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

Biological flora of the British isles: Ulmus glabra

1. This account presents information on all aspects of the biology of Ulmus glabra Hudson (wych elm) that are relevant to understanding its ecological characteristics and behaviour. The main topics are presented within the standard framework of the Biological Flora of the British Isles: distribution, habitat, communities, responses to biotic factors, responses to environment, structure and physiology, phenology, floral and seed characters, herbivores and disease, history and conservation. 2. Ulmus glabra is a large forest tree, and often an important canopy tree in ancient and seminatural woodlands. It is primarily native to the north and west of Britainand much of mainland Europe. It is the only elm native to Ireland. It is the most distinct of the British elms in that it rarely suckers and sets abundant viable seed. Although found on limestone screes and cliffs, and hedgerows, it is primarily awoodland tree, especially on moist, basic soils. In many secondary woodlands, it often cooccurs with Acer pseudoplatanus and has ecological needs that are similar to Fraxinus excelsior. 3. Ulmus glabra has clusters of c. 25 hermaphrodite flowers appearing before the leaves on previous year’s growth. Seeds are wind dispersed, falling in April to July, but remain viable for only a few days. Nevertheless, seedling establishment can be abundant. Hybridisation with other northern European elms is common but hybrids are notoriously difficult to identify and therefore probably under recorded. 4. The health and survival of wych elm in Europe has been seriously compromised since the 1970s due to Dutch elm disease caused by the fungus Ophiostoma novo ulmi, transmitted by elm bark beetles (Scolytus spp.). To the south of its Scottish stronghold, many elms are reduced to small trees regrowing from basal sprouts or seeds. These trees tend to be reinfected once trunk diameter exceeds 10 cm. Fortunately for its long term survival, seed production usually begins a number of years before they are reinfected