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.SignificanceDelta-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.
Highlights
Pediatric high grade gliomas and diffuse intrinsic pontine gliomas (DIPGs) are malignant tumors present with an aggressive behavior [7]
We evaluated whether the combination of the oncolytic adenovirus, Delta-24-RGD (DNX-2401) [36], genetically engineered to destroy cancer cells, in combination with RT would result in a superior antitumor effect in Pediatric high grade gliomas (pHGG) and DIPGs when compared to either agent alone
Combination of Delta-24-RGD with RT exerts a synergistic antitumor effect in pHGG and DIPG in vitro and in vivo First, to evaluate whether irradiation would interfere with viral replication, we infected pHGG and DIPG cells with Delta-24-RGD (10 MOIs) followed by increasing doses of RT: 3, 6 and 12 Gy
Summary
Pediatric high grade gliomas (pHGG) and diffuse intrinsic pontine gliomas (DIPGs) are malignant tumors present with an aggressive behavior [7]. Integrated molecular profiling has contributed to renew the classification of these tumors by considering the mutations encoding histone H3 variants that determine localization, age of presentation, clinical outcome or even radiological features [18, 25, 30, 41]. The current standard therapy for pHGG consists of maximal surgical resection followed by temozolomide/ radiotherapy (RT) [35]. RT offers a temporal decrease of clinical symptoms and an increase in the overall survival; it is not curative [12]. Despite combined efforts to develop new therapies for these aggressive tumors, over the last decade, the overall survival is 15 months for pHGG patients and approximately 9 to 11 months for DIPGs [16]
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