Delta-24-RGD combined with radiotherapy exerts a potent antitumor effect in diffuse intrinsic pontine glioma and pediatric high grade glioma models

Abstract

Pediatric high grade gliomas (pHGG), including diffuse intrinsic pontine gliomas (DIPGs), are aggressive tumors with a dismal outcome. Radiotherapy (RT) is part of the standard of care of these tumors; however, radiotherapy only leads to a transient clinical improvement. Delta-24-RGD is a genetically engineered tumor-selective adenovirus that has shown safety and clinical efficacy in adults with recurrent gliomas. In this work, we evaluated the feasibility, safety and therapeutic efficacy of Delta-24-RGD in combination with radiotherapy in pHGGs and DIPGs models. Our results showed that the combination of Delta-24-RGD with radiotherapy was feasible and resulted in a synergistic anti-glioma effect in vitro and in vivo in pHGG and DIPG models. Interestingly, Delta-24-RGD treatment led to the downregulation of relevant DNA damage repair proteins, further sensitizing tumors cells to the effect of radiotherapy. Additionally, Delta-24-RGD/radiotherapy treatment significantly increased the trafficking of immune cells (CD3, CD4+ and CD8+) to the tumor niche compared with single treatments. In summary, administration of the Delta-24-RGD/radiotherapy combination to pHGG and DIPG models is safe and significantly increases the overall survival of mice bearing these tumors. Our data offer a rationale for the combination Delta-24-RGD/radiotherapy as a therapeutic option for children with these tumors. Significance Delta-24-RGD/radiotherapy administration is safe and significantly increases the survival of treated mice. These positive data underscore the urge to translate this approach to the clinical treatment of children with pHGG and DIPGs. Electronic supplementary material The online version of this article (10.1186/s40478-019-0714-6) contains supplementary material, which is available to authorized users.

<p>Preclinical And Clinical Development Of Oncolytic Adenovirus For The Treatment Of Malignant Glioma</p>

“…Intratumoral administration of DNX-2401 was safe in mice and resulted in a significant increase of survival rate in both immunodeficient and immunocompetent models of pHGG and DIPG 61. The same group further showed that DNX-2401 treatment downregulated DNA damage repair proteins and when combined with radiotherapy mediated a synergistic anti-glioma effect in mouse models of pHGG and DIPG 62. Currently, a Phase I trial of DNX-2401 for newly diagnosed DIPG is ongoing in Spain (NCT0317803263).…”

Oncolytic Viruses as a Platform for the Treatment of Malignant Brain Tumors

“…The synergy between OVs and radiotherapy has also been assessed. Recently, Martínez-Velez et al demonstrated that combining the Delta-24-RGD virus with radiotherapy resulted in a synergistic antiglioma activity in vitro and in vivo in pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) models [ 135 ]. This combined therapy increased the tumor lymphocyte infiltration post-Delta-24-RGD injection, overcoming the immune “cold” status and potentially allowing the abscopal effect triggered by the radiotherapy to take place.…”

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“…Models using in utero electroporation to deliver PiggyBac DNA transposon plasmids expressing H3.3 K27M in neural progenitor cells have also been developed [22,23]. Marigil et al recently developed a guide-screw system based DIPG xenograft model, which allows the generation of tumors in a fast and reproducible fashion and allows to deliver the therapeutics via the same screw fixed system route [6,24,25]. Smith et al recently performed a comprehensive histopathological and molecular analysis of 37 novel patient-derived orthotopic xenograft (PDOX) models developed from pediatric brain tumor patients [26], associated datasets can be accessed at (http://pbtp.stjude.cloud).…”

“…The differentiation, maturation, activation, and proliferation of T cells are disrupted by these MDSCs, ultimately leading to T cell exhaustion and death. stand out as potential treatments due to their minimal invasiveness and comprehensive tumor-eradicating capability [6,7,25,27,34]. The DIPG microenvironment contains low levels of antigen presenting cells (APCs) and adaptive immune cells, contributing to the tumor's ability to grow undetected by the immune system [27,34,35].…”

“…These factors make immunotherapies strong candidates for DIPG treatment. Oncolytic adenoviruses have emerged as promising immunotherapies capable of effectively treating DIPGs [6,7,25,34]. One virus in particular, DNX-2401, is currently in Phase I trials (NCT03178032).…”