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

Paediatric endoscopic endonasal dacryocystorhinostomy in congenital nasolacrimal duct obstruction

The original publication can be found at www.springerlink.comObjectives The objectives of this study were to report a series of paediatric patients who underwent endoscopic endonasal dacryocystorhinostomy (DCR) for primary congenital nasolacrimal duct obstruction (NLDO). Methods This is a retrospective, noncomparative review of all consecutive cases in two lacrimal clinics between January 1999 and October 2004. The main outcome measures were patients’ demographics, previous treatments, clinical presentation, operative and postoperative complications, postoperative follow-up and resolution of epiphora. Results Twenty-one patients (15 males) with a mean age of 6±3.5 years (range, 2–14 years) underwent 26 endoscopic DCR operations for congenital NLDO. Sixteen cases were unilateral, and five were bilateral. In 13 cases (50.0%), there was a history of epiphora and chronic dacryocystitis with or without a mucocele. Two cases (7.7%) presented with acute dacryocystitis, and 11 (42.3%) had only a history of epiphora. Previous procedures included probing and irrigation in 25 cases (96.2%) and insertion of Crawford tubes in 19 cases 973.1%). During a mean postoperative follow-up period of 18±8 months, the anatomical success rate (free flow of fluorescein sodium and patency of ostium on nasal endoscopy) was 100%, and the clinical success rate (resolution of epiphora) was 92.3%. Conclusion Endoscopic endonasal DCR is an effective treatment modality for congenital NLDO that compares favourably with the reported success rates of external DCR.Igal Leibovitch, Dinesh Selva, Angelo Tsirbas, Edward Greenrod, John Pater and Peter J. Wormal