JAMA Neurol

Importance: Moderately effective therapies (METs) have been the main treatment in pediatric-onset multiple sclerosis (POMS) for years. Despite the expanding use of highly effective therapies (HETs), treatment strategies for POMS still lack consensus.Objective: To assess the real-world association of HET as an index treatment compared with MET with disease activity.Design, setting, and participants: This was a retrospective cohort study conducted from January 1, 2010, to December 8, 2022, until the last recorded visit. The median follow-up was 5.8 years. A total of 36 French MS centers participated in the Observatoire Français de la Sclérose en Plaques (OFSEP) cohort. Of the total participants in OFSEP, only treatment-naive children with relapsing-remitting POMS who received a first HET or MET before adulthood and at least 1 follow-up clinical visit were included in the study. All eligible participants were included in the study, and none declined to participate.Exposure: HET or MET at treatment initiation.Main outcomes and measures: The primary outcome was the time to first relapse after treatment. Secondary outcomes were annualized relapse rate (ARR), magnetic resonance imaging (MRI) activity, time to Expanded Disability Status Scale (EDSS) progression, tertiary education attainment, and treatment safety/tolerability. An adapted statistical method was used to model the logarithm of event rate by penalized splines of time, allowing adjustment for effects of covariates that is sensitive to nonlinearity and interactions.Results: Of the 3841 children (5.2% of 74 367 total participants in OFSEP), 530 patients (mean [SD] age, 16.0 [1.8] years; 364 female [68.7%]) were included in the study. In study patients, both treatment strategies were associated with a reduced risk of first relapse within the first 2 years. HET dampened disease activity with a 54% reduction in first relapse risk (adjusted hazard ratio [HR], 0.46; 95% CI, 0.31-0.67; P < .001) sustained over 5 years, confirmed on MRI activity (adjusted odds ratio [OR], 0.34; 95% CI, 0.18-0.66; P = .001), and with a better tolerability pattern than MET. The risk of discontinuation at 2 years was 6 times higher with MET (HR, 5.97; 95% CI, 2.92-12.20). The primary reasons for treatment discontinuation were lack of efficacy and intolerance. Index treatment was not associated with EDSS progression or tertiary education attainment (adjusted OR, 0.51; 95% CI, 0.24-1.10; P = .09).Conclusions and relevance: Results of this cohort study suggest that compared with MET, initial HET in POMS was associated with a reduction in the risk of first relapse with an optimal outcome within the first 2 years and was associated with a lower rate of treatment switching and a better midterm tolerance in children. These findings suggest prioritizing initial HET in POMS, although long-term safety studies are needed.Observatoire Français de la Sclérose en Plaque

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

L'interaction plaquettes sanguines-levures in vivo et ses conséquences

Les mycoses systémiques sont en constante augmentation depuis deux décennies. Parmi celles-ci, les candidoses et les cryptococcoses disséminées représentent à elles seules 80% des infections fongiques nosocomiales. Lorsque la dissémination des levures, à partir d'un foyer infectieux primaire, se fait par voie hématogène, elles peuvent interagir avec les composants sanguins en particulier avec les plaquettes. Dans le but d'étudier les mécanismes et les conséquences de l'interaction plaquettes sanguines-levures in vivo, nous avons développé un modèle de levurose disséminée chez la souris. Après injection intraveineuse des levures, leur cinétique de disparition du sang périphérique est très rapide d'où l'hypothèse d'une formation d'agrégats plaquettes-levures qui seraient bloqués dans les capillaires profonds. L'étude du sang des souris inoculées avec C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, C. krusei, C. guilliermondii et S. cerevisiae montre que plus de 90% des blastospores sont liées à une ou plusieurs plaquettes. Pour C. neoformans, la présence de la capsule inhibe l'interaction avec les plaquettes. Nous avons également constaté que l'interaction de C. albicans avec les plaquettes pouvait être affectée par l'EDTA ou l'EGTA, alors que ces agents ne modifient pas l'interaction des autres espèces avec les plaquettes. Deux systèmes de fixation entre les levures et les plaquettes ont été envisagés, un calcium dépendant pour C. albicans et un calcium non dépendant pour les autres espèces. Les résultats de la microscopie électronique montrent que la fixation des plaquettes sur C. albicans s'accompagne d'une modification morphologique et d'une agrégation plaquettaire ce qui suggère une activation et donc une libération de composants plaquettaires dont les protéines microbicides plaquettaires (PMP). L'étude de l'action des protéines microbicides plaquettaires induite par l'action de la thrombine (tPMPs) sur différentes levures a montré que S. cerevisiae est sensible à ces tPMPs alors que C. albicans et C. glabrata sont résistantes à leur action microbicide. Nous avons caractérisé comme récepteur fongique pour les plaquettes une mannoprotéine de 55kDa pour C. albicans et 2 mannoprotéines de 45 et 55 kDa pour S. cerevisiae. L'utilisation, in vivo, de mutants de S. cerevisiae pour des gènes codant pour des protéines de masse moléculaire de 45 à 60 kDa a montré que comparativement à la souche sauvage S288C, la capacité des souches PCK1 et TIR4 à fixer les plaquettes est diminuée d'environ 50%. Avec la souche WSC2, cette diminution atteint les 80%. On peut donc supposer que le gène WSC2 code pour une protéine de surface de 55 kDa pouvant se lier aux plaquettes. La comparaison de la séquence d'acides nucléiques du gène WSC2 avec celle du génome de C. albicans nous donne un pourcentage d'homologie de 63% pour une séquence située sur le contig 2519. Toutefois le gène et sa fonction ne sont pas connus chez cette levure. L'identification chez C. albicans des gènes intervenant dans l'interaction plaquettes-levures permettra la construction de mutants qui seront ensuite testés in vivo pour l'étude de leur pouvoir pathogène.ANGERS-BU Médecine-Pharmacie (490072105) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

New Monoclonal Antibody Specific for Candida albicans Germ Tube

Hydrophobic components of the germ tube of the dimorphic pathogenic fungus Candida albicans were used as immunogens to prepare monoclonal antibodies (MAbs). Among the resulting MAbs, one (MAb 16B1-F10) was shown by indirect immunofluorescence to be specific to the surface of the mycelium phase of the C. albicans and C. stellatoidea species. No labeling of any other genera and Candida species tested was observed, including C. dubliniensis, a newly described species which has many phenotypic similarities to C. albicans. This phase-specific epitope resides on a protein moiety. The molecular mass of the antigen released by Zymolyase digestion was determined by gel filtration and ranges from 25 to 166 kDa. The antigen was also shown to be highly hydrophobic. This anti-C. albicans cell wall surface-specific MAb may be a good candidate for use in tests for the rapid differentiation of the two closely related species C. albicans and C. dubliniensis