, commonly advanced by those who endorse the belief that the personhood of human beings begins at conception. One notable challenge of this sort, which the thesis aims to address, asserts that any graduated account of personhood before birth is logically inconsistent with basic human equality. Finally, the thesis considers a few practical implications for the legal regulation of abortion stemming from the gradualist thesis, and the rule of law standards by which a regulatory framework must abide.</p

Life before birth: abortion and prenatal personhood in morality and law

This thesis is about the legal and moral status of abortion. It is primarily concerned with the metaphysical status of the foetus, with particular attention to the question whether the foetus is properly characterised as a person in the philosophical sense. The argument of the thesis proceeds in two parts. The first part surveys certain lines of argument to the effect that the question of prenatal personhood is immaterial to the moral and legal permissibility of abortion. Against these claims, it argues that the personhood status of the foetus is indeed central to the moral and legal appraisal of abortion practice. The second part focuses on the metaphysical question in its own right. The thesis proposes a theoretical underpinning for the ‘gradualist’ view of human life before birth, according to which the human foetus is a fuller instantiation of a person the more biologically developed it is. It sets out to defend the kernel of the gradualist thesis against a cluster of criticisms, commonly advanced by those who endorse the belief that the personhood of human beings begins at conception. One notable challenge of this sort, which the thesis aims to address, asserts that any graduated account of personhood before birth is logically inconsistent with basic human equality. Finally, the thesis considers a few practical implications for the legal regulation of abortion stemming from the gradualist thesis, and the rule of law standards by which a regulatory framework must abide.This thesis is not currently available in ORA