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

Medical Expenditures during the Last Year of Life: Findings from the 1992–1996 Medicare Current Beneficiary Survey

OBJECTIVE: To compare medical expenditures for the elderly (65 years old) over the last year of life with those for nonterminal years. DATA SOURCE: From the 1992–1996 Medicare Current Beneficiary Survey (MCBS) data from about ten thousand elderly persons each year. STUDY DESIGN: Medical expenditures for the last year of life and nonterminal years by source of payment and type of care were estimated using robust covariance linear model approaches applied to MCBS data. DATA COLLECTION: The MCBS is a panel survey of a complex weighted multilevel random sample of Medicare beneficiaries. A structured questionnaire is administered at four-month intervals to collect all medical costs by payer and service. Medicare costs are validated by claims records. PRINCIPAL FINDINGS: From 1992 to 1996, mean annual medical expenditures (1996 dollars) for persons aged 65 and older were $37,581 during the last year of life versus$7,365 for nonterminal years. Mean total last-year-of-life expenditures did not differ greatly by age at death. However, non-Medicare last-year-of-life expenditures were higher and Medicare last-year-of-life expenditures were lower for those dying at older ages. Last-year-of-life expenses constituted 22 percent of all medical, 26 percent of Medicare, 18 percent of all non-Medicare expenditures, and 25 percent of Medicaid expenditures. CONCLUSIONS: While health services delivered near the end of life will continue to consume large portions of medical dollars, the portion paid by non-Medicare sources will likely rise as the population ages. Policies promoting improved allocation of resources for end-of-life care may not affect non-Medicare expenditures, which disproportionately support chronic and custodial care

The influence of social environment on endocrine, cardiovascular and tissue responses in the rabbit

Previous work from our lab demonstrated that social environment influences the progression of atherosclerosis in genetically hyperlipidemic rabbits. The purpose of the current study was to examine behavioral and physiological responses associated with these distinct chronic social conditions. Normolipidemic rabbits were exposed to one of 3 social environments for 4 hours/day over 20 weeks: 1) an Unstable Group in which animals were paired weekly with a different unfamiliar rabbit, 2) a Stable Group in which rabbits were paired with the same littermate for the entire study, and 3) an Individually Caged Group in which animals were socially isolated. It was found that the Unstable Group, characterized by increased agonistic behavior and relatively less affiliative behavior, exhibited physiological responses indicative of chronic stress (increased urinary norepinephrine, plasma cortisol, splenic weight, and decreased visceral fat and body weight compared to the other groups). These animals also had increased acute plasma oxytocin responses relative to the other groups 10 minutes into the social pairing. In contrast, the Stable Group exhibited more affiliative behavior and less stressful physiological and tissue responses. The Individually Caged Group had elevated urinary norepinephrine relative to the Stable Group, and they exhibited higher heart rates at the end of the study compared to the other groups, suggesting that this social environment is also associated with chronic sympathetic arousal. It was concluded that distinct social contexts lead to different patterns of behavioral and physiological responses, and these responses are relevant to the pathophysiology of atherosclerosis and cardiovascular disease