Journal
ACTA NEUROPATHOLOGICA COMMUNICATIONS
Volume 7, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s40478-019-0714-6
Keywords
pHGG; DIPG; Radiotherapy; Oncolytic virus; DNA damage; Immune response
Categories
Funding
- European Union (Marie Curie) [IRG270459]
- Instituto de Salud Carlos III y los Fondos Feder Europeos [PI13/125, PI16/0066]
- Spanish Ministry of Science and Innovation (Ramon y Cajal contract) [RYC-2009-05571, IEDI-2015-00638]
- Department of Health of the Government of Navarra
- Basque Foundation for Health Research (BIOEF) [BIO13/CI/005]
- Fundacion Caja Navarra (Convocatoria de Ayudas 2011)
- Foundation LA CAIXA-Caja Navarra
- DOD team science award
- AACR-AstraZeneca Immuno-oncology Research Fellowship [18-40-12-MART]
- European Research Council (ERC) under the European Union [817884]
- European Research Council (ERC) [817884] Funding Source: European Research Council (ERC)
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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.
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