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

International society of sports nutrition position stand: coffee and sports performance

Based on review and critical analysis of the literature regarding the contents and physiological effects of coffee related to physical and cognitive performance conducted by experts in the field and selected members of the International Society of Sports Nutrition (ISSN), the following conclusions represent the official Position of the Society: (1) Coffee is a complex matrix of hundreds of compounds. These are consumed with broad variability based upon serving size, bean type (e.g. common Arabica vs. Robusta), and brew method (water temperature, roasting method, grind size, time, and equipment). (2) Coffee’s constituents, including but not limited to caffeine, have neuromuscular, antioxidant, endocrine, cognitive, and metabolic (e.g. glucose disposal and vasodilation) effects that impact exercise performance and recovery. (3) Coffee’s physiologic effects are influenced by dose, timing, habituation to a small degree (to coffee or caffeine), nutrigenetics, and potentially by gut microbiota differences, sex, and training status. (4) Coffee and/or its components improve performance across a temporal range of activities from reaction time, through brief power exercises, and into the aerobic time frame in most but not all studies. These broad and varied effects have been demonstrated in men (mostly) and in women, with effects that can differ from caffeine ingestion, per se. More research is needed. (5) Optimal dosing and timing are approximately two to four cups (approximately 473–946 ml or 16–32 oz.) of typical hot-brewed or reconstituted instant coffee (depending on individual sensitivity and body size), providing a caffeine equivalent of 3–6 mg/kg (among other components such as chlorogenic acids at approximately 100–400 mg per cup) 60 min prior to exercise. (6) Coffee has a history of controversy regarding side effects but is generally considered safe and beneficial for healthy, exercising individuals in the dose range above. (7) Coffee can serve as a vehicle for other dietary supplements, and it can interact with nutrients in other foods. (8) A dearth of literature exists examining coffee-specific ergogenic and recovery effects, as well as variability in the operational definition of “coffee,” making conclusions more challenging than when examining caffeine in its many other forms of delivery (capsules, energy drinks, “pre-workout” powders, gum, etc.)