A phase I window-of-opportunity study of neoadjuvant avelumab and hypofractionated radiation therapy in radiation-relapsed meningioma

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. SummaryThis phase I window-of-opportunity trial demonstrates that neoadjuvant PD-L1 blockade combined with hypofractionated proton therapy can induce robust immunologic responses and prolonged progression-free survival in a subset of patients with radiation-relapsed meningioma, supported by multi-omic profiling of the tumor microenvironment and peripheral blood.