Processing laboratory considerations for multi-center cellular therapy clinical trials: a report from the Consortium for Pediatric Cellular Immunotherapy

``Cellular therapies first emerged as specialized therapies only available at a few “boutique” centers worldwide. To ensure broad access to these investigational therapies—regardless of geography, demographics and other factors—more and more academic clinical trials are becoming multi-center. Such trials are typically performed with a centralized manufacturing facility receiving the starting material and shipping the final product, either fresh or cryopreserved, to the patient's institution for infusion. As these academic multi-center trials increase in number, it is critical to have procedures and training programs in place to allow these sites that are remote from the production facility to successfully participate in these trials and satisfy regulatory compliance and patient safety best practices. Based on the collective experience of the Consortium for Pediatric Cellular Immunotherapy, the authors summarize the challenges encountered by institutions in shipping and receiving the starting material and final product as well as preparing the final product for infusion. The authors also discuss best practices implemented by each of the consortia institutions to overcome these challenges.     

Mechanical scale and load cell underwater weighing: a comparison of simultaneous measurements and the reliability of methods

Both load cell and mechanical scale-based hydrostatic weighing (HW) systems are used for the measurement of underwater weight. However, there has been no direct comparison of the 2 methods. The purpose of the current investigation was to simultaneously compare a load cell and mechanical scale for use in HW. Twenty-seven men and women (mean ± SD, age: 22 ± 2 years) participated in the 2-day investigation. Each subject completed 2 HW assessments 24 hours apart. Single-day comparisons of all trials for both days revealed no significant difference between the mechanical scale and the load cell (mean difference < 0.016 kg, p > 0.05). True underwater weight values were not significantly different between methods for either days (mean difference < 0.014 kg, p > 0.05) and accounted for a mean difference in percent fat (%FAT) of <0.108%. The 95% limits of agreement indicated a maximum difference between methods of 0.53% FAT. Both methods produced similar reliability SEM values (mechanical SEM < 0.72%FAT, load cell SEM < 0.75%FAT). In conclusion, there was no difference between mechanical scale and load cell measurements of underwater weights and the added precision of the load cell only marginally (<0.16%FAT) improved day-to-day reliability. Either a mechanical scale or load cell can be used for HW with similar accuracy and reliability in young adults with a body mass index of 18.7-34.4 (5-25%FAT).     

Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity

As an approved vaccine adjuvant for use in humans, alum has vast health implications, but, as it is a crystal, questions remain regarding its mechanism. Furthermore, little is known about the target cells, receptors, and signaling pathways engaged by alum. Here we report that, independent of inflammasome and membrane proteins, alum binds dendritic cell (DC) plasma membrane lipids with substantial force. Subsequent lipid sorting activates an abortive phagocytic response that leads to antigen uptake. Such activated DCs, without further association with alum, show high affinity and stable binding with CD4(+) T cells via the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1). We propose that alum triggers DC responses by altering membrane lipid structures. This study therefore suggests an unexpected mechanism for how this crystalline structure interacts with the immune system and how the DC plasma membrane may behave as a general sensor for solid structures.     

Efficacy in asthma of once-daily treatment with fluticasone furoate: a randomized,placebo-controlled trial

Background

Fluticasone furoate (FF) is a novel long-acting inhaled corticosteroid (ICS). This double-blind, placebo-controlled randomized study evaluated the efficacy and safety of FF 200 mcg or 400 mcg once daily, either in the morning or in the evening, and FF 200 mcg twice daily (morning and evening), for 8 weeks in patients with persistent asthma.

Methods

Asthma patients maintained on ICS for ≥ 3 months with baseline morning forced expiratory volume in one second (FEV₁) 50-80% of predicted normal value and FEV₁ reversibility of ≥ 12% and ≥ 200 ml were eligible. The primary endpoint was mean change from baseline FEV₁ at week 8 in pre-dose (morning or evening [depending on regimen], pre-rescue bronchodilator) FEV₁.

Results

A total of 545 patients received one of five FF treatment groups and 101 patients received placebo (intent-to-treat population). Each of the five FF treatment groups produced a statistically significant improvement in pre-dose FEV₁ compared with placebo (p < 0.05). FF 400 mcg once daily in the evening and FF 200 mcg twice daily produced similar placebo-adjusted improvements in evening pre-dose FEV₁ at week 8 (240 ml vs. 235 ml). FF 400 mcg once daily in the morning, although effective, resulted in a smaller improvement in morning pre-dose FEV₁ than FF 200 mcg twice daily at week 8 (315 ml vs. 202 ml). The incidence of oral candidiasis was low (0-4%) and UC excretion was comparable with placebo for all FF groups.

Conclusions

FF at total daily doses of 200 mcg or 400 mcg was significantly more effective than placebo. FF 400 mcg once daily in the evening had similar efficacy to FF 200 mcg twice daily and all FF regimens had a safety tolerability profile generally similar to placebo. This indicates that inhaled FF is an effective and well tolerated once-daily treatment for mild-to-moderate asthma.

Trial registration

NCT00398645     

Our microbial selves: what ecology can teach us

Advances in DNA sequencing have allowed us to characterize microbial communities--including those associated with the human body--at a broader range of spatial and temporal scales than ever before. We can now answer fundamental questions that were previously inaccessible and use well-tested ecological theories to gain insight into changes in the microbiome that are associated with normal development and human disease. Perhaps unsurprisingly, the ecosystems associated with our body follow trends identified in communities at other sites and scales, and thus studies of the microbiome benefit from ecological insight. Here, we assess human microbiome research in the context of ecological principles and models, focusing on diversity, biological drivers of community structure, spatial patterning and temporal dynamics, and suggest key directions for future research that will bring us closer to the goal of building predictive models for personalized medicine.     

Personality and social context

There has been considerable interest among biologists in the phenomenon of non‐human animal personality in recent years. Consistent variations among individuals in their behavioural responses to ecologically relevant stimuli, often relating to a trade‐off between level of risk and reward, have been recorded in a wide variety of species, representing many animal taxa. Research into behavioural variation among individuals has major implications for our understanding of ecological patterns and processes at scales from the level of the individual to the level of the population. Until recently, however, many studies that have considered the broader ecological implications of animal personality have failed to take into account the crucial moderating effect of social context. It is well documented that social processes, such as conformity and facilitation, exert considerable influence on the behaviour of grouping animals and hence that isolated individuals may often behave in a qualitatively as well as quantitatively different manner to those in groups. Recently, a number of studies have begun to address aspects of this gap in our knowledge and have provided vital insights. In this review we examine the state of our knowledge on the relationship between individual personality and sociality. In doing so we consider the influence of the social context on individual personality responses, the interaction between the collective personalities of group members and the expression of those personalities in the individual, and the influence of the personalities of group members on group structure and function. We propose key areas of focus for future studies in order to develop our understanding of this fundamentally important area.