Temporary Protection: Towards a New Regional and Domestic Framework

During the past thirty-five years, the United States has seen the direct influx of thousands of individuals leaving politically unstable countries. While some seeking entry have proved themselves to be refugees and obtained permanent protection in the United States, far more, including a large number of people fleeing civil war, natural disasters, or comparable forms of upheaval in their home countries, have failed to demonstrate that they would be targets of persecution. Yet, their return to their home countries has been complicated by the very circumstances that led to their flight: conflict, violence, and repression. Over time, the United States developed a series of ad hoc responses that protected such individuals, culminating in the Immigration Act of 1990 (“IMMACT”), which provided legislative authority for Temporary Protected Status (“TPS”). Nevertheless, after eight years, many problems remain in the application of the law. Solving these problems will contribute both to better immigration control and more humane responses to future crises. Current policies fail on two accounts. First, the temporary protection provision in the law generally has failed to protect the vast majority of those in danger as a crisis develops and unfolds. If the United States government protects significant numbers at all, protection is provided outside the confines of the United States. Even so, the mechanisms for responding extraterritorially are not well developed. Second, current policies regarding protection in the United States do not provide the control mechanisms to ensure that protection is not abused and that return, when appropriate, is effected. The choice to admit people for temporary protection has been a difficult one for the United States for two main reasons: the lack of control over entry; and the inability to implement a fair but firm end game. These constraints together with the fear of litigation challenging domestic protection regimes have led policymakers to keep protection seekers offshore, such as on Guantanamo, or to return them directly to countries they fled without providing an opportunity for them to present requests for protection. But not having a fully developed regional or domestic capability for addressing these complex movements comes at a considerable cost. Estimates for the agency costs of handling the 1994 Cuban exodus through the use of offshore safe havens were more than $500 million. Further, an immigration system that cannot fairly and efficiently process protection seekers lacks credibility for which it pays a significant public cost

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

Reorganizing the Immigration Function: Toward a New Framework for Accountability

A new era of large-scale immigration calls for new forms of governance and management. As we negotiate these demands it is important to ask ourselves a number of critical questions. First, are the intentions of the immigration system clear to all who engage with it? Second, are our institutional structures equal to the task of managing the responsibilities implied by large immigration numbers and ever more complex functions? Third, are various components of the immigration function rationally organized into a set of interrelated elements whose whole is clearly larger than the sum of its parts? Fourth, is the system we have in place-both in terms of its organization and of its location within our public administration apparatus-capable of delivering all the programs we expect of it? Fifth, can the system satisfy Americans that increasing public investments in the immigration function have in fact improved its two main elements: compliance with the law and provision of services in a timely, fair, and courteous manner? Finally, is the system flexible enough to learn from experience, embrace change, and meet the financial and programmatic criteria of accountability that the public has a right to expect