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

Touring Machine: A Software Platform for Distributed Multimedia Applications

The goal of the Touring Machine project is to provide a reliable and extensible software platform that supports independently-developed distributed multimedia applications. The project includes an experimental testbed composed of a network of desktop video and audio devices controlled via user workstations. Touring Machine is more than a research testbed; it is the basis of the communications tools used daily by 100 users in two Bellcore locations 50 miles apart. It supports multimedia conferencing and information services as well as point-to-point communications. This paper describes Touring Machine, its system model and its software architecture. 1 Introduction With the technological advances in computing and communication networks in recent years, we have seen the emergence of a variety of distributed multimedia applications[7, 22]. Examples of such applications include Computer Supported Cooperative Work (CSCW)[11], medical applications[9], multimedia conferencing[19, 21], and dis..

Growth and physiology of a dominant understory shrub, Hamamelis virginiana, following canopy disturbance in a temperate hardwood forest

As global climatic changes increase plant susceptibility to large-scale disturbances like drought and pathogens, understory responses to these disturbances will become increasingly important to long-term forest dynamics. To better understand understory responses to canopy disturbance, we measured changes in the growth and physiology of the dominant understory shrub, American witch-hazel (Hamamelis virginiana), in response to girdling of canopy oaks in a northeastern U.S. temperate hardwood forest. Changes in the growth and physiology of H. virginiana may be important to the regeneration of northeastern temperate forests, as this common shrub largely shapes the microenvironment for seedlings on the forest floor where it occurs. Canopy disturbance by girdling resulted in significant increases in light and soil nitrogen availability. In response to these environmental changes, basal-area growth of H. virginiana increased by an average 334%. This growth increase corresponded to significant increases in foliar nitrogen, respiration, and leaf chlorophyll and carotenoid concentrations. These findings indicate improved environmental conditions and increased growth for this understory shrub following the loss of dominant canopy trees. This study suggests that following large-scale canopy disturbance, H. virginiana and shrubs like it may play an important role in competing for soil N and shading seedlings of regenerating canopy species.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author