Barber, Jason

Abstract Background Adult onset medulloblastoma (aMB) is a rare tumor with limited available evidence. We present a large multi-institutional retrospective cohort of aMB patients treated in the modern era, with an emphasis on understanding the role of chemotherapy at initial diagnosis. Methods We included 267 consecutive patients with aMB treated at 7 different institutions from 2000-present, controlling for chemotherapy regimen and cycles received. Results Treatment factors were highly intercorrelated with one another and with treating institution. Concurrent chemotherapy was not associated with overall survival (OS). Adjuvant chemotherapy was associated with OS on univariable analyses (HR = 0.55, P = .029) and on multivariable analysis when adjusting for risk status (HR 0.55, P = .026) but not when also adjusting for treating institution. Proton craniospinal irradiation was associated with improved survival on univariable (HR = 0.50, P = .019) and multivariable analysis adjusting for risk status (HR = 0.51, P = .024) but not when treating institution was also considered. On subgroup analysis, adjuvant chemotherapy was associated with improved survival in M0 (HR = 0.55, P = .043) but not M1 disease, in patients with subtotal resection (HR = 0.43, P = .048) but not those with GTR. Similarly, progression-free survival was improved with chemotherapy in patients with M0 (HR = 0.57, P = .032) but not M1 disease, and in patients with subtotal (HR = 0.50, P = .054) but not gross total resection. Conclusions There was no benefit of concurrent chemotherapy. Adjuvant chemotherapy was associated with improved overall survival and this effect was driven by select subgroups, specifically those with M0 disease and those with residual tumor. We could not confirm that these associations are independent of the treating institution.

Abstract Background Most glioblastomas recur near prior radiation treatment sites. Future clinical success will require achieving and optimizing an “abscopal effect,” whereby unirradiated neoplastic cells outside treatment sites are recognized and attacked by the immune system. Radiation combined with anti–programmed cell death ligand 1 (PD-L1) demonstrated modest efficacy in phase II human glioblastoma clinical trials, but the mechanism and relevance of the abscopal effect during this response remain unknown. Methods We modified an immune-competent, genetically driven mouse glioma model (forced platelet derived growth factor [PDGF] expression + phosphatase and tensin homolog loss) where a portion of the tumor burden is irradiated (PDGF) and another unirradiated luciferase-expressing tumor (PDGF + luciferase) is used as a readout of the abscopal effect following systemic anti–PD-L1 immunotherapy. We assessed relevance of tumor neoepitope during the abscopal response by inducing expression of epidermal growth factor receptor variant III (EGFRvIII) (PDGF + EGFRvIII). Statistical tests were two-sided. Results Following radiation of one lesion, anti–PD-L1 immunotherapy enhanced the abscopal response to the unirradiated lesion. In PDGF-driven gliomas without tumor neoepitope (PDGF + luciferase, n = 8), the abscopal response occurred via anti–PD-L1 driven, extracellular signal-regulated kinase–mediated, bone marrow–derived macrophage phagocytosis of adjacent unirradiated tumor cells, with modest survival implications (median survival 41 days vs radiation alone 37.5 days, P = 0.03). In PDGF-driven gliomas with tumor neoepitope (PDGF + EGFRvIII, n = 8), anti–PD-L1 enhanced abscopal response was associated with macrophage and T-cell infiltration and increased survival benefit (median survival 36 days vs radiation alone 28 days, P = 0.001). Conclusion Our results indicate that anti–PD-L1 immunotherapy enhances a radiation- induced abscopal response via canonical T-cell activation and direct macrophage activation in glioblastoma.