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

Plasma and Adipose Tissue Levels of Selected Growth/Inhibitory Factors, Proteolytic Enzymes and Sphingosine-1-Phosphate in Humans

Recent studies have shown that adipose tissue (AT), while implicated in orchestrating the sophisticated process termed “immunometabolism,” may also serve as a potential niche for various bone marrow-derived (stem) cells. However, at present, the direct biochemical and immunomodulatory composition of the human AT environment has not been studied. Several substances that might play a crucial role in regulating stem cell migration and/or homing to AT, have been implicated, namely, hepatocyte/vascular endothelial growth factor (VEGF/HGF), leukemia inhibitory factor (LIF), and sphingosine-1-phosphate (SIP). Therefore, we examined and compared the AT concentrations of these substances between plasma, subcutaneous, and omental AT samples derived from 35 generally healthy subjects. VEGF, HGF, LIF, and metalloproteinases (MMP)-2 and MMP9 levels were measured using ELISA, and S1P concentrations were analyzed using reverse-phase high performance liquid chromatography. We found that AT levels of analyzed growth/inhibitory factors were generally comparable (VEGF and LIF) or even higher (HGF) than the corresponding levels in the peripheral blood, particularly in overweight/obese subjects. In subcutaneous AT, significantly lower VEGF and LIF concentrations were observed, and these were accompanied by higher MMP levels. No depot-specific differences in S1P concentrations were found in all examined groups. Moreover, we established several associations between analyzed molecular substances and body composition, BMI, or adiposity index of the examined patients. In conclusion, our study revealed that human AT possesses relatively high levels of selected growth/inhibitory factors and of chemoattractants involved in the regulation of stem cell trafficking, and these factors are associated with the metabolic status of an individual. Further studies are needed to clearly establish the role of these factors in the regulation of bone marrow-derived (stem) cell homeostasis and homing in human AT

Immunogenicity of a recombinant Pre-S2-containing hepatitis B vaccine versus plasma-derived vaccine administered as a booster

GenHevac B Pasteur is a recombinant hepatitis B vaccine derived from a mammalian cell line and containing HBs as well as pre-S2 antigens. Its immunogenicity was compared to that of the plasma-derived vaccine Hevac B Pasteur in a population primovaccinated 5.5 years earlier with four injections of the same plasma vaccine. The booster injection with either GenHevac or Hevac was administered to 295 subjects with residual anti-HBs titres below 500 IU/l (group 1: 0-9; group 2: 10-99; group 3: 100-499 IU/l). After four weeks, GenHevac had induced higher anti-HBs responses than Hevac in all groups, particularly among the low responders of group 1. Response to the vaccine occurred earlier with GenHevac. Mean anti-pre-S2 production was moderate in all groups for both vaccines (GenHevac: 60 IU/l; Hevac: 31 IU/l) and was not found in the 32 subjects who produced less than 100 IU/l anti-HBs. The results of the present study indicate that GenHevac is at least as immunogenic as Hevac