{"doi":"10.1101/2025.09.26.25336740","title":"A phase I window-of-opportunity study of neoadjuvant avelumab and hypofractionated radiation therapy in radiation-relapsed meningioma","abstract":"Effective treatments for recurrent, radiation-relapsed meningiomas (RR-meningiomas) following surgery and radiation therapy (RT) are limited. Inhibitors of the programmed-death-1 (PD-1) or programmed-death ligand-1 (PD-L1) pathway have shown modest activity in single-arm phase II studies of RR-meningiomas. This study aimed to evaluate the immunological effects of combining avelumab, a PD-L1 inhibitory antibody, with proton beam therapy (PBT) in RR-meningiomas. Patients with grade 1-3 RR-meningiomas were treated with neoadjuvant avelumab plus hypofractionated PBT, followed by surgery and adjuvant avelumab. Correlative analyses included RNA-sequencing (RNA-seq), whole exome sequencing (WES), multiplex immunofluorescence (MxIF), single-nucleus RNA-seq (snRNA-seq) of pre- and post-treatment tumor tissues, and flow cytometry (FC) of serial blood samples. Nine patients were enrolled: three achieved an immunologic response and prolonged progression-free survival (PFS > 36 months). At a median follow-up of 47.2 months, the median PFS was 19.1 months (95% CI: 15.2-23.0). RNA-seq showed a dynamic change of tumor microenvironment (TME) signatures. MxIF revealed marked infiltration of T cells and CD68+CD206- (M1-phenotype) macrophages in the post-treatment tissues of responders, a pattern absent in non-responders, whose pre- and post-treatment tissues predominantly featured CD206+ (M2-phenotype) macrophages. These findings were supported by snRNA-seq, which identified FN1-associated immunosuppressive macrophage subtype enriched in non-responders. Additionally, FC revealed elevated peripheral primed T-cell signatures one-month after treatment initiation in responders, suggesting a potential predictive biomarker. Avelumab combined with RT may elicit an immune response in a subset of RR-meningiomas, leading to prolonged remission. Further investigations are warranted to validate these findings and to develop predictive biomarkers in larger prospective studies.","journal":"medRxiv","year":2025,"id":576176,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9499,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":297957,"name":"Tanner M. Johanns","orcid":"0000-0003-1094-1528","position":1,"is_corresponding":false},{"id":225598,"name":"Jian Campian","orcid":"0000-0002-5317-8481","position":2,"is_corresponding":false},{"id":611834,"name":"Michael R. Chicoine","orcid":"0000-0002-0689-8603","position":3,"is_corresponding":false},{"id":394789,"name":"Gregory J. Zipfel","orcid":"0000-0003-2737-9084","position":4,"is_corresponding":false},{"id":225141,"name":"Milan G. Chheda","orcid":"0000-0001-8282-9098","position":5,"is_corresponding":false},{"id":482274,"name":"Omar H. 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Patel","orcid":"0000-0002-1280-2989","position":16,"is_corresponding":false},{"id":88538,"name":"David R. Raleigh","orcid":"0000-0001-9299-8864","position":17,"is_corresponding":false},{"id":294383,"name":"Albert H. Kim","orcid":"0000-0002-1751-8493","position":18,"is_corresponding":false},{"id":618594,"name":"Chun‐Kan Chen","orcid":"0000-0002-1194-9137","position":19,"is_corresponding":false},{"id":530607,"name":"Jiayi Huang","orcid":"0000-0002-5153-506X","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:57:56.636458Z","pmid":"41040714","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":[]}