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

Erosional truncation of uppermost Permian shallow-marine carbonates and implications for Permian-Triassic boundary events

On shallow-marine carbonate buildups in south China, Turkey, and Japan, uppermost Permian skeletal limestones are truncated by an erosional surface that exhibits as much as 10 cm of topography, including overhanging relief. Sedimentary facies, microfabrics, carbon isotopes, and cements together suggest that erosion occurred in a submarine setting. Moreover, biostratigraphic data from south China demonstrate that the surface postdates the uppermost Permian sequence boundary at the global stratotype section and truncates strata within the youngest known Permian conodont zone. The occurrences of similar truncation surfaces at the mass-extinction horizon on carbonate platforms across the global tropics, each overlain by microbial buildups, and their association with a large negative excursion in delta C-13 further suggest a causal link between erosion of shallow-marine carbonates and mass extinction. Previously proposed to account for marine extinctions, the hypothesis of rapid carbon release from sedimentary reservoirs or the deep ocean can also explain the petro-graphic observations. Rapid, unbuffered carbon release would cause submarine carbonate dissolution, accounting for erosion of uppermost Permian skeletal carbonates, and would be followed by a pulse of high carbonate saturation, explaining the precipitation of microbial limestones containing upward-growing carbonate crystal fans. Models for other carbon-release events suggest that at least 5 x 1018 g of carbon, released in < 100 key., would be required. Of previously hypothesized Permian-Triassic boundary scenarios, thermogenic methane production from heating of coals during Siberian Traps emplacement best accounts for petrographic characteristics and depositional environment of the truncation surface and overlying microbial limestone, as well as an associated carbon isotope excursion and physiologically selective extinction in the marine realm

Diet quality and its implications on the cardio-metabolic, physical and general health of older men: The Concord Health and Ageing in Men Project (CHAMP)

The revised Dietary Guideline Index (DGI-2013) scores individuals’ diets according to their compliance with the Australian Dietary Guideline (ADG). This cross-sectional study assesses the diet quality of 794 community-dwelling men aged 74 years and older, living in Sydney, Australia participating in the Concord Health and Ageing in Men Project; it also examines sociodemographic and lifestyle factors associated with DGI-2013 scores; it studies associations between DGI-2103 scores and the following measures: homoeostasis model assessment – insulin resistance, LDLcholesterol, HDL-cholesterol, TAG, blood pressure, waist:hip ratio, BMI, number of co-morbidities and medications and frailty status while also accounting for the effect of ethnicity in these relationships. Median DGI-2013 score was 93·7 (54·4, 121·2); most individuals failed to meet recommendations for vegetables, dairy products and alternatives, added sugar, unsaturated fat and SFA, fluid and discretionary foods. Lower education, income, physical activity levels and smoking were associated with low scores. After adjustments for confounders, high DGI-2013 scores were associated with lower HDL-cholesterol, lower waist:hip ratios and lower probability of being frail. Proxies of good health (fewer comorbidities and medications) were not associated with better compliance to the ADG. However, in participants with a Mediterranean background, low DGI-2013 scores were not generally associated with poorer health. Older men demonstrated poor diet quality as assessed by the DGI-2013, and the association between dietary guidelines and health measures and indices may be influenced by ethnic background

Early-phase clinical trial eligibility and response evaluation criteria for refractory, relapsed, or progressive neuroblastoma: A consensus statement from the National Cancer Institute Clinical Trials Planning Meeting

Background International standardized criteria for eligibility, evaluable disease sites, and disease response assessment in patients with refractory, progressive, or relapsed high-risk neuroblastoma enrolled in early-phase clinical trials are lacking. Methods A National Cancer Institute-sponsored Clinical Trials Planning Meeting was convened to develop an international consensus to refine the tumor site eligibility criteria and evaluation of disease response for early-phase clinical trials in children with high-risk neuroblastoma. Results Standardized data collection of patient and disease characteristics (including specified genomic data), eligibility criteria, a definition of evaluable disease, and response evaluations for primary and metastatic sites of disease were developed. Eligibility included two distinct patient groups: progressive disease and refractory disease. The refractory disease group was subdivided into responding persistent disease and stable persistent disease to better capture the clinical heterogeneity of refractory neuroblastoma. Requirements for defining disease evaluable for a response assessment were provided; they included requirements for biopsy to confirm viable neuroblastoma and/or ganglioneuroblastoma in those patients with soft tissue or bone disease not avid for iodine-123 meta-iodobenzylguanidine. Standardized evaluations for response components and time intervals for response evaluations were established. Conclusions The use of international consensus eligibility, evaluability, and response criteria for early-phase clinical studies will facilitate the collection of comparable data across international trials and promote more rapid identification of effective treatment regimens for high-risk neuroblastoma