The overreaching goal of my lab is to improve the prognosis of patients with high-risk pediatric brain tumors. To this end, I propose to integrate clinical and lab-based research to develop tumor-targeted oncolytic adenoviruses with the capacity to elicit a therapeutic immune response in those tumors. Our research will use novel and relevant models to accomplish the experimental aims. We have previously worked with Delta-24-RGD (DNX-2401) a replication-competent adenovirus that has been translated to the clinical scenario. In 2017, the first clinical trial phase I with DNX-2401 for newly diagnosed Diffuse Intrinsic Pontine Gliomas (DIPG; a lethal pediatric brain tumor) opened propelled by my team. Preliminary results from the first trials revealed that the intratumoral injection of the virus instigated an initial phase of oncolysis followed by a delayed inflammatory response that ultimately resulted in complete regression in a subset of the patients without associated toxicities. I hypothesized that enhancement of the immune component of the DNX-2401-based therapy will result in the complete regression of the vast majority of pediatric brain tumors. In our specific approach, we propose to understand the immune microenvironment of DIPGs and the response to viral therapy in the context of the trial. Moreover, that knowledge will leverage the design of Delta-24-based adenoviruses to recruit lymphocytes to the tumor with the competence of different type of ligands to activate the tumor infiltrating lymphocytes. I expect that this combinatorial innovative treatment will efficiently challenge the profound and inherent tumor immunosuppression and, in turn, will elicit a robust anti-tumor immune response resulting in the significant improvement of the prognosis and quality of life of patients with pediatric brain tumors. This project has the potential to produce a vertical advance in the field of pediatric oncology.