Abstract
Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors in desperate need of a curative treatment. Oncolytic virotherapy is emerging as a solid therapeutic approach. Delta-24-RGD is a replication competent adenovirus engineered to replicate in tumor cells with an aberrant RB pathway. This virus has proven to be safe and effective in adult gliomas. Here we report that the administration of Delta-24-RGD is safe in mice and results in a significant increase in survival in immunodeficient and immunocompetent models of pHGG and DIPGs. Our results show that the Delta-24-RGD antiglioma effect is mediated by the oncolytic effect and the immune response elicited against the tumor. Altogether, our data highlight the potential of this virus as treatment for patients with these tumors. Of clinical significance, these data have led to the start of a phase I/II clinical trial at our institution for newly diagnosed DIPG (NCT03178032).
Highlights
Pediatric high-grade glioma and diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors in desperate need of a curative treatment
The knowledge acquired from genomic data has supported the 2016 WHO reclassification of central nervous system (CNS) tumors in which DIPG is included in a new category named diffuse midline glioma (DMG) H3K27M-mutant[4]
To evaluate whether Pediatric high-grade glioma (pHGG) and DMG/DIPG are susceptible to viral infection, using a cohort of 220 patient samples of pHGG and DMG/DIPG previously published[1], we performed “in silico analyses” of the expression of the following main receptors that use Delta-24-RGD to enter cells: Coxsackie adenovirus receptor (CAR; CXADR), integrinαVβ3 (ITGA3), integrinαVβ5 (ITGA5), and integrinαVβ (ITGAV)
Summary
Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors in desperate need of a curative treatment. 2 Program of Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Navarra, Pamplona, Spain. Division of Pediatric Neurosurgery, Department of Surgery, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, USA. Pediatric high-grade glioma (pHGG), including diffuse intrinsic pontine glioma (DIPG), are aggressive solid tumors that develop during childhood. The knowledge acquired from genomic data has supported the 2016 WHO reclassification of central nervous system (CNS) tumors in which DIPG is included in a new category named diffuse midline glioma (DMG) H3K27M-mutant[4]. The recent approval of T-VEC (Talimogene laherparepvec), which is an oncolytic herpes virus, by the FDA for metastatic melanoma has enabled the possibility to use other oncolytic viruses as standard treatment for cancer[11]
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