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

Nasal potential difference test for detection of treatment response in cystic fibrosis

Cystic Fibrosis (CF) is the most common severe genetic disease among the Caucasian population. It is caused by mutations in the gene encoding the CFTR protein. CFTR is a c-AMP regulated anion channel expressed in the airways, intestine, pancreas and other epithelias. In the respiratory tract, CFTR is expressed at the apical pole of many bronchial, bronchiolar and alveolar cells. Loss of CFTR impairs electrolytes transport, causing hyperviscous mucus and a loss of pulmonary host defense due to impaired mucociliary clearance of bacteria. Nasal transepithelial ion transport generates a potential difference which is measurable and characteristic in CF patients. This test has long been used to assist in the diagnosis of atypical CF and CFTRopathies. More recently, it has been used as an outcome measure in clinical trials of new CF therapies. The technique is tricky. It is applicable in animal models and in humans. The expertise is rare in the field requiring dedicated equipment, supplies and well trained operators. This thesis aims at evaluating the potential and /or limitations of nasal potential difference (NPD) test as an effective tool to measure treatment effect in CF. The first objective of the thesis is to evaluate the therapeutic efficacy of miglustat in F508del homozygous CF patients using NPD as a primary endpoint. With the development of multicenter clinical trials around the world, an urgent need of standardizing the NPD test has emerged. A standardized operating protocol(SOP)has been validated and adopted by CF centers worldwide. However, data on reproducibility of this method in CF patients is missing. While practicing bench-to-bedside translational research, the second objective of the thesis is to compare variability of the NPD test in humans and mice using the latest SOP. A further objective of the thesis is to evaluate repeatability of TCS measurements with the latest SOP in CF patients homozygous for the F508del mutation in two different CF centres with two skilled and certified operators.(MED - Sciences médicales) -- UCL, 201

Mucoviscidose : l’espace bleu entre les nuages ?

Découvrir un traitement plus fondamental de la mucoviscidose est nécessaire, même si n’en profiteront pleinement que les patients dont les poumons auront pu être largement préservés jusque là. La voie la plus prometteuse est aujourd’hui celle d’une approche pharmacologique taillée sur mesure en fonction des mutations de chaque patient. Elle vise à remédier en partie à leurs conséquences sur la fonction de la protéine cystic fibrosis transmembrane conductance regulator (CFTR), déficiente dans cette affection. En 14 ans, 15 études impliquant des patients ont été publiées dans ce domaine. Elles concernaient 7substances : 8-cyclopentyl-1,3-dipropylxanthine (CPX), 4-Phenylbutyrate (4PBA), gentamicine, Ataluren® (PTC124), Miglustat et les composés Ivacaftor (VX-770) et Lumacaftor (VX-809). Un postulat commun à 14 de ces études était qu’un traitement efficace doit induire chez le patient une augmentation de la sécrétion de chlorure documentée in vivo par des mesures de la différence de potentiel nasal. Les résultats de ces études sont discutés dans cette mise au point, ainsi que leurs limitations, leurs contradictions apparentes et les questions qu’elles peuvent soulever sur l’outil d’évaluation. Ciblant une mutation qui concerne moins de 2 % des patients en France, les 2 études sur l’Ivacaftor sortent du lot et semblent constituer un jalon sur le chemin vers un traitement curatif de l’atteinte respiratoire de la mucoviscidose. La tolérance mais aussi l’efficacité à long terme de cette substance restent cependant à évaluer. En outre, son prix de vente actuellement très élevé aux États-Unis pose question

A randomized placebo-controlled trial of miglustat in cystic fibrosis based on nasal potential difference

BACKGROUND: Preclinical data suggest that miglustat could restore the function of the cystic fibrosis transmembrane conductance regulator gene in cystic fibrosis cells. METHODS: Single-center, randomized, double-blind, placebo-controlled, crossover Phase II study in 11 patients (mean±SD age, 26.3±7.7 years) homozygous for the F508del mutation received oral miglustat 200 mgt.i.d. or placebo for two 8-day cycles separated by a 14-day washout period. The primary endpoint was the change in total chloride secretion (TCS) assessed by nasal potential difference. RESULTS: No statistically significant changes in TCS, sweat chloride values or FEV(1) were detected. Pharmacokinetic and safety were similar to those observed in patients with other diseases exposed to miglustat. CONCLUSIONS: There was no evidence of a treatment effect on any nasal potential difference variable. Further studies with miglustat need to adequately address criteria for assessment of nasal potential difference

Mucoviscidose : les techniques instrumentales de désencombrement des voies aériennes

Introduction : Le recours aux manœuvres de désencombrement des voies aériennes fait partie intégrante de la prise en charge de la mucoviscidose. De nombreuses techniques sont décrites sans qu’une unanimité existe. Les techniques sont regroupées en techniques manuelles et instrumentales. État des connaissances : Les techniques instrumentales de désencombrement reposent sur l’application de vibrations ou d’une pression positive lors de la phase expiratoire. Cette pression positive est soit continue, soit oscillante. Plusieurs études ont tenté d’expliquer leurs effets au moyen de données physiologiques et se sont intéressées à leurs répercussions pour les patients avec des résultats non univoques. Perspectives : Bien qu’encore peu utilisées dans de nombreux pays, ces techniques reposent pourtant sur des données physiologiques qui méritent de leur accorder une place dans l’arsenal du kinésithérapeute. Conclusions : Une meilleure connaissance des techniques instrumentales devrait permettre de les intégrer au mieux dans la prise en charge des patients atteints de mucoviscidose

Sweat potassium concentration may help to identify falsification of sweat test: A case report

OBJECTIVES: To document the relevance of sweat potassium concentration in a reported case of a white Caucasian 27-month-old boy who presented with non-specific respiratory symptoms and several abnormal sweat test results compatible with cystic fibrosis (CF). DESIGN AND METHODS: Repeated sweat tests using the Gibson-Cooke technique in the presence and absence of the mother. RESULTS: The high within- and between-test variability, the very low sweat potassium concentrations, several aspects of the family's history and a negative exhaustive genetic analysis to identify any CFTR mutation, raised suspicion for pediatric condition falsification. Two additional sweat tests performed in the absence of the mother were normal. CONCLUSION: CF diagnosis was then discarded and a Munchausen syndrome by proxy diagnosis was proposed