Rechberger, Julian S

High-grade gliomas (HGG) are devastating diseases in children and adults. In the pediatric population, diffuse midline gliomas (DMG) harboring H3K27 alterations are the most aggressive primary malignant brain tumors. With no effective therapies available, children typically succumb to disease within one year of diagnosis. In adults, glioblastoma (GBM) remains largely intractable, with a median survival of approximately 14 months despite standard clinical care of radiation and temozolomide. Therefore, effective therapies for these tumors remain one of the most urgent and unmet needs in modern medicine. Interleukin 13 receptor subunit alpha 2 (IL-13Rα2) is a cell-surface transmembrane protein upregulated in many HGGs, including DMG and adult GBM, posing a potentially promising therapeutic target for these tumors. In this study, we investigated the pharmacological effects of GB-13 (also known as IL13.E13K-PE4E), a novel peptide–toxin conjugate that contains a targeting moiety designed to bind IL-13Rα2 with high specificity and a point-mutant cytotoxic domain derived from Pseudomonas exotoxin A. Glioma cell lines demonstrated a spectrum of IL-13Rα2 expression at both the transcript and protein level. Anti-tumor effects of GB-13 strongly correlated with IL-13Rα2 expression and were reflected in apoptosis induction and decreased cell proliferation in vitro. Direct intratumoral administration of GB-13 via convection-enhanced delivery (CED) significantly decreased tumor burden and resulted in prolonged survival in IL-13Rα2-upregulated orthotopic xenograft models of HGG. In summary, administration of GB-13 demonstrated a promising pharmacological response in HGG models both in vitro and in vivo in a manner strongly associated with IL-13Rα2 expression, underscoring the potential of this IL-13Rα2-targeted therapy in a subset of HGG with increased IL-13Rα2 levels.

Intra-arterial drug delivery circumvents the first-pass effect and is believed to increase both efficacy and tolerability of primary and metastatic brain tumor therapy. The aim of this update is to report on pertinent articles and clinical trials to better understand the research landscape to date and future directions. Elsevier’s Scopus and ClinicalTrials.gov databases were reviewed in August 2021 for all possible articles and clinical trials of intra-arterial drug injection as a treatment strategy for brain tumors. Entries were screened against predefined selection criteria and various parameters were summarized. Twenty clinical trials and 271 articles satisfied all inclusion criteria. In terms of articles, 201 (74%) were primarily clinical and 70 (26%) were basic science, published in a total of 120 different journals. Median values were: publication year, 1986 (range, 1962–2021); citation count, 15 (range, 0–607); number of authors, 5 (range, 1–18). Pertaining to clinical trials, 9 (45%) were phase 1 trials, with median expected start and completion years in 2011 (range, 1998–2019) and 2022 (range, 2008–2025), respectively. Only one (5%) trial has reported results to date. Glioma was the most common tumor indication reported in both articles (68%) and trials (75%). There were 215 (79%) articles investigating chemotherapy, while 13 (65%) trials evaluated targeted therapy. Transient blood–brain barrier disruption was the commonest strategy for articles (27%) and trials (60%) to optimize intra-arterial therapy. Articles and trials predominately originated in the United States (50% and 90%, respectively). In this bibliometric and clinical trials analysis, we discuss the current state and trends of intra-arterial therapy for brain tumors. Most articles were clinical, and traditional anti-cancer agents and drug delivery strategies were commonly studied. This was reflected in clinical trials, of which only a single study had reported outcomes. We anticipate future efforts to involve novel therapeutic and procedural strategies based on recent advances in the field.

OBJECTIVE Convection-enhanced delivery (CED) and osmotic pump delivery both have been promoted as promising techniques to deliver drugs to pediatric diffuse intrinsic pontine gliomas (DIPGs). Correspondingly, the aim of this study was to understand how infusate molecular weight (MW), duration of delivery, and mechanism of delivery (CED or osmotic pump) affect volume of distribution (V d ) in the brainstem, to better inform drug selection and delivery in future DIPG investigations. METHODS A series of in vivo experiments were conducted using rat models. CED and osmotic pump delivery systems were surgically implanted in the brainstem, and different MW fluorescent dextran beads were infused either once (acute) or daily for 5 days (chronic) in a volume infused (V i ). Brainstems were harvested after the last infusion, and V d was quantified using serial sectioning and fluorescence imaging. RESULTS Fluorescence imaging showed infusate uptake within the brainstem for both systems without complication. A significant inverse relationship was observed between infusate MW and V d in all settings, which was distinctly exponential in nature in the setting of acute delivery across the 570-Da to 150-kDa range. Chronic duration and CED technique resulted in significantly greater V d compared to acute duration or osmotic pump delivery, respectively. When accounting for V i , acute infusion yielded significantly greater V d /V i than chronic infusion. The distribution in CED versus osmotic pump delivery was significantly affected by infusate MW at higher weights. CONCLUSIONS Here the authors demonstrate that infusate MW, duration of infusion, and infusion mechanism all impact the V d of an infused agent and should be considered when selecting drugs and infusion parameters for novel investigations to treat DIPGs.