Game Changer Grant Awarded to Marta Alonso

Diffuse midline gliomas (DMGs) including DIPGs, are aggressive pediatric brain tumors in desperate need of curative treatments Oncolytic viruses are proving to be a promising new category of anticancer bio-therapeutic agents because they offer the unique combination of an encouraging safety profile, pronounced direct antineoplastic activity, and the potential to induce anti-tumoral immune responses. We recently finished the accrual of a phase I clinical trial at our institution for pediatric patients with newly diagnosed DIPGs (NCT03178032) where we combined the virus Delta-24-RGD with radiotherapy. Preliminary results from this trial showed that the combination of Delta-24-RGD and radiotherapy is non-toxic and that may result in prolonged survival. These clinical data as well as our confirmatory studies in immune competent mice emphasize the urgent need to amplify the anti-tumor immune response as a means of enhancing the efficacy of oncolytic viroimmunotherapy of DIPGs. It has been postulated that DIPGs may not establish an immunosuppressive microenvironment as is seen in adult CNS tumors and instead reflect a failure of immune surveillance. These analyses showed lack of infiltrating lymphocytes and the abundances of CD11b+ cells. Since the microglia/myeloid cell population constitutes a significant component of the DIPGs microenvironment leading to a non-inflammatory scenario in this proposal we want to explore whether modulating these populations could aid to improve the therapeutic effect of oncolytic virus. In addition, we will delve in our understanding of the interface between the DIPGs cells and their tumor microenvironment in the context of virotherapy. We expect that the results yield by this project will show new and efficient combination of treatments for DIPGs while maintaining a safe profile. In addition, the proposed research design should allow us to understand the underlying immune mechanisms of the viroimmunotherapy strategy and uncover additional targetable vulnerabilities in this disease. These data should place us in a strong position to translate to the clinical scenario a new successful therapy for children with DIPGs.