{"doi":"10.1093/neuonc/noae066","title":"The oncolytic adenovirus Delta-24-RGD in combination with ONC201 induces a potent antitumor response in pediatric high-grade and diffuse midline glioma models","abstract":"<jats:title>Abstract</jats:title>\n               <jats:sec>\n                  <jats:title>Background</jats:title>\n                  <jats:p>Pediatric high-grade gliomas (pHGGs), including diffuse midline gliomas (DMGs), are aggressive pediatric tumors with one of the poorest prognoses. Delta-24-RGD and ONC201 have shown promising efficacy as single agents for these tumors. However, the combination of both agents has not been evaluated.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Methods</jats:title>\n                  <jats:p>The production of functional viruses was assessed by immunoblotting and replication assays. The antitumor effect was evaluated in a panel of human and murine pHGG and DMG cell lines. RNAseq, the seahorse stress test, mitochondrial DNA content, and γH2A.X immunofluorescence were used to perform mechanistic studies. Mouse models of both diseases were used to assess the efficacy of the combination in vivo. The tumor immune microenvironment was evaluated using flow cytometry, RNAseq, and multiplexed immunofluorescence staining.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Results</jats:title>\n                  <jats:p>The Delta-24-RGD/ONC201 combination did not affect the virus replication capability in human pHGG and DMG models in vitro. Cytotoxicity analysis showed that the combination treatment was either synergistic or additive. Mechanistically, the combination treatment increased nuclear DNA damage and maintained the metabolic perturbation and mitochondrial damage caused by each agent alone. Delta-24-RGD/ONC201 cotreatment extended the overall survival of mice implanted with human and murine pHGG and DMG cells, independent of H3 mutation status and location. Finally, combination treatment in murine DMG models revealed a reshaping of the tumor microenvironment to a proinflammatory phenotype.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions</jats:title>\n                  <jats:p>The Delta-24-RGD/ONC201 combination improved the efficacy compared to each agent alone in in vitro and in vivo models by potentiating nuclear DNA damage and in turn improving the antitumor (immune) response to each agent alone.</jats:p>\n               </jats:sec>","journal":"Neuro-Oncology","year":2024,"id":646330,"datarank":0.3958585994422889,"base_score":2.639057329615259,"endowment":2.639057329615259,"self_citation_contribution":0.3958585994422889,"citation_network_contribution":0.0,"self_endowment_contribution":0.3958585994422889,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1683376,"name":"Iker Ausejo-Mauleon","orcid":"0000-0002-0590-6579","position":1,"is_corresponding":false},{"id":1280766,"name":"Virginia Laspidea","orcid":"0000-0001-6017-7295","position":2,"is_corresponding":false},{"id":1683377,"name":"Marisol Gonzalez-Huarriz","orcid":null,"position":3,"is_corresponding":false},{"id":1683378,"name":"Andrea Lacalle","orcid":null,"position":4,"is_corresponding":false},{"id":1683379,"name":"Noelia Casares","orcid":null,"position":5,"is_corresponding":false},{"id":1683380,"name":"Marta Zalacain","orcid":null,"position":6,"is_corresponding":false},{"id":1683382,"name":"Lucía Marrodan","orcid":null,"position":7,"is_corresponding":false},{"id":1280765,"name":"Marc García-Moure","orcid":"0000-0002-4365-7753","position":8,"is_corresponding":false},{"id":1683383,"name":"Maria C Ochoa","orcid":null,"position":9,"is_corresponding":false},{"id":1683385,"name":"Antonio Carlos Tallon-Cobos","orcid":null,"position":10,"is_corresponding":false},{"id":1683387,"name":"Reyes Hernandez-Osuna","orcid":null,"position":11,"is_corresponding":false},{"id":1683388,"name":"Javier Marco-Sanz","orcid":null,"position":12,"is_corresponding":false},{"id":1683389,"name":"Laasya Dhandapani","orcid":null,"position":13,"is_corresponding":false},{"id":1683390,"name":"Irati Hervás-Corpión","orcid":null,"position":14,"is_corresponding":false},{"id":1683391,"name":"Oren J Becher","orcid":null,"position":15,"is_corresponding":false},{"id":32665,"name":"Javad Nazarian","orcid":"0000-0002-1951-9828","position":16,"is_corresponding":false},{"id":302163,"name":"Sabine Mueller","orcid":"0000-0002-8216-9357","position":17,"is_corresponding":false},{"id":1683393,"name":"Timothy N Phoenix","orcid":null,"position":18,"is_corresponding":false},{"id":1151399,"name":"Jasper van der Lugt","orcid":"0000-0002-8186-338X","position":19,"is_corresponding":false},{"id":1683394,"name":"Mikel Hernaez","orcid":null,"position":20,"is_corresponding":false},{"id":148279,"name":"Elizabeth Guruceaga","orcid":null,"position":21,"is_corresponding":false},{"id":32692,"name":"Carl J. Koschmann","orcid":"0000-0002-0825-7615","position":22,"is_corresponding":false},{"id":302164,"name":"Sriram Venneti","orcid":"0000-0001-9764-0423","position":23,"is_corresponding":false},{"id":1683395,"name":"Joshua E Allen","orcid":null,"position":24,"is_corresponding":false},{"id":842668,"name":"Matthew D. Dun","orcid":"0000-0002-9063-5370","position":25,"is_corresponding":false},{"id":1683396,"name":"Juan Fueyo","orcid":null,"position":26,"is_corresponding":false},{"id":1683397,"name":"Candelaria Gomez-Manzano","orcid":null,"position":27,"is_corresponding":false},{"id":1683398,"name":"Jaime Gallego Perez-Larraya","orcid":null,"position":28,"is_corresponding":false},{"id":1683399,"name":"Ana Patiño-García","orcid":null,"position":29,"is_corresponding":false},{"id":1683400,"name":"Sara Labiano","orcid":null,"position":30,"is_corresponding":false},{"id":661955,"name":"Marta M. Alonso","orcid":"0000-0002-7520-7351","position":31,"is_corresponding":false},{"id":1016830,"name":"Daniel de la Nava","orcid":"0000-0003-0626-0711","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"The oncolytic adenovirus Delta-24-RGD in combination with ONC201 induces a potent antitumor response in pediatric high-grade and diffuse midline glioma models","abstract":"<jats:title>Abstract</jats:title>\n               <jats:sec>\n                  <jats:title>Background</jats:title>\n                  <jats:p>Pediatric high-grade gliomas (pHGGs), including diffuse midline gliomas (DMGs), are aggressive pediatric tumors with one of the poorest prognoses. Delta-24-RGD and ONC201 have shown promising efficacy as single agents for these tumors. However, the combination of both agents has not been evaluated.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Methods</jats:title>\n                  <jats:p>The production of functional viruses was assessed by immunoblotting and replication assays. The antitumor effect was evaluated in a panel of human and murine pHGG and DMG cell lines. RNAseq, the seahorse stress test, mitochondrial DNA content, and γH2A.X immunofluorescence were used to perform mechanistic studies. Mouse models of both diseases were used to assess the efficacy of the combination in vivo. The tumor immune microenvironment was evaluated using flow cytometry, RNAseq, and multiplexed immunofluorescence staining.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Results</jats:title>\n                  <jats:p>The Delta-24-RGD/ONC201 combination did not affect the virus replication capability in human pHGG and DMG models in vitro. Cytotoxicity analysis showed that the combination treatment was either synergistic or additive. Mechanistically, the combination treatment increased nuclear DNA damage and maintained the metabolic perturbation and mitochondrial damage caused by each agent alone. Delta-24-RGD/ONC201 cotreatment extended the overall survival of mice implanted with human and murine pHGG and DMG cells, independent of H3 mutation status and location. Finally, combination treatment in murine DMG models revealed a reshaping of the tumor microenvironment to a proinflammatory phenotype.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions</jats:title>\n                  <jats:p>The Delta-24-RGD/ONC201 combination improved the efficacy compared to each agent alone in in vitro and in vivo models by potentiating nuclear DNA damage and in turn improving the antitumor (immune) response to each agent alone.</jats:p>\n               </jats:sec>","is_dataset_classified":null,"base_score":2.5649493574615367,"endowment":2.5649493574615367,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"38554031","pmcid":"PMC11300018","openalex_id":"https://openalex.org/W4393356365","authors":[],"funders":[{"funder_name":"Instituto de Salud Carlos III","grant_id":"FI20/00020","title":null},{"funder_name":"Gobierno de Navarra","grant_id":"FPU21/00603","title":null},{"funder_name":"European Research Council","grant_id":"817884","title":"Oncolytic viruses for the treatment of pediatric brain tumors: An integrated clinical and lab approach"},{"funder_name":"NCI NIH HHS","grant_id":"R01 CA261926","title":null},{"funder_name":"NINDS NIH HHS","grant_id":"R01 NS110572","title":null},{"funder_name":"NINDS NIH HHS","grant_id":"R01 NS127799","title":null},{"funder_name":"NINDS NIH HHS","grant_id":"R01 NS119231","title":null},{"funder_name":"Fundação para a Ciência e a Tecnologia, I.P.","grant_id":"Incentivo/SAU/LA0002/2013","title":"Incentive - LA 2 - 2013"}],"total_grants":8,"fwci":4.6153,"citation_percentile":0.94969587,"influential_citations":0,"citation_trend":[{"year":2024,"count":1},{"year":2025,"count":4},{"year":2026,"count":7}],"oa_status":"hybrid","license":"cc-by-nc","oa_locations":[{"url":"https://academic.oup.com/neuro-oncology/advance-article-pdf/doi/10.1093/neuonc/noae066/57124101/noae066.pdf","host_type":"journal"},{"url":"https://academic.oup.com/neuro-oncology/advance-article-pdf/doi/10.1093/neuonc/noae066/57124101/noae066.pdf","host_type":"publisher"},{"url":"https://academic.oup.com/neuro-oncology/advance-article-pdf/doi/10.1093/neuonc/noae066/57420152/noae066.pdf","host_type":"publisher"},{"url":"https://academic.oup.com/neuro-oncology/article-pdf/26/8/1509/58740046/noae066.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1093/neuonc/noae066","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/38554031","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/11300018","host_type":"repository"},{"url":"https://hdl.handle.net/10919/140528","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC11300018","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC11300018?pdf=render","host_type":"Europe_PMC"},{"url":"https://dx.doi.org/10.5167/uzh-270333","host_type":""},{"url":"http://dx.doi.org/10.1093/neuonc/noae066","host_type":""},{"url":"https://doi.org/10.5167/uzh-270333","host_type":""},{"url":"https://www.zora.uzh.ch/id/eprint/270333/","host_type":""}],"fields_of_study":["Virus-based gene therapy research","Cancer Research and Treatments","Glioma Diagnosis and Treatment","0301 basic medicine","03 medical and health sciences","0303 health sciences","Animals","Humans","Mice","Oncolytic Virotherapy","Glioma","Brain Neoplasms","Xenograft Model Antitumor Assays","Tumor Microenvironment","Adenoviridae","Combined Modality Therapy","Oncolytic Viruses","Tumor Cells, Cultured","Child","Virus Replication"],"mesh_terms":["Adenoviridae","Animals","Brain Neoplasms","Child","Combined Modality Therapy","Glioma","Humans","Tumor Cells, Cultured","Virus Replication","Xenograft Model Antitumor Assays","Oncolytic Virotherapy","Oncolytic Viruses","Mice","Tumor Microenvironment"],"keywords":["In vivo","Oncolytic virus","Cancer research","Glioma","Combination therapy","Tumor microenvironment","Apoptosis","Biology","Flow cytometry","Cytotoxicity","In vitro","Immune system","Pharmacology","Molecular biology","Immunology","Biochemistry","Genetics","Immunovirotherapy","Onc201","Dmgs","Delta-24-rgd","Phggs","Medical Sciences","Bioinformatics","610","610 Medicine & health","diffuse midline gliomas (DMGs)","Virus Replication","pediatric high-grade gliomas (pHGGs)","Biomedical Informatics","Adenoviridae","Mice","Medical Specialties","Medicine and Health Sciences","Tumor Cells, Cultured","Animals","Humans","1306 Cancer Research","Child","610 Medicine &amp; health","Oncolytic Virotherapy","Cultured","Brain Neoplasms","Neurosciences","Xenograft Model Antitumor Assays","Combined Modality Therapy","Tumor Cells","Oncolytic Viruses","2728 Neurology (clinical)","Neurology","Oncology","10036 Medical Clinic","2730 Oncology","Pediatric Neuro-Oncology"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"geo"},{"name":"nct"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-09T12:42:25.701871Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}