Abstract
Abstract BACKGROUND Pediatric high-grade (pHGGs) and diffuse midline gliomas (DMGs) patients have the worst survival rates in childhood cancer. The oncolytic adenovirus Delta-24-RGD and the imipridone ONC201 are two of the most promising therapeutic agents in the field, having demonstrated safety and effectiveness in clinical trials. Therefore, we evaluated whether the Delta-24-RGD/ONC201 combination could increase the therapeutic benefit in pHGGs and DMGs. METHODS A battery of human pHGG, DMG, and murine DMG cell lines was used for the study. Viral replication was assessed by hexon titration. Characterization of combination response was assessed by MTS, RNAseq, Seahorse, and immunofluorescence. In vivo experiments were performed to assess the efficacy of the proposed combination. The tumor microenvironment infiltration was evaluated by flow cytometry. RESULTS ONC201 cotreatment with Delta-24-RGD did not affect the virus replication capability in vitro. Cytotoxicity studies showed that cotreatment was either synergistic or additive. Importantly, cells treated with the combination maintain the mitochondrial damage caused by ONC201, showed a significant reduction of IGF1/IGF1R and PDGF pathways, and increased nuclear DNA damage. Remarkably, Delta-24-RGD/ONC201 treatment in human pHGG and DMG xenograft-bearing mice showed a safe toxicity profile and a significant increase in the median overall survival compared to each agent alone. Combination treatment in murine DMG models revealed a reshaping of the tumor microenvironment towards a proinflammatory phenotype. We observed an increase in both lymphoid and myeloid lineage in the combined treatment versus either single treatment. Interestingly, Delta-24-RGD/ONC201 produces a higher activation in CD8+ T cells, higher activation and proliferation in CD4+ T cells, and less immunosuppressed regulatory T cells. CONCLUSIONS Our data supports that the Delta-24-RGD/ONC201 combination improved the efficacy compared to each agent alone by potentiating nuclear DNA damage and improving the antitumor (immune) response. Altogether, our results reveal the potential of this combination for future clinical trials.
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