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

Steinalderlokalitet. Haga av Ormestad, 114/1, Sandefjord kommune, Vestfold.

Etter en forundersøkelse foretatt i 1995 ble det besluttet en 2 ukers utgravning av steinalderboplasser i og delvis utenfor en frukthage. På grunn av områdets størrelse måtte det sterk prioritering til, og prioriteringene ble i hovedsak tatt på grunnlag av topografien og resultatet av fjorårets undersøkelser. Undersøkelsen foregikk i en frukthage, som hadde vært dyrket i lengre tid og derfor var omrotet, i et tildels sterkt skrånenede terreng, hvor funn var forflyttet. Vi valge å foreta undersøkelse hvor vi mente vi kunne finne gjenstander som hørte sammen, og lå på opprinnelig sted. Fomålet var å samle inn gjenstander som kunne fortelle om aktiviteter, og finne materiale som kunne datere disse. Tre områder ble prioritert: Brink I (øverst), Brink 3, R 1 og Brink 3 R 2 (som delvis lå utenfor hagen). Det er gravet frem 854 gjenstander på Brink 3 R 1, 1376 på Brink 3 R 2 og 70 på Brink 1, tilsammen 2300 gjenstander, det aller meste av flint. Mye av dette er avslag, dvs. rester etter redskapsproduksjon. På alle lokalitetene er det funnet kjerner, noen mikroflekker og flekker, på R 1 og R 2 også redskaper. Av redskapene har det vært mulig å definere borspiss, skraper og fiskesøkke på R 1 og borspisser og kniver på R 2

Expansion of HAART Coverage Is Associated with Sustained Decreases in HIV/AIDS Morbidity, Mortality and HIV Transmission : The “HIV Treatment as Prevention” Experience in a Canadian Setting

Background There has been renewed call for the global expansion of highly active antiretroviral therapy (HAART) under the framework of HIV treatment as prevention (TasP). However, population-level sustainability of this strategy has not been characterized. Methods We used population-level longitudinal data from province-wide registries including plasma viral load, CD4 count, drug resistance, HAART use, HIV diagnoses, AIDS incidence, and HIV-related mortality. We fitted two Poisson regression models over the study period, to relate estimated HIV incidence and the number of individuals on HAART and the percentage of virologically suppressed individuals. Results HAART coverage, median pre-HAART CD4 count, and HAART adherence increased over time and were associated with increasing virological suppression and decreasing drug resistance. AIDS incidence decreased from 6.9 to 1.4 per 100,000 population (80% decrease, p = 0.0330) and HIV-related mortality decreased from 6.5 to 1.3 per 100,000 population (80% decrease, p = 0.0115). New HIV diagnoses declined from 702 to 238 cases (66% decrease; p = 0.0004) with a consequent estimated decline in HIV incident cases from 632 to 368 cases per year (42% decrease; p = 0.0003). Finally, our models suggested that for each increase of 100 individuals on HAART, the estimated HIV incidence decreased 1.2% and for every 1% increase in the number of individuals suppressed on HAART, the estimated HIV incidence also decreased by 1%. Conclusions Our results show that HAART expansion between 1996 and 2012 in BC was associated with a sustained and profound population-level decrease in morbidity, mortality and HIV transmission. Our findings support the long-term effectiveness and sustainability of HIV treatment as prevention within an adequately resourced environment with no financial barriers to diagnosis, medical care or antiretroviral drugs. The 2013 Consolidated World Health Organization Antiretroviral Therapy Guidelines offer a unique opportunity to further evaluate TasP in other settings, particularly within generalized epidemics, and resource-limited setting, as advocated by UNAIDS.Medicine, Faculty ofOther UBCNon UBCMedicine, Department ofReviewedFacultyResearche

Processing of a 22 kDa precursor protein to produce the circular protein tricyclon A

Cyclotides are a family of plant proteins that have the unusual combination of head-to-tail backbone cyclization and a cystine knot motif. They are exceptionally stable and show resistance to most chemical, physical, and enzymatic treatments. The structure of tricyclon A, a previously unreported cyclotide, is described here. In this structure, a loop that is disordered in other cyclotides forms a beta sheet that protrudes from the globular core. This study indicates that the cyclotide fold is amenable to the introduction of a range of structural elements without affecting the cystine knot core of the protein, which is essential for the stability of the cyclotides. Tricyclon A does not possess a hydrophobic patch, typical of other cyclotides, and has minimal hemolytic activity, making it suitable for pharmaceutical applications. The 22 kDa precursor protein of tricyclon A was identified and provides clues to the processing of these fascinating miniproteins

Number and rate of AIDS and death (HIV-related) cases by calendar year, 1996–2011.

<p>AIDS: data for AIDS defining illness reported by the BC Centre for Disease Control, based on the first AIDS-defining illness reported for each person. Denominator for rates was BC population counts based on Statistics Canada estimates during 1996–2011.</p

Distribution of individuals’ adherence to antiretrovirals by calendar year, 1996–2012.

<p>Distribution of individuals’ adherence to antiretrovirals by calendar year, 1996–2012.</p

Selected HIV epidemic indicators for British Columbia by calendar year, 1996–2012.

<p>Selected HIV epidemic indicators for British Columbia by calendar year, 1996–2012.</p

Distribution of the highest plasma viral load from HIV infected individuals by calendar year, 1996–2012.

<p>Includes all individuals ever having a plasma viral load test done regardless of whether they received antiretroviral therapy.</p

Distribution of HIV drug resistance among individuals with unsuppressed viral load by calendar year, 1996–2012.

<p>Distribution of HIV drug resistance among individuals with unsuppressed viral load by calendar year, 1996–2012.</p