Chagas disease treatment efficacy markers: experiences from a Phase III study with nifurtimox in children

Determining the success of antitrypanosomal therapy for Chagas disease is challenging, particularly in the chronic phase of the disease, because seropositivity persists for a long time after successful antitrypanosomal treatment and is known to be related to the duration of Trypanosoma cruzi infection. Seroconversion to negative by two or more conventional serologic tests is the currently accepted measure of efficacy, and studies suggest no significant change in seropositivity if left untreated. However, there is no guidance for industry on how to establish the effectiveness of drugs intended for the treatment of Chagas disease. Due to the lack of validated sensitive, specific, easy-to-use markers that allow early monitoring of the efficacy of antitrypanosomal treatment in an efficient manner, we used seroreduction measured by two conventional enzyme-linked immunosorbent assays in addition to the currently accepted criterion for what constitutes a cure, seroconversion to negative, as a surrogate parameter for efficacy in a Phase III pediatric trial with nifurtimox. The measures for confirmation of the antitrypanosomal efficacy of nifurtimox were discussed with US FDA. In this perspective article, we present our experiences obtained from a pediatric study on Chagas disease with an established drug using a surrogate efficacy parameter in addition to the established criterion for a cure

PhotoSpec: A new instrument to measure spatially distributed red and far-red Solar-Induced Chlorophyll Fluorescence

Solar-Induced Chlorophyll Fluorescence (SIF) is an emission of light in the 650–850 nm spectral range from the excited state of the chlorophyll-a pigment after absorption of photosynthetically active radiation (PAR). As this is directly linked to the electron transport chain in oxygenic photosynthesis, SIF is a powerful proxy for photosynthetic activity. SIF observations are relatively new and, while global scale measurements from satellites using high-resolution spectroscopy of Fraunhofer bands are becoming more available, observations at the intermediate canopy scale using these techniques are sparse. We present a novel ground-based spectrometer system - PhotoSpec - for measuring SIF in the red (670–732 nm) and far-red (729–784 nm) wavelength range as well as canopy reflectance (400–900 nm) to calculate vegetation indices, such as the normalized difference vegetation index (NDVI), the enhanced vegetation index (EVI), and the photochemical reflectance index (PRI). PhotoSpec includes a 2D scanning telescope unit which can be pointed to any location in a canopy with a narrow field of view (FOV = 0.7°). PhotoSpec has a high signal-to-noise ratio and spectral resolution, which allows high precision solar Fraunhofer line retrievals over the entire fluorescence wavelength range under all atmospheric conditions using a new two-step linearized least-squares retrieval procedure. Initial PhotoSpec observations include the diurnal SIF cycle of single broad leaves, grass, and dark-light transitions. Results from the first tower-based measurements in Costa Rica show that the instrument can continuously monitor SIF of several tropical species throughout the day. The PhotoSpec instrument can be used to explore the relationship between SIF, photosynthetic efficiencies, Gross Primary Productivity (GPP), and the impact of canopy radiative transfer, viewing geometry, and stress conditions at the canopy scale

Moxifloxacin in Pediatric Patients With Complicated Intra-abdominal Infections: Results of the MOXIPEDIA Randomized Controlled Study

Background: This study was designed to evaluate primarily the safety and also the efficacy of moxifloxacin (MXF) in children with complicated intraabdominal infections (cIAIs). Methods: In this multicenter, randomized, double-blind, controlled study, 451 pediatric patients aged 3 months to 17 years with cIAIs were treated with intravenous/oral MXF (N = 301) or comparator (COMP, intravenous ertapenem followed by oral amoxicillin/clavulanate; N = 150) for 5 to 14 days. Doses of MXF were selected based on the results of a Phase 1 study in pediatric patients (NCT01049022). The primary endpoint was safety, with particular focus on cardiac and musculoskeletal safety; clinical and bacteriologic efficacy at test of cure was also investigated. Results: The proportion of patients with adverse events (AEs) was comparable between the 2 treatment arms (MXF: 58.1% and COMP: 54.7%). The incidence of drug-related AEs was higher in the MXF arm than in the COMP arm (14.3% and 6.7%, respectively). No cases of QTc interval prolongation-related morbidity or mortality were observed. The proportion of patients with musculoskeletal AEs was comparable between treatment arms; no drug-related events were reported. Clinical cure rates were 84.6% and 95.5% in the MXF and COMP arms, respectively, in patients with confirmed pathogen(s) at baseline. Conclusions: MXF treatment was well tolerated in children with cIAIs. However, a lower clinical cure rate was observed with MXF treatment compared with COMP. This study does not support a recommendation of MXF for children with cIAIs when alternative more efficacious antibiotics with better safety profile are available

Prospective, historically controlled study to evaluate the efficacy and safety of a new paediatric formulation of nifurtimox in children aged 0 to 17 years with chagas disease one year after treatment (Chico)

Nifurtimox is a recommended treatment for Chagas disease, but data from treated children are limited. We investigated the efficacy, safety and tolerability of nifurtimox administered as divisible, dispersible 30 mg and 120 mg tablets in children with Chagas disease. In this blinded, controlled study conducted January 2016–July 2018, 330 patients aged <18 years from 25 medical centres across three South American countries were randomised 2:1 to nifurtimox 10–20 mg/kg/day (aged <12 years) or 8–10 mg/kg/day (aged ≥12 years) for 60 days (n = 219), or for 30 days plus placebo for 30 days (n = 111) (ClinicalTrials.gov NCT02625974). The primary outcome was anti-Trypanosoma cruzi serological response (negative seroconversion or seroreduction ≥20% in mean optical density from baseline determined by two conventional enzyme-linked immunosorbent assays) at 12 months in the 60-day treatment group versus historical placebo controls. Nifurtimox for 60 days achieved negative seroconversion (n = 10) and seroreduction (n = 62) in 72 patients (serological response 32.9%; 95% confidence interval [CI] 26.4%, 39.3%, of all treated patients), confirming superiority relative to the upper 95% CI of 16% for controls. In patients aged <8 months, 10/12 treated for 60 days (83.3%) and 5/7 treated for 30 days (71.4%) achieved negative seroconversion. Overall serological response was lower for 30-day than for 60-day nifurtimox (between-treatment difference 14.0% [95% CI 3.7%, 24.2%]). The frequency of T. cruzi-positive quantitative polymerase chain reactions decreased substantially from baseline levels (60-day regimen 53.4% versus 1.4%; 30-day regimen 51.4% versus 4.5%). Study drug-related treatment-emergent adverse events (TEAEs), which were observed in 62 patients (28.3%) treated for 60 days and 29 patients (26.1%) treated for 30 days, were generally mild or moderate and resolved without sequelae; 4.2% of all TEAEs led to nifurti-mox discontinuation. Age-and weight-adjusted nifurtimox for 60 days achieved a serological response at 12 months post-treatment that was superior to historical placebo, was well tolerated and had a favourable safety profile in children with Chagas disease. Although, at 1 year serological follow-up, efficacy of the shorter nifurtimox treatment was not comparable to the 60-day treatment regimen for the overall study population, further long-term follow-up of the patients will provide important information about the progress of serological conversion in children treated with nifurtimox, as well as the potential efficacy difference between the two regimens over time.Fil: Altcheh, Jaime Marcelo. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; ArgentinaFil: Castro, Luis. Centro de Atención E Investigación Médica; ColombiaFil: Dib, Juan C.. Universidad del Norte; ColombiaFil: Grossmann, Ulrike. No especifíca;Fil: Huang, Erya. No especifíca;Fil: Moscatelli, Guillermo. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; ArgentinaFil: Pinto Rocha, Jimy José. Fundación Ceades; BoliviaFil: Ramírez, Teresa Estela. Centro de Enfermedad de Chagas y Patologias Regionales; Argentin

PhotoSpec: A new instrument to measure spatially distributed red and far-red Solar-Induced Chlorophyll Fluorescence

Solar-Induced Chlorophyll Fluorescence (SIF) is an emission of light in the 650–850 nm spectral range from the excited state of the chlorophyll-a pigment after absorption of photosynthetically active radiation (PAR). As this is directly linked to the electron transport chain in oxygenic photosynthesis, SIF is a powerful proxy for photosynthetic activity. SIF observations are relatively new and, while global scale measurements from satellites using high-resolution spectroscopy of Fraunhofer bands are becoming more available, observations at the intermediate canopy scale using these techniques are sparse. We present a novel ground-based spectrometer system - PhotoSpec - for measuring SIF in the red (670–732 nm) and far-red (729–784 nm) wavelength range as well as canopy reflectance (400–900 nm) to calculate vegetation indices, such as the normalized difference vegetation index (NDVI), the enhanced vegetation index (EVI), and the photochemical reflectance index (PRI). PhotoSpec includes a 2D scanning telescope unit which can be pointed to any location in a canopy with a narrow field of view (FOV = 0.7°). PhotoSpec has a high signal-to-noise ratio and spectral resolution, which allows high precision solar Fraunhofer line retrievals over the entire fluorescence wavelength range under all atmospheric conditions using a new two-step linearized least-squares retrieval procedure. Initial PhotoSpec observations include the diurnal SIF cycle of single broad leaves, grass, and dark-light transitions. Results from the first tower-based measurements in Costa Rica show that the instrument can continuously monitor SIF of several tropical species throughout the day. The PhotoSpec instrument can be used to explore the relationship between SIF, photosynthetic efficiencies, Gross Primary Productivity (GPP), and the impact of canopy radiative transfer, viewing geometry, and stress conditions at the canopy scale

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