Delta-24-RDG as an alternative therapeutic tool for pHGG/DIPG
Naiara Martinez-Velez1, Enric Xipell1, Arlet Maria Acanda de la Rocha1, Marisol González-Huarriz1, Hong Jiang2, Cande Gómez-Manzano2, Juan Fueyo2, Marie-Pierre Junier3, Hervé Chneiweiss3, Elias El Habr3, Michelle Monje4, Oren Becher5 and Marta M. Alonso1
- Author Affiliations
1Clinica Universidad de Navarra, Pamplona, Navarra, Spain
2MD Anderson Cancer Center, Houston, TX, USA
3Inserm, Paris, France
4Stanford University, Stanford, CA, USA
5Duke University School of Medicine, Durham, NC, USA
Pediatric high-grade gliomas (pHGG) including diffuse intrinsic pontine gliomas (DIPG) are one of the most formidable challenges faced by pediatric oncologist. Despite great advances in new therapies and genetic research the outcome for these tumors remains dismal. Delta-24-RGD is an adenovirus that is currently being tested in adults with malignant gliomas in several Phase I clinical trial with promising results. The aim of this work was to evaluate the antitumor effect of Δ24-RGD in pHGG/DIPGs in vitro and in immune deficient and in immune competent models in vivo.
Evaluation of viral cytotoxicity was performed in pHGG and DIPG cell lines by MTT. Our results showed that Delta-24-RGD displayed a potent antiglioma effect in all the cell lines that was mediated by an effective replication, as shown by antihexon staining and expression of late proteins.
In addition, we assess the cytotoxicity in 2 murine DIPG cell lines (XFM and NP53). The virus induced an antitumor effect in both cell lines. Moreover, we observe viral replication as evaluated by antihexon staining, expression of late proteins and electron microscopy. This data is relevant because murine cells are not permissive to viral replication therefore opening the door to evaluate the immune response to the virus. .
In order to test if Delta-24-RGD administration would unleash an immune response we implanted intracraneally DIPG cells in mice and treated them either with PBS or Delta-24-RGD. Animals were sacrificed 15 days after administration we evaluated the production of IFN-γ by splenocytes. Importantly, splenocytes from Delta-24-RGD treated mice significantly produced more IFN-γ when co-cultured with tumor cells. Survival studies are currently on going.
Our results show that Delta-24-RGD exerts an effective antiglioma effect in vitro that is able to trigger an immune response in vivo. These result warrants further studies regarding the antitumor effect of Delta-24-RGD in pHGG/DIPG.