Defining the Critical Hurdles in Cancer Immunotherapy

ABSTRACT: Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators, others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet be overcome to improve outcomes of patients with cancer

Antibody Blood-Brain Barrier Efflux Is Modulated by Glycan Modification

Background Drug delivery to the brain is a major roadblock to treatment of Alzheimer\u27s disease. Recent results of the PRIME study indicate that increasing brain penetration of antibody drugs improves Alzheimer\u27s treatment outcomes. New approaches are needed to better accomplish this goal. Based on prior evidence, the hypothesis that glycan modification alters antibody blood-brain barrier permeability was tested here. Methods The blood-brain barrier permeability coefficient Pe of different glycosylated states of anti-amyloid IgG was measured using in vitro models of brain microvascular endothelial cells. Monoclonal antibodies 4G8, with sialic acid, and 6E10, lacking sialic acid, were studied. The amount of sialic acid was determined using quantitative and semi-quantitative surface plasmon resonance methods. Results Influx of IgG was not saturable and was largely insensitive to IgG species and glycosylation state. By contrast, efflux of 4G8 efflux was significantly lower than both albumin controls and 6E10. Removal of α2,6-linked sialic acid group present on 12% of 4G8 completely restored efflux to that of 6E10 but increasing the α2,6-sialylated fraction to 15% resulted in no change. Removal of the Fc glycan from 4G8 partially restored efflux. Alternate sialic acid groups with α2,3 and α2,8 linkages, nor on the Fc glycan, were not detected at significant levels on either 4G8 or 6E10. Conclusions These results support a model in which surface-sialylated 4G8 inhibits its own efflux and that of asialylated 4G8. General significance Glycan modification has the potential to increase antibody drug penetration into the brain through efflux inhibition. © 2017 Elsevier B.V

Spatial updating of targets in front and behind

This research compared the accuracy of spatial updating of targets in front with that of targets behind. The participant viewed a target on the ground several meters away and then, without vision, sidestepped along a guide rope while trying to mentally update the location of the target. On some trials, the target location was in front as the person sidestepped and, on other trials, the target location was behind. Participants responded by facing the updated target location with eyes closed. The results indicate that people are able to update target locations behind them very nearly as well as target locations in front

Discovery of Thanafactin A, a Linear Proline-containing Octa-Lipopeptide from Pseudomonas sp. SH-C52, Motivated by Genome Mining

Genome mining of the bacterial strains Pseudomonas sp. SH-C52 and Pseudomonas fluorescens DSM 11579 showed that both strains contained a highly similar gene cluster encoding an octamodular nonribosomal peptide synthetase (NRPS) system which was not associated with a known secondary metabolite. Insertional mutagenesis of an NRPS component followed by comparative profiling led to the discovery of the corresponding novel linear octalipopeptide thanafactin A, which was subsequently isolated and its structure determined by two-dimensional NMR and further spectroscopic and chromatographic methods. In bioassays, thanafactin A exhibited weak protease inhibitory activity and was found to modulate swarming motility in a strain-specific manner