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

ADAPTATION OF SOFTWARE SYSTEMS TO USER TASKS BASED ON THE METHOD OF CONFIGURATION MODELING

In this paper, we discuss task of adaptation of software systems (PCs) and complexes (PCs) on the basis of the configuration modeling (MCM) method is considered. The article describes designated purpose of MCM in the field of SSs development, describes background and justification for the development of adap- tive SSs, and many of the advantages of creating configurable SSs. The main attention is paid to the analysis and research of the software engineering and implementation of adaptive SSs using the configuration mechanism as a mean of adapting SSs to the problem of interest. The potential for using configuration modeling in this area is determined. The meaning of the concepts «configurator», «configuration» and «reconfiguration» in the context of the description of MCM implementation of adaptive SSs creation is considered. The article gives a real example of an adaptive SS describing MCMs application in the process of software engineering. A conceptual model of such a SS is described, and its interpretation is implement- ed in the form of a modular complex data processing system (CDPS). The example of the CDPS shows the structural scheme of the conceptual model of the data handling process, decomposes the CDPS into the basic modules, including the built-in configuration module. Special attention to a detailed description of the problem of interest and the functionality of each module is paid, as well as to the description of the relationships between them. On the basis of the CDPS, the solution of the problem of adapting PSs with the elements of dynamic configuration based on the input data is realized. The example of the CDPS describes user-accessible operating modes of the SS corresponding to various system configurations determined according to the tasks to be solved. The article makes it possible to obtain an abstract presentation on the methods and principles for the creation of adaptive SS. Moreover, a concrete understanding of the imple- mentation of adaptation by using the configuration management mechanism is covered. Additionally, the article highlights direct benefits and potential profit from using of configurator in software engineering