9 research outputs found

    31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

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    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

    MICROBIAL INVOLVEMENT IN TRACE ORGANIC REMOVAL FROM GROUND WATER RECHARGE DURING RAPID INFILTRATION

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    A series of soil column tests and field experiments were designed to evaluate microbial removal of trace organics during rapid infiltration recharge of ground water. Field experiments demonstrated that operation of rapid infiltration systems using either primary or secondary wastewater can contribute trace organics to associated ground waters although concentrations of individual compounds can be reduced by the treatment process. Most of the removal occurred in the upper meter of the soil. Soil column tests demonstrated that trace organic removal from either primary or secondary wastewater was minimal when non-acclimated soil was conditioned by continuous flooding to eliminate adsorption as a removal mechanism. Batch tests indicated that most of the removal occurred in the wastewater prior to infiltration. Conversely, column tests using acclimated soil from an operational system demonstrated good removal of trace organics. Increased concentrations of target compounds in the feed did not always result in corresponding increases in the column effluent. Microbial adaptation was evident for some compounds. Other compounds appeared to exhibit a minimum concentration below which biodegradation did not proceed. Microbial activity was confirmed as a fate mechanism for several target compounds using radiolabels. In direct correlation with field results, the induction of anaerobiosis in the soil columns resulted in increased fractional breakthrough of trace organics

    Emergent Experience and the Connected Consumer in the Smart Home Assemblage and the Internet of Things

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    World War II: the city in ruins

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    British–Jewish Writing and the turn towards diaspora