A Window of Opportunity to Overcome Therapeutic Failure in Neuro-Oncology

Abstract

Glioblastoma is the most common primary malignant brain neoplasm and it remains one of the most difficult-to-treat human cancers despite decades of discovery and translational and clinical research. Many advances have been made in our understanding of the genetics and epigenetics of gliomas in general; yet, there remains an urgent need to develop novel agents that will improve the survival of patients with this deadly disease. What sets glioblastoma apart from all other cancers is that it develops and spreads within an organ that renders tumor cells inaccessible to most systemically administered agents because of the presence of the blood-brain barrier. Inadequate drug penetration into the central nervous system is often cited as the most common cause of trial failure in neuro-oncology, and even so-called brain-penetrant therapeutics may not reach biologically relevant concentrations in tumor cells. Evaluation of the pharmacokinetics and pharmacodynamics of a novel therapy is a cornerstone of drug development, but few trials for glioma therapeutics have incorporated these basic elements in an organ-specific manner. Window-of-opportunity clinical trial designs can provide early insight into the biological plausibility of a novel therapeutic strategy in the clinical setting. A variety of window-of-opportunity trial designs, which take into account the limited access to treated tissue and the challenges with obtaining pretreatment control tissues, have been used for the initial development of traditional and targeted small-molecule drugs and biologic therapies, including immunotherapies and oncolytic viral therapies. Early-stage development of glioma therapeutics should include a window-of-opportunity component whenever feasible.

Strategies to Improve Drug Delivery Across the Blood–Brain Barrier for Glioblastoma

“…2 ). The tissue also provides researchers with the potential to identify key biomarkers that can serve as endpoints to assess treatment response more faithfully [ 129 ]. In contrast to phase 0 trials, WoO trials occur after phase I evaluations and typically use higher drug concentrations than the sub-therapeutic microdoses used in phase 0 trials to establish human pharmacokinetics and the suitability of drug candidates to advance to phase 1.…”

Protocol to quantify immune cell distribution from the vasculature to the glioma microenvironment on sequential immunofluorescence multiplex images

“… 3 With the development of strategies that now open the BBB in clinical trials 4 and a variety of immune therapeutics that may enhance distribution, 5 quantification of immune cells in various TME regions will be increasingly needed for endpoint evaluations during window-of-opportunity clinical trials. 6 , 7 The protocol below describes the specific steps for spatial bioinformatic analysis of immune cell distribution from the tumor vasculature on sequential multiplex immunofluorescence images. Baseline immune cell distribution including markers of activation and immune suppression in gliomas, before initiating an immunotherapy clinical trial, were quantified based on the distribution in the TME as a function of the tumor vasculature.…”

Drug Repurposing, a Fast-Track Approach to Develop Effective Treatments for Glioblastoma

“…These “window-of-opportunity” phase 0 trials, as recently reviewed by Vogelbaum et al [ 219 ], have successfully demonstrated target delivery and drug activity for some of these agents, subsequently allowing them to move to phase 2 clinical investigations. As a next step, even more personalized approaches can be envisioned, in which confirmed drug delivery is a pre-requisite for follow-up treatment with any drug being investigated, therewith accounting for inter-patient variability in BBB functionality.…”