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

Comparison in the quality of distractors in three and four options type of multiple choice questions

Nourelhouda A A Rahma,1 Mahdi M A Shamad,2 Muawia E A Idris,1 Omer Abdelgadir Elfaki,3 Walyedldin E M Elfakey,4&ndash;6 Karimeldin M A Salih3,7 1Pediatrics Department, University of Bahri, College of Medicine, Sudan; 2Dermatology and Venereology Department, University of Bahri, College of Medicine, Khartoum, Sudan; 3Medical Education Department, King Khalid University, College of Medicine, Kingdom of Saudi Arabia; 4Department of Pediatrics, University of Bahri, College of Medicine, 5Medical Education Department, 6Pediatrics Department, Albaha University, College of Medicine, Kingdom of Saudi Arabia; 7Medical Education Department, University of Bahri, College of Medicine, Pediatrics, Khartoum, Sudan Introduction: The number of distractors needed for high quality multiple choice questions (MCQs) will be determined by many factors. These include firstly whether English language is their mother tongue or a foreign language; secondly whether the instructors who construct the questions are experts or not; thirdly the time spent on constructing the options is also an important factor. It has been observed by Tarrant et al that more time is often spent on constructing questions than on tailoring sound, reliable, and valid distractors. Objectives: Firstly, to investigate the effects of reducing the number of options on psychometric properties of the item. Secondly, to determine the frequency of functioning distractors among three or four options in the MCQs examination of the dermatology course in University of Bahri, College of Medicine.Materials and methods: This is an experimental study which was performed by means of a dermatology exam, MCQs type. Forty MCQs, with one correct answer for each question were constructed. Two sets of this exam paper were prepared: in the first one, four options were given, including one key answer and three distractors. In the second set, one of the three distractors was deleted randomly, and the sequence of the questions was kept in the same order. Any distracter chosen by less than 5% of the students was regarded as non-functioning. Kuder-Richardson Formula 20 (Kr-20) measures the internal consistency and reliability of an examination with an acceptable range 0.8&ndash;1.0. Chi square test was used to compare the distractors in the two exams. Results: A significant difference was observed in discrimination and difficulty indexes for both sets of MCQs. More distractors were non-functional for set one (of four options), but slightly more reliable. The reliability (Kr-20) was slightly higher for set one (of four options). The average marks in option three and four were 34.163 and 33.140, respectively. Conclusion: Compared to set 1 (four options), set 2 (of three options) was more discriminating and associated with low difficulty index but its reliability was low. Keywords: option, distractors, reliability, discrimination, MCQ

The complement regulator CD46 is bactericidal to Helicobacter pylori and blocks urease activity

BACKGROUND & AIMS: CD46 is a C3b/C4b binding complement regulator and a receptor for several human pathogens. We examined the interaction between CD46 and Helicobacter pylori (a bacterium that colonizes the human gastric mucosa and causes gastritis), peptic ulcers, and cancer. METHODS: Using gastric epithelial cells, we analyzed a set of H pylori strains and mutants for their ability to interact with CD46 and/or influence CD46 expression. Bacterial interaction with full-length CD46 and small CD46 peptides was evaluated by flow cytometry, fluorescence microscopy, enzyme-linked immunosorbent assay, and bacterial survival analyses. RESULTS: H pylori infection caused shedding of CD46 into the extracellular environment. A soluble form of CD46 bound to H pylori and inhibited growth, in a dose- and time-dependent manner, by interacting with urease and alkyl hydroperoxide reductase, which are essential bacterial pathogenicity-associated factors. Binding of CD46 or CD46-derived synthetic peptides blocked the urease activity and ability of bacteria to survive in acidic environments. Oral administration of one CD46 peptide eradicated H pylori from infected mice. CONCLUSIONS: CD46 is an antimicrobial agent that can eradicate H pylori. CD46 peptides might be developed to treat H pylori infection

Empowering the immune fate of bone marrow mesenchymal stromal cells: gene and protein changes

Objective and design: Bone marrow mesenchymal stromal cells (BM-MSCs) are referred as a promising immunotherapeutic cell product. New approaches using empowered MSCs should be developed as for the treatment or prevention of different immunological diseases. Such preconditioning by new licensing stimuli will empower the immune fate of BM-MSCs and, therefore, promote a better and more efficient biological. Here, our main goal was to establish the immunological profile of BM-MSCs following inflammatory priming and in particular their capacity to adjust their immune-related proteome and transcriptome. Material and methods: To run this study, we have used BM-MSC cell cultures, a pro-inflammatory cytokine cocktail priming, flow cytometry analysis, qPCR and ELISA techniques. Results: Different expression levels of several immunological mediators such as COX-1, COX-2, LIF, HGF, Gal-1, HO-1, IL-11, IL-8, IL-6 and TGF-β were constitutively observed in BM-MSCs. Inflammation priming substantially but differentially modulated the gene and protein expression profiles of these mediators. Thus, expressions of COX-2, LIF, HGF, IL-11, IL-8 and IL-6 were highly increased/induced and those of COX-1, Gal-1, and TGF-β were reduced. Conclusions: Collectively, we demonstrated that BM-MSCs are endowed with a specific and modular regulatory machinery which is potentially involved in immunomodulation. Moreover, BM-MSCs are highly sensitive to inflammation and respond to such signal by properly adjusting their gene and protein expression of regulatory factors. Using such preconditioning may empower the immune fate of MSCs and, therefore, enhance their value for cell-based immunotherapy.SCOPUS: ar.jinfo:eu-repo/semantics/publishe