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

An addressless reconfigurable routing architecture for fast FPGA reconfigurations

The aim of this thesis is to develop a hardware support which enables faster run-time partial reconfigurations for reconfigurable systems. The current configuration routing architecture of the reconfigurable systems imposes considerable amount of overheads by loading more configuration data than required onto the configuration memory. The overheads can be as costly as contributing up to 98.5% of the configuration latency. This leads to one of the major shortcomings in current FPGA technologies. Therefore, in order to increase the efficiency of run-time reconfiguration systems, it is crucial to reduce the reconfiguration overhead by reducing the lengths of the reconfiguration bitstreams. In this thesis, the reconfiguration bitstreams are minimized by two techniques: the concept of partial reconfigurations and the reduced reconfiguration granularities.The proposed configuration routing system provides efficient access to non-contiguous reconfigurable locations in reconfigurable systems. It reduces the amount of configuration data in a partial reconfiguration bitstream by removing all the addressing information and pad zeroes which are present in Virtex-4 partial bitstreams. The system allows variable frame set sizes as well as variable reconfiguration granularities, thereby providing sufficient scalability and flexibility. The proposed system is readily applicable to SRAM-based FPGAs. The major advantage of the proposed system over the Virtex-4 architecture is the ability to reduce the configuration data significantly without additional addressing information when the reconfiguration granularities are small. The experimental results and simulations show that a proposed system with its hardware cost less than 50% of the Virtex-4 configuration routing architecture achieves speedups of up to 14.84% over the Virtex-4 devices when the reconfiguration granularity equals to a Virtex-4 frame. Moreover, the speedups increase up to 17.33% when the granularity is set to half of a Virtex-4 frame, and up to 56.51% when the granularity is set to a quarter of a Virtex-4 frame while maintaining the same hardware cost

Bare coordination: the semantic shift

This paper develops an analysis of the syntax-semantics interface of two types of split coordination structures. In the first type, two bare singular count nouns appear as arguments in a coordinated structure, as in bride and groom were happy. We call this the N&N construction. In the second type, the determiner shows agreement with the first conjunct, while the second conjunct is bare, as in the Spanish example el hornero y hornera cobraban en panes (‘thesg.m bakersg.m and bakersg.f werepl paid in bread loaves’). We call this the DN&N construction. Both N&N and DN&N constructions are common in languages that otherwise require an article or determiner on singular count nouns in regular argument position, and give rise to ‘split’ readings that cannot be accounted for by the standard semantics of conjunction in terms of set intersection. Furthermore, they are restricted to instances of ‘natural’ coordination. We formalize the semantics of split conjunction in terms of intersection between sets of matching pairs, which correlates with the lexical semantics and pragmatics of natural coordination. We maintain that an N&N construction gets either a definite or an indefinite interpretation by covert type-shifting, because projection of an article ranging over the coordination as a whole is blocked in languages like English and Spanish. For DN&N structures, we propose a syntactic structure in which D is in construction with the first conjunct. Coordination with a second, bare conjunct requires a covert type-shift that is licensed only under the special matchmaking semantics of conjunction. The analysis addresses a range of issues these coordinate structures raise about syntactic and semantic agreement, in particular with respect to number. Next to English and Spanish we will look into Dutch and French in detail