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

Data from: Nutrient distribution and absorption in the colonial hydroid Podocoryna carnea is sequentially diffusive and directional

The distribution and absorption of ingested protein was characterized within a colony of Podocoryna carnea when a single polyp was fed. Observations were conducted at multiple spatial and temporal scales at three different stages of colony ontogeny with an artificial food item containing Texas Red conjugated albumin. Food pellets were digested and all tracer absorbed by digestive cells within the first 2–3 hours post-feeding. The preponderance of the label was located in the fed polyp and in a transport-induced diffusion pattern surrounding the fed polyp. After 6 hours post-feeding particulates re-appeared in the gastrovascular system and their absorption increased the area over which the nutrients were distributed, albeit still in a pattern that was centered on the fed polyp. At later intervals, tracer became concentrated in some stolon tips, but not in others, despite the proximity of these stolons either to the fed polyp or to adjacent stolons receiving nutrients. Distribution and absorption of nutrients is sequentially diffusive and directional

Factors Associated with Leaving Hospital against Medical Advice among People Who Use Illicit Drugs in Vancouver, Canada

Background Leaving hospital against medical advice (AMA) is common among people who use illicit drugs (PWUD) and is associated with severe health-related harms and costs. However, little is known about the prevalence of and factors associated with leaving AMA among PWUD. Methods Data were collected through two Canadian prospective cohort studies involving PWUD between September 2005 and July 2011 and linked to a hospital admission/discharge database. Bivariable and multivariable generalized estimating equations were used to examine factors associated with leaving hospital AMA among PWUD who were hospitalized. Results Among 488 participants who experienced at least one hospitalization, 212 (43.4%) left the hospital AMA at least once during the study period. In multivariable analyses, factors positively and significantly associated with leaving hospital AMA included: unstable employment (AOR = 1.92; 95% confidence interval [CI]: 1.22–3.03); recent incarceration (AOR = 1.63; 95%CI: 1.07–2.49); ≥ daily heroin injection (AOR = 1.49; 95%CI: 1.05–2.11); and younger age per year younger (adjusted odds ratio [AOR] = 1.04; 95%CI: 1.02–1.06). Conclusions We found a substantial proportion of PWUD in this setting left hospital AMA and that various markers of risk and vulnerability were associated with this phenomenon. Our findings highlight the need to address substance abuse issues early following hospital admission. These findings further suggest a need to develop novel interventions to minimize PWUD leaving hospital prematurely.Medicine, Faculty ofOther UBCMedicine, Department ofPopulation and Public Health (SPPH), School ofReviewedFacultyResearcherGraduat