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

After the epidemic: Ongoing declines, stabilizations and recoveries in amphibians afflicted by chytridiomycosis

The impacts of pathogen emergence in naïve hosts can be catastrophic, and pathogen spread now ranks as a major threat to biodiversity. However, pathogen impacts can persist for decades after epidemics and produce variable host outcomes. Chytridiomycosis in amphibians (caused by the fungal pathogen Batrachochytrium dendrobatidis, Bd) is an exemplar, with impacts ranging from rapid population crashes and extinctions, to population declines and subsequent recoveries. Here, we investigate long-term impacts associated with chytridiomycosis in Australia. We conducted a continent-wide assessment of the disease, reviewing data collected since the arrival of Bd in about 1978, to assess and characterize mechanisms driving past, present and future impacts.Wefound chytridiomycosis to be implicated in the extinction or decline of 43 of Australia's 238 amphibian species. Population trajectories of declined species are highly variable; six species are experiencing ongoing declines, eight species are apparently stable and 11 species are recovering. Our results highlight that while some species are expanding, Bd continues to threaten species long after its emergence. Australian case-studies and synthesis of the global chytridiomycosis literature suggests that amphibian reservoir hosts are associated with continued declines in endemically infected populations, while population stability is promoted by environmental conditions that restrict Bd impact, andmaintenance of high recruitment capacity that can offsetmortality. Host genetic adaptation or decreased pathogen virulence may facilitate species recovery, but neither has been empirically demonstrated. Understanding processes that influence Bd-host dynamics and population persistence is crucial for assessing species extinction risk and identifying strategies to conserve disease-threatened species